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Posts Tagged ‘Clinical Development Oncology’


The Delicate Connection:  IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology

Author and Curator: Demet Sag, PhD, CRA, GCP      

Table of Contents:

  1. Abstract
  2. Dual role for IDO
  3. Immune System and IDO
  4. Autoimmune disorders and IDO
  5. Cancer and Ido
  6. Clinical Interventions
  7. Clinical Trials
  8. Future Actions for Molecular Dx and Targeted Therapies:
  9. Conclusion
  10. References

TABLE 1- IDO Clinical Trials

TABLE 2- Kyn induced Genes

TABLE 3 Possible biomarkers and molecular diagnostics targets

TABLE 4: Current Interventions ______________________________________________________________________________________________________________

ABSTRACT:

Overall purpose is to find a method to manipulate IDO for clinical applications, mainly the focus of this review is is cancer prevention and treatment.  The first study proving the connection between IDO and immune response came from, a very natural event, a protection of pregnancy in human. This led to discover that high IDO expression is a common factor in cancer tumors. Thus, attention promoted investigations on IDO’s role in various disease states, immune disorders, transplantation, inflammation, women health, mood disorders.
Many approaches, vaccines and adjuvants are underway to find new immunotherapies by combining the power of DCs in immune response regulation and specific direction of siRNA.  As a result, with this unique qualities of IDO, DCs and siRNA, we orchestrated a novel intervention for immunomodulation of IDO by inhibiting with small interference RNA, called siRNA-IDO-DCvax.  Proven that our DCvax created a delay and regression of tumor growth without changing the natural structure and characterization of DCs in melanoma and breast cancers in vivo. (** The shRNA IDO- DCvax is developed by Regen BioPhrama, San Diego, CA ,  Thomas Ichim, Ph.D, CSO. and David Koos, CEO)

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Double-Edged Sword of IDO: The Good and The Bad for Clinical intervention and Developments

IDO almost has a dual role. There is a positive side of high expression of IDO during pregnancy (29; 28; 114), transplants (115; 116; 117; 118; 119), infectious diseases (96) and but this tolerance is negative during autoimmune-disorders (120; 121; 122), tumors of cancer (123; 124; 117; 121; 125; 126; 127) (127), and mood disorders (46). The increased IDO expression has a double-edged sword in human physiology provides a positive role during protection of fetus and grafts after transplantations but becomes a negative factor during autoimmune disorders, cancer, sepsis and mood disorders.

Prevention of allogeneic fetal rejection is possible by tryptophan metabolism (26) rejecting with lack of IDO but allocating if IDO present (29; 28; 114). These studies lead to find “the natural regulation mechanism” for protecting the transplants from graft versus host disease GVHD (128) and getting rid of tumors.

The plasticity of  mammary and uterus during reproduction may hold some more answers to prevent GVHD and tumors of cancer with good understanding of IDO and tryptophan mechanism (129; 130). After allogeneic bone marrow transplants the risk of solid tumor development increased about 80% among 19,229 patients even with a greater risk among patients under 18 years old (117).  The adaptation of tolerance against host mechanism is connected to the IDO expression (131). During implantation and early pregnancy IDO has a role by making CD4+CD25+Foxp3+ regulatory T cells (Tregs) and expressing in DCs and  MQs  (114; 132; 133).

Clonal deletion mechanism prevents mother to react with paternal products since female mice accepted the paternal MHC antigen-expressing tumor graft during pregnancy and rejected three weeks after delivery (134). CTLA-4Ig gene therapy alleviates abortion through regulation of apoptosis and inhibition of spleen lymphocytes (135).  

 Immune System and IDO DCs are the orchestrator of the immune response (56; 57; 58) with list of functions in uptake, processing, and presentation of antigens; activation of effector cells, such as T-cells and NK-cells; and secretion of cytokines and other immune-modulating molecules to direct the immune response. The differential regulation of IDO in distinct DC subsets is widely studied to delineate and correct immune homeostasis during autoimmunity, infection and cancer and the associated immunological outcomes. Genesis of antigen presenting cells (APCs), eventually the immune system, require migration of monocytes (MOs), which is originated in bone marrow. Then, these MOs move from bloodstream to other tissues to become macrophages and DCs (59; 60).

Initiation of immune response requires APCs to link resting helper T-cell with the matching antigen to protect body. DCs are superior to MQs and MOs in their immune action model. When DCs are first described (61) and classified, their role is determined as a highly potent antigen-presenting cell (APC) subset with 100 to 1000-times more effective than macrophages and B-cells in priming T-cells. Both MQs and monocytes phagocytize the pathogen, and their cell structure contains very large nucleus and many internal vesicles. However, there is a nuance between MQ and DCs, since DCs has a wider capacity of stimulation, because MQs activates only memory T cells, yet DCs can activate both naïve and memory T cells.

DCs are potent activators of T cells and they also have well controlled regulatory roles. DC properties determine the regulation regardless of their origin or the subset of the DCs. DCs reacts after identification of the signals or influencers for their inhibitory, stimulatory or regulatory roles, before they express a complex repertoire of positive and negative cytokines, transmembrane proteins and other molecules. Thus, “two signal theory” gains support with a defined rule.  The combination of two signals, their interaction with types of cells and time are critical.

In short, specificity and time are matter for a proper response. When IDO mRNA expression is activated with CTL40 ligand and IFNgamma, IDO results inhibition of T cell production (4).  However, if DCs are inhibited by 1MT, an inhibitor of IDO, the response stop but IgG has no affect (10).  In addition, if the stimulation is started by a tryptophan metabolite, which is downstream of IDO, such as 3-hydroxyantranilic or quinolinic acids, it only inhibits Th1 but not Th2 subset of T cells (62).

Furthermore, inclusion of signal molecules, such as Fas Ligand, cytochrome c, and pathways also differ in the T cell differentiation mechanisms due to combination, time and specificity of two-signals.  The co-culture experiments are great tool to identify specific stimuli in disease specific microenvironment (63; 12; 64) for discovering the mechanism and interactions between molecules in gene regulation, biochemical mechanism and physiological function during cell differentiation.

As a result, the simplest differential cell development from the early development of DCs impact the outcome of the data. For example, collection of MOs from peripheral blood mononuclear cells (PBMCs) with IL4 and GM-CSF leads to immature DCs (iDCs). On next step, treatment of iDCs with tumor necrosis factor (TNF) or other plausible cytokines (TGFb1, IFNgamma, IFNalpha,  IFNbeta, IL6 etc.) based on the desired outcome differentiate iDCs  into mature DCs (mDCs). DCs live only up to a week but MOs and generated MQs can live up to a month in the given tissue. B cells inhibit T cell dependent immune responses in tumors (65).

AutoImmune Disorders:

The Circadian Clock Circuitry and the AHR

The balance of IDO expression becomes necessary to prevent overactive immune response self-destruction, so modulation in tryptophan and NDA metabolisms maybe essential.  When splenic IDO-expressing CD11b (+) DCs from tolerized animals applied, they suppressed the development of arthritis, increased the Treg/Th17 cell ratio, and decreased the production of inflammatory cytokines in the spleen (136).

The role of Nicotinamide prevention on type 1 diabetes and ameliorates multiple sclerosis in animal model presented with activities of  NDAs stimulating GPCR109a to produce prostaglandins to induce IDO expression, then these PGEs and PGDs converted to the anti-inflammatory prostaglandin, 15d-PGJ(2) (137; 138; 139).  Thus, these events promotes endogenous signaling mechanisms involving the GPCRs EP2, EP4, and DP1 along with PPARgamma. (137).

Modulating the immune response at non-canonical at canonocal pathway while keeping the non-canonical Nf-KB intact may help to mend immune disorders. As a result, the targeted blocking in canonical at associated kinase IKKβ and leaving non-canonocal Nf-kB pathway intact, DCs tips the balance towards immune supression. Hence, noncanonical NF-κB pathway for regulatory functions in DCs required effective IDO induction, directly or indirectly by endogenous ligand Kyn and negative regulation of proinflammatory cytokine production. As a result, this may help to treat autoimmune diseases such as rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease, and multiple sclerosis, or allergy or transplant rejection.

While the opposite action needs to be taken during prevention of tumors, that is inhibition of non-canonical pathway.  Inflammation induces not only relaxation of veins and lowering blood pressure but also stimulate coagulopathies that worsen the microenvironment and decrease survival rate of patients after radio or chemotherapies.Cancer Generating tumor vaccines and using adjuvants underway (140).

Clinical correlation and genetic responses also compared in several studies to diagnose and target the system for cancer therapies (127; 141; 131).  The recent surveys on IDO expression and human cancers showed that IDO targeting is a candidate for cancer therapy since IDO expression recruiting Tregs, downregulates MHC class I and creating negative immune microenvironment for protection of development of tumors (125; 27; 142).  Inhibition of IDO expression can make advances in immunotherapy and chemotherapy fields (143; 125; 131; 144).

IDO has a great importance on prevention of cancer development (126). There are many approaches to create the homeostasis of immune response by Immunotherapy.  However, given the complexity of immune regulations, immunomodulation is a better approach to correct and relieve the system from the disease.  Some of the current IDO targeted immunotherapy or immmunomodulations with RNA technology for cancer prevention (145; 146; 147; 148; 149; 150) or applied on human or animals  (75; 151; 12; 115; 152; 9; 125) or chemical, (153; 154) or  radiological (155).  The targeted cell type in immune system generally DCs, monocytes (94)T cells (110; 156)and neutrophils (146; 157). On this paper, we will concentrate on DCvax on cancer treatments.

 T-reg, regulatory T cells; Th, T helper; CTLA-4, cytotoxic T lymphocyte-associated antigen 4; TCR, T cell receptor; IDO, indoleamine 2,3-dioxygenase. (refernece: http://www.pnas.org/content/101/28/10398/suppl/DC)

T-reg, regulatory T cells; Th, T helper; CTLA-4, cytotoxic T lymphocyte-associated antigen 4; TCR, T cell receptor; IDO, indoleamine 2,3-dioxygenase. (refernece: http://www.pnas.org/content/101/28/10398/suppl/DC)

IDO and the downstream enzymes in tryptophan pathway produce a series of immunosuppressive tryptophan metabolites that may lead into Tregs proliferation or increase in T cell apoptosis (62; 16; 27; 158), and some can affect NK cell function (159).

The interesting part of the mechanism is even without presence of IDO itself, downstream enzymes of IDO in the kynurenine tryptophan degradation still show immunosuppressive outcome (160; 73) due to not only Kyn but also TGFbeta stimulated long term responses. DC vaccination with IDO plausible (161) due to its power in immune response changes and longevity in the bloodstream for reversing the system for Th17 production (162).

Clinical Interventions are taking advantage of the DC’s central role and combining with enhancing molecules for induction of immunity may overcome tolerogenic DCs in tumors of cancers (163; 164).

The first successful application of DC vaccine used against advanced melanoma after loading DCs with tumor peptides or autologous cell lysate in presence of adjuvants keyhole limpet hematocyanin (KLH) (165).  Previous animal and clinical studies show use of DCs against tumors created success (165; 166; 167) as well as some problems due to heterogeneity of DC populations in one study supporting tumor growth rather than diminishing (168).

DC vaccination applied onto over four thousand clinical trial but none of them used siRNA-IDO DC vaccination method. Clinical trials evaluating DCs loaded ex vivo with purified TAAs as an anticancer immunotherapeutic interventions also did not include IDO (Table from (169). This table presented the data from 30 clinical trials, 3 of which discontinued, evaluating DCs loaded ex vivo with TAAs as an anticancer immunotherapy for 12 types of cancer [(AML(1), Breast cancer (4), glioblastoma (1), glioma (2), hepatocellular carcinoma (1), hematological malignancies (1), melanoma (6), neuroblastoma sarcoma (2), NSCLC (1), ovarian cancer (3), pancreatic cancer (3), prostate cancer (10)] at phase I, II or I/II.

Tipping the balance between Treg and Th17 ratio has a therapeutic advantage for restoring the health that is also shown in ovarian cancer by DC vaccination with adjuvants (161).  This rebalancing of the immune system towards immunogenicity may restore Treg/Th17 ratio (162; 170) but it is complicated. The stimulation of IL10 and IL12 induce Treg produce less Th17 and inhibiting CTL activation and its function (76; 171; 172) while animals treated with anti-TGFb before vaccination increase the plasma levels of IL-15 for tumor specific T cell survival in vivo (173; 174) ovarian cancer studies after human papilloma virus infection present an increase of IL12 (175).

Opposing signal mechanism downregulates the TGFb to activate CTL and Th1 population with IL12 and IL15 expression (162; 173).  The effects of IL17 on antitumor properties observed by unique subset of CD4+ T cells (176) called also CD8+ T cells secrete even more IL17 (177).

Using cytokines as adjuvants during vaccination may improve the efficacy of vaccination since cancer vaccines unlike infections vaccines applied after the infection or disease started against the established adoptive immune response.  Adjuvants are used to improve the responses of the given therapies commonly in immunotherapy applications as a combination therapy (178).

Enhancing cancer vaccine efficacy via modulation of the microenvironment is a plausible solution if only know who are the players.  Several molecules can be used to initiate and lengthen the activity of intervention to stimulate IDO expression without compromising the mechanism (179).  The system is complicated so generally induction is completed ex-vivo stimulation of DCs in cell lysates, whole tumor lysates, to create the microenvironment and natural stimulatory agents. Introduction of molecules as an adjuvants on genetic regulation on modulation of DCs are critical, because order and time of the signals, specific location/ tissue, and heterogeneity of personal needs (174; 138; 180). These studies demonstrated that IL15 with low TGFb stimulates CTL and Th1, whereas elevated TGFb with IL10 increases Th17 and Tregs in cancer microenvironments.

IDO and signaling gene regulation

For example Ret-peptide antitumor vaccine contains an extracellular fragment of Ret protein and Th1 polarized immunoregulator CpG oligonucleotide (1826), with 1MT, a potent inhibitor of IDO, brought a powerful as well as specific cellular and humoral immune responses in mice (152).

The main idea of choosing Ret to produce vaccine in ret related carcinomas fall in two criterion, first choosing patients self-antigens for cancer therapy with a non-mutated gene, second, there is no evidence of genetic mutations in Ret amino acids 64-269. Demonstration of proliferating hemangiomas, benign endothelial tumors and often referred as hemangiomas of infancy appearing at head or neck, express IDO and slowly regressed as a result of immune mediated process.

After large scale of genomic analysis show insulin like growth factor 2 as the key regulator of hematoma growth (Ritter et al. 2003). We set out to develop new technology with our previous expertise in immunotherapy and immunomodulation (181; 182; 183; 184), correcting Th17/Th1 ratio (185), and siRNA technology (186; 187).  We developed siRNA-IDO-DCvax. Patented two technologies “Immunomodulation using Altered DCs (Patent No: US2006/0165665 A1) and Method of Cancer Treatments using siRNA Silencing (Patent No: US2009/0220582 A1).

In melanoma cancer DCs were preconditioned with whole tumor lysate but in breast cancer model pretreatment completed with tumor cell lysate before siRNA-IDO-DCvax applied. Both of these studies was a success without modifying the autanticity of DCs but decreasing the IDO expression to restore immunegenity by delaying tumor growth in breast cancer (147) and in melanoma (188).  Thus, our DCvax specifically interfere with Ido without disturbing natural structure and content of the DCs in vivo showed that it is possible to carry on this technology to clinical applications.

Furthermore, our method of intervention is more sophisticated since it has a direct interaction mechanism with ex-vivo DC modulation without creating long term metabolism imbalance in Trp/Kyn metabolite mechanisms since the action is corrective and non-invasive.

There were several reasons.

First, prevention of tumor development studies targeting non-enzymatic pathway initiated by pDCs conditioned with TGFbeta is specific to IDO1 (189).

Second, IDO upregulation in antigen presenting cells allowing metastasis show that most human tumors express IDO at high levels (123; 124).

Third, tolerogenic DCs secretes several molecules some of them are transforming growth factor beta (TGFb), interleukin IL10), human leukocyte antigen G (HLA-G), and leukemia inhibitory factor (LIF), and non-secreted program cell death ligand 1 (PD-1 L) and IDO, indolamine 2.3-dioxygenase, which promote tumor tolerance. Thus, we took advantage of DCs properties and Ido specificity to prevent the tolerogenicity with siRNA-IDO DC vaccine in both melanoma and breast cancer.

Fourth, IDO expression in DCs make them even more potent against tumor antigens and create more T cells against tumors. IDOs are expressed at different levels by both in broad range of tumor cells and many subtypes of DCs including monocyte-derived DCs (10), plasmacytoid DCs (142), CD8a+ DCs (190), IDO compotent DCs (17), IFNgamma-activated DCs used in DC vaccination.  These DCs suppress immune responses through several mechanisms for induction of apoptosis towards activated T cells (156) to mediate antigen-specific T cell anergy in vivo (142) and for enhancement of Treg cells production at sites of vaccination with IDO-positive DCs+ in human patients (142; 191; 192; 168; 193; 194). If DCs are preconditioned with tumor lysate with 1MT vaccination they increase DCvax effectiveness unlike DCs originated from “normal”, healthy lysate with 1MT in pancreatic cancer (195).  As a result, we concluded that the immunesupressive effect of IDO can be reversed by siRNA because Treg cells enhances DC vaccine-mediated anti-tumor-immunity in cancer patients.

Gene silencing is a promising technology regardless of advantages simplicity for finding gene interaction mechanisms in vitro and disadvantages of the technology is utilizing the system with specificity in vivo (186; 196).  siRNA technology is one of the newest solution for the treatment of diseases as human genomics is only producing about 25,000 genes by representing 1% of its genome. Thus, utilizing the RNA open the doors for more comprehensive and less invasive effects on interventions. Thus this technology is still improving and using adjuvants. Silencing of K-Ras inhibit the growth of tumors in human pancreatic cancers (197), silencing of beta-catenin in colon cancers causes tumor regression in mouse models (198), silencing of vascular endothelial growth factor (VGEF) decreased angiogenesis and inhibit tumor growth (199).

Combining siRNA IDO and DCvax from adult stem cell is a novel technology for regression of tumors in melanoma and breast cancers in vivo. Our data showed that IDO-siRNA reduced tumor derived T cell apoptosis and tumor derived inhibition of T cell proliferation.  In addition, silencing IDO made DCs more potent against tumors since treated or pretreated animals showed a delay or decreased the tumor growth (188; 147)

 

Clinical Trials:

First FDA approved DC-based cancer therapies for treatment of hormone-refractory prostate cancer as autologous cellular immunotherapy (163; 164).  However, there are many probabilities to iron out for a predictive outcome in patients.

Table 2 demonstrates the current summary of clinical trials report.  This table shows 38 total studies specifically Ido related function on cancer (16), eye (3), surgery (2), women health (4), obesity (1), Cardiovascular (2), brain (1), kidney (1), bladder (1), sepsis shock (1), transplant (1),  nervous system and behavioral studies (4), HIV (1) (Table 4).  Among these only 22 of which active, recruiting or not yet started to recruit, and 17 completed and one terminated.

Most of these studies concentrated on cancer by the industry, Teva GTC ( Phase I traumatic brain injury) Astra Zeneca (Phase IV on efficacy of CRESTOR 5mg for cardiovascular health concern), Incyte corporation (Phase II ovarian cancer) NewLink Genetics Corporation Phase I breast/lung/melanoma/pancreatic solid tumors that is terminated; Phase II malignant melanoma recruiting, Phase II active, not recruiting metastatic breast cancer, Phase I/II metastatic melanoma, Phase I advanced malignancies) , HIV (Phase IV enrolling by invitation supported by Salix Corp-UC, San Francisco and HIV/AIDS Research Programs).

Many studies based on chemotherapy but there are few that use biological methods completed study with  IDO vaccine peptide vaccination for Stage III-IV non-small-cell lung cancer patients (NCT01219348), observational study on effect of biological therapy on biomarkers in patients with untreated hepatitis C, metastasis melanoma, or Crohn disease by IFNalpha and chemical (ribavirin, ticilimumab (NCT00897312), polymorphisms of patients after 1MT drug application in treating patients with metastatic or unmovable refractory solid tumors by surgery (NCT00758537), IDO expression analysis on MSCs (NCT01668576), and not yet recruiting intervention with adenovirus-p53 transduced dendric cell vaccine , 1MT , radiation, Carbon C 11 aplha-methyltryptophan- (NCT01302821).

Among the registered clinical trials some of them are not interventional but  observational and evaluation studies on Trp/Kyn ratio (NCT01042847), Kyn/Trp ratio (NCT01219348), Kyn levels (NCT00897312, NCT00573300),  RT-PCR analysis for Kyn metabolism (NCT00573300, NCT00684736, NCT00758537), and intrinsic IDO expression of mesenchymal stem cells in lung transplant with percent inhibition of CD4+ and CD8+ T cell proliferation toward donor cells (NCT01668576), determining polymorphisms (NCT00426894). These clinical trials/studies are immensely valuable to understand the mechanism and route of intervention development with the data collected from human populations   

Future Actions for Molecular Dx and Targeted Therapies:

Viable tumor environment. Tumor survival is dependent upon an exquisite interplay between the critical functions of stromal development and angiogenesis, local immune suppression and tumor tolerance, and paradoxical inflammation. TEMs: TIE-2 expressing monocytes; “M2” TAMs: tolerogenic tumor-associated macrophages; MDSCs: myeloid-derived suppressor cells; pDCs: plasmacytoid dendritic cells; co-stim.: co-stimulation; IDO: indoleamine 2,3-dioxygenase; VEGF: vascular endothelial growth factor; EGF: epidermal growth factor; MMP: matrix metaloprotease; IL: interleukin; TGF-β: transforming growth factor-beta; TLRs: toll-like receptors.  (reference: http://www.hindawi.com/journals/cdi/2012/937253/fig1/)

Viable tumor environment. Tumor survival is dependent upon an exquisite interplay between the critical functions of stromal development and angiogenesis, local immune suppression and tumor tolerance, and paradoxical inflammation. TEMs: TIE-2 expressing monocytes; “M2” TAMs: tolerogenic tumor-associated macrophages; MDSCs: myeloid-derived suppressor cells; pDCs: plasmacytoid dendritic cells; co-stim.: co-stimulation; IDO: indoleamine 2,3-dioxygenase; VEGF: vascular endothelial growth factor; EGF: epidermal growth factor; MMP: matrix metaloprotease; IL: interleukin; TGF-β: transforming growth factor-beta; TLRs: toll-like receptors. (reference: http://www.hindawi.com/journals/cdi/2012/937253/fig1/)

Current survival or response rate is around 40 to 50 % range.  By using specific cell type, selected inhibition/activation sequence based on patient’s genomic profile may improve the efficacy of clinical interventions on cancer treatments. Targeted therapies for specific gene regulation through signal transduction is necessary but there are few studies with genomics based approach.

On the other hand, there are surveys, observational or evaluations (listed in clinical trials section) registered with www.clinicaltrials.gov that will provide a valuable short-list of molecules.  Preventing stimulation of Ido1 as well as Tgfb-1gene expression by modulating receptor mediated phosphorylation between TGFb/SMAD either at Mad-Homology 1 (MH1) or Mad-Homology 1 (MH2) domains maybe possible (79; 82; 80). Within Smads are the conserved Mad-Homology 1 (MH1) domain, which is a DNA binding module contains tightly bound Zinc atom.

Smad MH2 domain is well conserved and one the most diverse protein-signal interacting molecule during signal transduction due to two important Serine residues located extreme distal C-termini at Ser-Val-Ser in Smad 2 or at pSer-X-PSer in RSmads (80). Kyn activated orphan G protein–coupled receptor, GPR35 with unknown function with a distinct expression pattern that collides with IDO sites since its expression at high levels of the immune system and the gut (63) (200; 63).  

The first study to connect IDO with cancer shows that group (75).  The directly targeting to regulate IDO expression is another method through modulating ISREs in its promoter with RNA-peptide combination technology. Indirectly, IDO can be regulated through Bin1 gene expression control over IDO since Bin1 is a negative regulator of IDO and prevents IDO expression.  IDO is under negative genetic control of Bin1, BAR adapter–encoding gene Bin1 (also known as Amphiphysin2). Bin1 functions in cancer suppression since attenuation of Bin1 observed in many human malignancies (141; 201; 202; 203; 204; 205; 206) .  Null Bin-/- mice showed that when there is lack of Bin1, upregulation of IDO through STAT1- and NF-kB-dependent expression of IDO makes tumor cells to escape from T cell–dependent antitumor immunity.

This pathway lies in non-enzymatic signal transducer function of IDO after stimulation of DCs by TGFb1.  The detail study on Bin1 gene by alternative spicing also provided that Bin1 is a tumor suppressor.  Its activities also depends on these spliced outcome, such as  Exon 10, in muscle, in turn Exon 13 in mice has importance in role for regulating growth when Bin1 is deleted or mutated C2C12 myoblasts interrupted due to its missing Myc, cyclinD1, or growth factor inhibiting genes like p21WAF1 (207; 208).

On the other hand alternative spliced Exon12A contributing brain cell differentiation (209; 210). Myc as a target at the junction between IDO gene interaction and Trp metabolism.  Bin1 interacts with Myc either early-dependent on Myc or late-independent on Myc, when Myc is not present. This gene regulation also interfered by the long term signaling mechanism related to Kynurenine (Kyn) acting as an endogenous ligand to AHR in Trp metabolite and TGFb1 and/or IFNalpha and IFNbeta up regulation of DCs to induce IDO in noncanonical pathway for NF-kB and myc gene activations (73; 74).  Hence, Trp/Kyn, Kyn/Trp, Th1/Th17 ratios are important to be observed in patients peripheral blood. These direct and indirect gene interactions place Bin1 to function in cell differentiation (211; 212; 205).

Regulatory T-cel generation via reverse and non-canonical signaliing to pDCs

Table 3 contains the microarray analysis for Kyn affect showed that there are 25 genes affected by Kyn, two of which are upregulated and 23 of them downregulated (100). This list of genes and additional knowledge based on studies creating the diagnostics panel with these genes as a biomarker may help to analyze the outcomes of given interventions and therapies. Some of these molecules are great candidate to seek as an adjuvant or co-stimulation agents.  These are myc, NfKB at IKKA, C2CD2, CREB3L2, GPR115, IL2, IL8, IL6, and IL1B, mir-376 RNA, NFKB3, TGFb, RelA, and SH3RF1. In addition, Lip, Fox3P, CTLA-4, Bin1, and IMPACT should be monitored.

In addition, Table 4 presents the other possible mechanisms. The highlights of possible target/biomarkers are specific TLRs, conserved sequences of IDO across its homologous structures, CCR6, CCR5, RORgammat, ISREs of IDO, Jak, STAT, IRFs, MH1 and MH2 domains of Smads. Endothelial cell coagulation activation mechanism and pDC maturation or immigration from lymph nodes to bloodstream should marry to control not only IDO expression but also genesis of preferred DC subsets. Stromal mesenchymal cells are also activated by these modulation at vascular system and interferes with metastasis of cancer. First, thrombin (human factor II) is a well regulated protein in coagulation hemostasis has a role in cell differentiation and angiogenesis.

Protein kinase activated receptors (PARs), type of GPCRs, moderate the actions. Second, during hematopoietic response endothelial cells produce hematopoietic growth factors (213; 214). Third, components of bone marrow stroma cells include monocytes, adipocytes, and mesenchymal stem cells (215). As a result, addressing this issue will prevent occurrence of coagulapathologies, namely DIC, bleeding, thrombosis, so that patients may also improve response rate towards therapies. Personal genomic profiles are powerful tool to improve efficacy in immunotherapies since there is an influence of age (young vs. adult), state of immune system (innate vs. adopted or acquired immunity). Table 5 includes some of the current studies directly with IDO and indirectly effecting its mechanisms via gene therapy, DNA vaccine, gene silencing and adjuvant applications as an intervention method to prevent various cancer types.

CONCLUSION

IDO has a confined function in immune system through complex interactions to maintain hemostasis of immune responses. The genesis of IDO stem from duplication of bacterial IDO-like genes.  Inhibition of microbial infection and invasion by depleting tryptophan limits and kills the invader but during starvation of trp the host may pass the twilight zone since trp required by host’s T cells.  Thus, the host cells in these small pockets adopt to new microenvironment with depleted trp and oxygen poor conditions. Hence, the cell metabolism differentiate to generate new cellular structure like nodules and tumors under the protection of constitutively expressed IDO in tumors, DCs and inhibited T cell proliferation.

On the other hand, having a dichotomy in IDO function can be a potential limiting factor that means is that IDOs impact on biological system could be variable based on several issues such as target cells, IDO’s capacity, pathologic state of the disease and conditions of the microenvironment. Thus, close monitoring is necessary to analyze the outcome to prevent conspiracies since previous studies generated paradoxical results.

Current therapies through chemotherapies, radiotherapies are costly and effectiveness shown that the clinical interventions require immunotherapies as well as coagulation and vascular biology manipulations for a higher efficacy and survival rate in cancer patients. Our siRNA and DC technologies based on stem cell modulation will provide at least prevention of cancer development and hopefully prevention in cancer.

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141. BIN1 is a novel MYC-interacting protein with features of a tumor suppressor. . Sakamuro, D., Elliott, K., Wechsler-Reya, R. & Prendergast, G.C. 1996, Nat. Genet. , pp. 14, 69−77.

142. Expression of Indolamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor draining nodes. Munn, S.H., Sharma, M.D., Hou, D., Baban, B. et al. 2004, J. Clin. Invest. , pp. 114: 280-290.

143. Indoleamine 2,3-Dioxygenase Expression in Human Cancers: Clinical and Immunologic Perspectives. Jessica Godin-Ethier, Laïla-Aïcha Hanafi, Ciriaco A. Piccirillo, and Réjean Lapointe. 2011 , Clin Cancer Res, pp. 17; 6985, http://dx.doi.org:/10.1158/1078-0432.CCR-11-1331.

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148. Immunosuppressive CD14+HLA-DRlow/neg IDO+ myeloid cells in patients following allogeneic hematopoietic stem cell transplantation. Mougiakakos D, Jitschin R, von Bahr L, Poschke I, Gary R, Sundberg B, Gerbitz A, Ljungman P, Le Blanc K. 2013, Leukemia. , pp. 27(2):377-88.
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150. Skin delivery of short hairpin RNA of indoleamine 2,3 dioxygenase induces antitumor immunity against orthotopic and metastatic liver cancer. Huang TT, Yen MC, Lin CC, Weng TY, Chen YL, Lin CM, Lai MD. 2011, Cancer Sci. , pp. 102(12):2214-20. http://dx.doi.org:/10.1111/j.1349-7006.2011.02094.x.

151. Indoleamine 2,3-dioxygenase expression in transplanted NOD Islets prolongs graft survival after adoptive transfer of diabetogenic splenocytes. . Alexander AM, Crawford M, Bertera S, et al. 2002, Diabetes. , pp. 51(2):356–365.

152. Prevention of Spontaneous Tumor Development in a ret Transgenic Mouse Model by Ret Peptide Vaccination with Indoleamine 2,3-Dioxygenase Inhibitor 1-Methyl Tryptophan. Zeng, J., Cai, S., Yi, Y., et al. 2009, Cancer Res., pp. 69: 3963-3970,  http://dx.doi.org:/10.1158/0008-5472.CAN-08-2476.

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171. IFNgamma promotes generationof Il-10 secreting CD4+ T cells that suppress generationof CD8responses in an antigen-experienced host. Liu, X.S., Leerberg, J., MacDonald, K., Leggatt, G.R., Frazer, I.H. 2009, J. Immunol., pp. 183: 51-58.

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175. IL-12 enhances CTL synapse formationand induces self-reactivity. Markinewicz, MA, Wise, EL, Buchwald, ZS et al. 2009, J. Immunol., pp. 182: 1351-1362.

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177. Type17 CD8+ T cells dispplay enhanced antitumor immunity. Hinrichs, C.S., Kaiser, A., Paulos, C.M., et al. 2008, Blood., pp. 112:362-373.

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179. Enhancing Cancer Vaccine efficacy via Modulationof the Tumor Environment. Disis, ML. 2009, Clin Cancer Res, pp. 15: 6476-6478.

180. Systemic inhibition of transforming growth factor beta 1 in glioma bearing mice improves the therapeutic efficacy of glioma-associated antigen peptide vaccines. Ueda, R., Fujita, M., Zhu, X., et al. 2009, Clin. Cancer res., pp. 15: 6551-9.

181. Immune modulation by silencing IL-12 productionin dendritic cells using smal interfering RNA. Hill, JA, Ichim, TE, Kusznieruk, KP, et al. 2003, J. Immunol, pp. 171:809-813.

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184. Dendritic cells genetically engineered to express Fas ligand induce donor-specific hyporesponsiveness and prolong allograft survival. Min, WP. Gorczynki, R., huang, XY et al. 2000, J. Immunol., pp. 164:161-167.

185. LF15-0195 generates tolerogenic dendritic cells by supressionof NF-kappaB signaling through inhibitionof IKK activity. . Yang, J., Bernier, SM, Ichim, TE, et al. 2003, J Leukoc. Biol., pp. 74: 438-447.

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187. A novel in vivo siRNA delivery system specifically targeting dendritic cells and silencing CD40 genes for immunomodulation. Zheng, X., Vladau, C., Zhang, X. et al. 2009, Blood, pp. 113:2646-2654.

188. Reinstalling Antitumor Immunity by Inhibiting Tumor derived ImmunoSupressive Molecule IDO through RNA interference. Zheng, X et al. 2006, Int. Journal of Immunology., pp. 177:5639-5646.

189. Roles of TGFbeta in metastasis. Padua, D., Massague, J. 2009, Cell Res., pp. 19;89-102.

190. Functional expression of indolamine2,3-dioxygenase by murine CDalpha+dendritic cells. Fallarino, F., Vacca, C, Orabona, C et al. 2002, Int Immunol., pp. 14:65-8.

191. Indolamine2,3-dioxygenase controls conversion of Fox3+ Tregs to TH17-like cells in tumor draining lymph nodes. Sharma, MD, Hou, DY, Liu, Y et al. 2009, Blood, pp.113: 6102-11.

192. IDO upregulates regulatory T cells via tryptoophan catabolite and supresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis. Yan, Y, Zhang, GX, Gran, B et al. 2010, J Immunol, pp. 185; 5953-61.

193. IDO activates regulatory T cells and blocks their conversion into Th-17-like T cells. Baban, B, Chandler, PR, Sharma, MD et al. 2009, J Immunol, pp. 183; 2475-83.

194. Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletionof regulatory T cells. Dannull, J., Farrand, KJ, Mathews, SA, et al. 2005, J Clin Invest, pp. 115: 3623-33.

195. 1-MT enhances potency of tumor cell lysate pulled dentritic cells against pancreatic adenocarcinoma by downregulating percentage of Tregs. Li, Y, Xu, J, Zhou, H. et al. 2010, J Huazhong Univ Sci Technol Med Sci , pp. 30: 344-8.

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Conference Programs

 

May 6 – 7, 2013 

 

Track 1: Translational Biomarkers in Drug Development

Track 2: Clinical Assay Development

Track 3: Cancer Tissue Diagnostics

 

May 6 – 8, 2013 

Track 4: Executive Summit: Companion Diagnostics

 

May 7 – 8, 2013

Track 5: Biomarkers for Patient Selection

Track 6: Cancer Drug Resistance

Track 7: Exosomes and Microvesicles as Biomarkers 

               and Diagnostics

 
SPEAKERS

SPEAKERS

Jason M. Aliotta, M.D., Assistant Professor, Medicine, Warren Alpert Medical School, Brown University

John L. Allinson, FIBMS, Vice President, Biomarker Laboratory Services, ICON Development Solutions

Maria E. Arcila, M.D., Department of Pathology, Memorial Sloan-Kettering Cancer Center

Khusru Asadullah, M.D., Vice President and Head, Global Biomarkers, Bayer Pharma

Jiri Aubrecht, Pharm.D., Ph.D., Senior Director, Safety Biomarker Group Lead, Drug Safety Research & Development, Pfizer

M.J. Finley Austin, Ph.D., Personalized Healthcare & Biomarker Strategy Director, AstraZeneca

Nazneen Aziz, Ph.D., Director, Molecular Medicine, Transformation Program Office, College of American Pathologists

Geoffrey Stuart Baird, M.D., Ph.D., Assistant Professor, Laboratory Medicine, University of Washington

Robert A. Beckman, M.D., External Faculty, Center for Evolution and Cancer, Helen Diller Family Cancer Center, UCSF; Executive Director, Clinical Development Oncology, Daiichi Sankyo Pharma Development

Darrell R. Borger, Ph.D., Co-Director, Translational Research Laboratory, Massachusetts General Hospital Cancer Center

Mark Broenstrup, Ph.D., Director, Biomarker and Diagnostics, R&D Diabetes Division, Sanofi

Michael Burczynski, Ph.D., Executive Director, Biomarker Technologies, Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb

Claudio Carini, M.D., Global Clinical Immunology and Biomarkers Lead, Bioenhancement Development Unit, Pfizer

Luigi Catanzariti, Ph.D., Executive Director and Global Program Director, Diagnostics, Novartis

David Chen, Ph.D., Senior Director, Correlative Sciences, Oncology Clinical Development, Novartis Pharmaceuticals

Carol Cheung, M.D., Ph.D., Department of Pathology, University Health Network

Atish Choudhury, M.D., Instructor in Medicine, Medical Oncology, Dana-Farber Cancer Institute

Seth Crosby, M.D., Director, Partnerships & Alliances, Washington University School of Medicine

Mark E. Curran, Ph.D., Vice President, Immunology Biomarkers, Janssen Research & Development

Stephen P. Day, Ph.D., Director, Medical Affairs, Hologic

Viswanath Devanarayan, Ph.D., Global Head, Exploratory Statistics, AbbVie, Inc.

Luis Alberto Diaz, M.D., Associate Professor of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Max Diem, Ph.D., Professor, Chemistry and Chemical Biology, Northeastern University

Nicholas C. Dracopoli, Ph.D., Vice President, Janssen R&D, Johnson & Johnson

Crislyn D’Souza-Schorey, Ph.D., Professor, Biological Sciences, University of Notre Dame

Dominik Duelli, Ph.D., Assistant Professor, Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine & Science, Chicago Medical School

Daniel Edelman, Ph.D., Facility Head, Clinical Molecular Profiling Core, National Cancer Institute, NIH

Reyna Favis, Ph.D., Scientific Director, Clinical Research & Development, Janssen Pharmaceutical Companies of Johnson & Johnson

Andrea Ferreira-Gonzalez, Ph.D., Professor and Chair, Division of Molecular Diagnostics; Director, Molecular Diagnostics Laboratory, Department of Pathology, Virginia Commonwealth University

Andrew Fish, Executive Director, AdvaMedDx

Herbert A. Fritsche, Ph.D., Senior Vice President and CSO, Health Discovery Corporation

Felix Frueh, Entrepreneur-in-Residence, Third Rock Ventures

Steve Furlong, Ph.D., Safety Science Lead, AstraZeneca Clinical Development

George A. Green IV, Ph.D., Director, Pharmacodiagnostics, Bristol-Myers Squibb

Patrick Groody, Ph.D., Divisional Vice President, Research & Development, Abbott

Steven Gutman, M.D., MBA, Strategic Advisor, Myraqa

Abdel Halim, Pharm.D., Ph.D., DABCC-MDx, DABCC-TOX, DABCC-CC, FACB, Director, Clinical Biomarkers, Daiichi Sankyo Pharma Development

Sam Hanash, M.D., Ph.D., Director, McCombs Institute for Cancer Early Detection and Treatment, MD Anderson Cancer Center

Charles R. Handorf, M.D., Ph.D., Professor and Chair, Pathology and Laboratory Medicine, University of Tennessee

Amir Handzel, Ph.D., Associate Director, Translational and Clinical Sciences, OSI Pharma (Astellas)

Chunhai “Charlie” Hao, M.D., Ph.D., Associate Professor, Neuropathology Attending, Department of Pathology & Laboratory Medicine, Emory University School of Medicine

Madhuri Hegde, Ph.D., Executive Director, Emory Genetics Laboratory; Associate Professor, Human Genetics, Emory University School of Medicine

Philip Hewitt, Ph.D., Head, Early Non-Clinical Safety (Liver and Kidney), Merck Serono

Stephen M. Hewitt, M.D., Ph.D., Clinical Investigator, Laboratory of Pathology, National Cancer Institute, NIH

Holly Hilton, Ph.D., Head, Disease and Translational Genomics, Hoffmann-La Roche; Adjunct Professor, University of Medicine and Dentistry New Jersey

Fred H. Hochberg, M.D., Associate Professor, Neurology, Massachusetts General Hospital

Shidong Jia, Ph.D., Scientist, Oncology Biomarker Development, Genentech

Chris Jowett, General Manager, Commercial Operations, Abbott Molecular

Jingfang Ju, Ph.D., Co-Director of Translational Research, Pathology, Stony Brook University

Peter M. Kazon, General Counsel, American Clinical Laboratory Association

Eric Lai, Ph.D., Senior Vice President and Head, Pharmacogenomics, Takeda Pharmaceuticals International

Ira M. Lubin, Ph.D., Team Lead, Genetics Laboratory Research and Evaluation Branch, CDC

Johan Luthman, D.D.S., Ph.D., Senior Program Leader, Neuroscience & Ophthalmology Research & Development Franchise Integrator, Merck

Elaine Lyon, Ph.D., Medical Director, Molecular Genetics, ARUP Laboratories

Ron Mazumder, Ph.D., MBA, Global Head, Research and Product Development, Janssen Diagnostics, Janssen Pharmaceutical Companies of Johnson & Johnson

Duncan McHale, Ph.D., Vice President, Global Exploratory Development at UCB Pharma

Alan Mertz, President, American Clinical Laboratory Association

Yoshi Oda, Ph.D., President, Biomarkers and Personalized Medicine Core Function Unit, Eisai

Lorraine O’Driscoll, Ph.D., Associate Professor, Pharmacology; Director, Research, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin

Carol S. Palackdharry, M.D., MS, Medical Director, ActiveHealth Management; Clinical Lead, Oncology Condition Analysis, Aetna

Saumya Pant, Ph.D., Research Fellow, Merck

Liron Pantanowitz, M.D., Associate Professor, Pathology and Biomedical Informatics, University of Pittsburgh Medical Center

Scott D. Patterson, Ph.D., Executive Director, Medical Sciences, Amgen

Sonia Pearson-White, Ph.D., Scientific Program Manager, Oncology, The Biomarkers Consortium, Foundation for the National Institutes of Health

Emanuel Petricoin III, Ph.D., Co-Director, The Center for Applied Proteomics and Molecular Medicine, George Mason University

Suso Platero, Ph.D., Director, Oncology Biomarkers, Janssen Pharmaceuticals

Mark Priebe, MT(ASCP)SBB, Managing Director, QualityStar Quality Consortium

Debra Rasmussen, MBA, Senior Director, Regulatory Affairs, Johnson & Johnson

Hallgeir Rui, M.D., Ph.D., Professor, Cancer Biology, Medical Oncology, and Pathology, Thomas Jefferson University

Hakan Sakul, Ph.D., Executive Director and Head, Diagnostics, Worldwide R&D, Clinical Research and Precision Medicine, Pfizer

Kurt A. Schalper, M.D., Ph.D., Associate Research Scientist, Pathology, Yale School of Medicine

Stephen C. Schmechel, M.D., Ph.D., Associate Professor, Pathology, University of Washington School of Medicine

Robert Schupp, Ph.D., Executive Director, Diagnostics Hematology/Oncology, Celgene Corporation

Jason S. Simon, Ph.D., Director, Immuno-Oncology Biomarkers, Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb

Sharon Sokolowski, Ph.D., Principal Scientist, Pfizer Global Research & Development

Gyongyi Szabo, M.D., Ph.D., Professor, Gastroenterology, University of Massachusetts Medical School

Douglas D. Taylor, Ph.D., Professor, Obstetrics and Gynecology, University of Louisville School of Medicine

Meghna Das Thakur, Ph.D., Presidential PostDoctoral Fellow, Novartis Institutes for BioMedical Research

Emina Torlakovic, M.D., Ph.D., Associate Professor, Laboratory Medicine and Pathobiology, University of Toronto

Jessie Villanueva, Ph.D., Assistant Professor, Molecular & Cellular Oncogenesis Program, The Wistar Institute

Glen J. Weiss, M.D., Co-Head, Lung Cancer Unit, The Translational Genomics Research Institute (TGen); Director, Clinical Research, Cancer Treatment Centers of America; CMO, CRAB-Clinical Trials Consortium

David Wholley, Director, Biomarkers Consortium, Foundation for the NIH

David T.W. Wong, D.M.D., D.M.Sc., Professor, Associate Dean of Research, UCLA School of Dentistry and Director of Dental Research Institute

Janghee Woo, M.D., Albert Einstein Medical Center

Wen Jin Wu, M.D., Ph.D., Principal Investigator, Division of Monoclonal Antibodies, Office of Biotechnology Products, Center for Drug Evaluation and Research, FDA

Brenda Yanak, Ph.D., Precision Medicine Leader, Clinical Innovation, Pfizer

Tammie Yeh, Ph.D., Molecular Biomarkers, Oncology Lead, Merck

Eunhee S. Yi, M.D., Consultant, Anatomic Pathology, Mayo Clinic; Professor, Pathology, Mayo Clinic College of Medicine

Malcolm York, MPhil, Director and Head, Clinical Pathology and Safety Assessment, GlaxoSmithKline R&D

Theresa Zhang, Ph.D., Associate Director, Exploratory and Translational Sciences, Merck

 

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world congress 2013

MAY 6 – 8, 2013 | LOEWS PHILADELPHIA HOTEL | PHILADELPHIA, PA

Cambridge Healthtech Institute’s Ninth Annual

BiomarkerWorldCongress.com

The Leading Annual Meeting Dedicated to Biomarkers

and Diagnostics Research and Implementation

Dinner Courses:

Fit-for-Purpose Biomarker Assay

Development and Validation

Next-Generation Sequencing as

a Clinical Test

Laboratory-Developed Tests

Conference Programs:

May 6 – 7, 2013

Track 1: Translational

Biomarkers in Drug Development

Track 2: Clinical Assay

Development

Track 3: Cancer Tissue

Diagnostics

May 6 – 8, 2013

Track 4: Executive Summit:

Companion Diagnostics

May 7 – 8, 2013

Track 5: Biomarkers for

Patient Selection

Track 6: Cancer Drug Resistance

Track 7: Exosomes and

Microvesicles as Biomarkers

and Diagnostics

Register by March 29th and SAVE up to $250!

Premier Sponsor

Featured Speakers

Hakan Sakul

Head, Diagnostics

Pfizer

Yoshi Oda

President, Biomarkers & Personalized Medicine

Eisai

David Wholley

Director

Biomarkers Consortium

Khusru Asadullah

VP, Head, Global Biomarkers

Bayer

Nicholas C. Dracopoli

VP, Janssen R&D

Johnson & Johnson

Eric Lai

SVP, Head, Pharmacogenomics

Takeda

2 | Biomarkers & Diagnostics World Congress BiomarkerWorldCongress.com

BIOMARKERS & DIAGNOSTICS

world congress 2013

Track 1: Translational Biomarkers

in Drug Development

Track 2: Clinical

Assay Development

Track 3: Cancer Tissue Diagnostics Track 4: Executive Summit:

Companion Diagnostics*

Sunday, May 5

5:00-6:00 Conference Pre-Registration

Monday, May 6

8:30-10:00 Biomarkers in Translational Medicine From Research Biomarkers to

Clinical Assays

Whole-Slide Imaging and

Digital Pathology

Commercialization of

Companion Diagnostics

10:00-10:30 Networking Coffee Break

10:30-11:50 Biomarkers in Translational Medicine From Research Biomarkers to

Clinical Assays

Whole-Slide Imaging and

Digital Pathology

Commercialization of

Companion Diagnostics

11:50-1:20 Luncheon Presentation

Sponsored by

Lunch on Your Own

1:20-2:40 Biomarker Utility in Clinical Development NGS in Clinical Use Strategies for Rx-Dx Partnerships

2:40-3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

3:40-5:00 Biomarker Utility in Clinical Development NGS in Clinical Use Strategies for Rx-Dx Partnerships

5:00-6:00 Networking Reception in the Exhibit Hall with Poster Viewing

6:00-9:00 Dinner Courses (Separate registration required)

Fit-for-Purpose Biomarker Assay Development and Validation

Next-Generation Sequencing as a Clinical Test

Tuesday, May 7

7:30-8:15 Breakfast Presentation Sponsored by

8:25-10:00 Biomarkers for Safety Assessment Choosing a Platform for

Companion Diagnostics

Advances in IHC: Guiding

Therapy Decisions

Choosing a Platform for

Companion Diagnostics

10:00-11:00 Coffee Break in the Exhibit Hall with Poster Viewing

11:00-12:15 Biomarker Collaborations and Consortia Multiplexed Assays Tissue Biomarkers for Targeted Therapy Panel Discussion: Next-Generation

CDx Platforms

12:15-1:45 Lunch on Your Own and Conference Registration for Tracks 5-7

Track 5: Biomarkers for

Patient Selection

Track 6: Cancer Drug Resistance Track 7: Exosomes and Microvesicles

as Biomarkers and Diagnostics

12:15-1:45 Conference Registration

1:45-2:40 Biomarkers to Diagnostics Exosome Biomarkers in

Drug Development

Biomarkers to Diagnostics

2:40-3:45 Refreshment Break in the Exhibit Hall with Poster Viewing

3:45-5:30 Molecular Profiling of Tumor Heterogeneity to Guide Therapy Exosome Biomarkers in

Drug Development

Timeline for CDx Development

6:00-9:00 Dinner Course (Separate registration required)

Laboratory-Developed Tests

Wednesday, May 8

7:30-8:15 Breakfast Presentation (Sponsorship Opportunity Available) or Morning Coffee

8:25-10:30 Advancing Personalized Medicine 8:05 Secondary Resistance to Targeted

Cancer Therapy

Exosomes as Disease Markers Advancing Personalized Medicine

10:30-11:30 Coffee Break in the Exhibit Hall with Poster Viewing

11:30-12:45 Advancing Personalized Medicine 11:30-1:15 Resistance to

Various Therapies: Cancer Does

Not Discriminate

11:30-1:15 Exosomes as Novel

Cancer Biomarkers

Advancing Personalized Medicine

12:45 Close of Conference 1:15 Close of Conference 1:15 Close of Conference Close of Conference

*Executive pricing registration required

Conference-at-a-Glance

BiomarkerWorldCongress.com Biomarkers & Diagnostics World Congress | 3

BIOMARKERS & DIAGNOSTICS

world congress 2013

Distinguished Faculty

Jason M. Aliotta, M.D., Assistant Professor,

Medicine, Warren Alpert Medical School,

Brown University

John L. Allinson, FIBMS, Vice President,

Biomarker Laboratory Services, ICON

Development Solutions

Maria E. Arcila, M.D., Department of Pathology,

Memorial Sloan-Kettering Cancer Center

Khusru Asadullah, M.D., Vice President and

Head, Global Biomarkers, Bayer Pharma AG

Jiri Aubrecht, Pharm.D., Ph.D., Senior Director,

Safety Biomarker Group Lead, Drug Safety

Research & Development, Pfizer

M.J. Finley Austin, Ph.D., Personalized

Healthcare & Biomarker Strategy

Director, AstraZeneca

Nazneen Aziz, Ph.D., Director, Molecular

Medicine, Transformation Program Office,

College of American Pathologists

Geoffrey Stuart Baird, M.D., Ph.D., Assistant

Professor, Laboratory Medicine, University

of Washington

Robert A. Beckman, M.D., External Faculty,

Center for Evolution and Cancer, Helen Diller

Family Cancer Center, UCSF; Executive

Director, Clinical Development Oncology,

Daiichi Sankyo Pharma Development

Darrell R. Borger, Ph.D., Co-Director,

Translational Research Laboratory,

Massachusetts General Hospital Cancer Center

Mark Broenstrup, Ph.D., Director, Biomarker

and Diagnostics, R&D Diabetes Division, Sanofi

Michael Burczynski, Ph.D., Executive

Director, Biomarker Technologies, Discovery

Medicine and Clinical Pharmacology,

Bristol-Myers Squibb

Claudio Carini, M.D., Global Clinical

Immunology and Biomarkers Lead,

Bioenhancement Development Unit, Pfizer

Luigi Catanzariti, Ph.D., Executive Director and

Global Program Director, Diagnostics, Novartis

David Chen, Ph.D., Senior Director, Correlative

Sciences, Oncology Clinical Development,

Novartis Pharmaceuticals

Carol Cheung, M.D., Ph.D., Department of

Pathology, University Health Network

Atish Choudhury, M.D., Instructor in

Medicine, Medical Oncology, Dana-Farber

Cancer Institute

Seth Crosby, M.D., Director, Partnerships

& Alliances, Washington University School

of Medicine

Mark E. Curran, Ph.D., Vice President,

Immunology Biomarkers, Janssen Research &

Development

Stephen P. Day, Ph.D., Director, Medical

Affairs, Hologic

Viswanath Devanarayan, Ph.D., Global Head,

Exploratory Statistics, AbbVie, Inc

Luis Alberto Diaz, M.D., Associate Professor

of Oncology, Johns Hopkins Sidney Kimmel

Comprehensive Cancer Center

Max Diem, Ph.D., Professor, Chemistry and

Chemical Biology, Northeastern University

Nicholas C. Dracopoli, Ph.D., Vice President,

Janssen R&D, Johnson & Johnson

Crislyn D’Souza-Schorey, Ph.D., Professor,

Biological Sciences, University of Notre Dame

Dominik Duelli, Ph.D., Assistant Professor,

Cellular and Molecular Pharmacology, Rosalind

Franklin University of Medicine & Science,

Chicago Medical School

Daniel Edelman, Ph.D., Facility Head, Clinical

Molecular Profiling Core, National Cancer

Institute, NIH

Reyna Favis, Ph.D., Scientific Director,

Clinical Research & Development, Janssen

Pharmaceutical Companies of Johnson &

Johnson

Andrea Ferreira-Gonzalez, Ph.D., Professor

and Chair, Division of Molecular Diagnostics;

Director, Molecular Diagnostics Laboratory,

Department of Pathology, Virginia

Commonwealth University

Andrew Fish, Executive Director, AdvaMedDx

Herbert A. Fritsche, Ph.D., Senior

Vice President and CSO, Health

Discovery Corporation

Felix Frueh, Entrepreneur-in-Residence, Third

Rock Ventures

Steve Furlong, Ph.D., Safety Science Lead,

AstraZeneca Clinical Development

George A. Green IV, Ph.D., Director,

Pharmacodiagnostics, Bristol-Myers Squibb

Patrick Groody, Ph.D., Divisional Vice President,

Research & Development, Abbott

Steven Gutman, M.D., MBA, Strategic

Advisor, Myraqa

Abdel Halim, Pharm.D., Ph.D., DABCCMDx,

DABCC-TOX, DABCC-CC, FACB,

Director, Clinical Biomarkers, Daiichi Sankyo

Pharma Development

Sam Hanash, M.D., Ph.D., Director, McCombs

Institute for Cancer Early Detection and

Treatment, MD Anderson Cancer Center

Charles R. Handorf, M.D., Ph.D., Professor

and Chair, Pathology and Laboratory Medicine,

University of Tennessee

Amir Handzel, Ph.D., Associate Director,

Translational and Clinical Sciences, OSI

Pharma (Astellas)

Chunhai “Charlie” Hao, M.D., Ph.D., Associate

Professor, Neuropathology Attending,

Department of Pathology & Laboratory

Medicine, Emory University School of Medicine

Madhuri Hegde, Ph.D., Associate Professor,

Human Genetics; Senior Director, Emory

Genetics Laboratory, Emory University

Philip Hewitt, Ph.D., Head, Early Non-Clinical

Safety (Liver and Kidney), Merck Serono

Stephen M. Hewitt, M.D., Ph.D., Clinical

Investigator, Laboratory of Pathology, National

Cancer Institute, NIH

Holly Hilton, Ph.D., Head, Disease and

Translational Genomics, Hoffmann-La Roche;

Adjunct Professor, University of Medicine and

Dentistry New Jersey

Fred H. Hochberg, M.D., Associate Professor,

Neurology, Massachusetts General Hospital

Shidong Jia, Ph.D., Scientist, Oncology

Biomarker Development, Genentech

Chris Jowett, General Manager, Commercial

Operations, Abbott Molecular

Jingfang Ju, Ph.D., Co-Director of Translational

Research, Pathology, Stony Brook University

Peter M. Kazon, General Counsel, American

Clinical Laboratory Association

Eric Lai, Ph.D., Senior Vice President

and Head, Pharmacogenomics, Takeda

Pharmaceuticals International

Ira M. Lubin, Ph.D., Team Lead, Genetics

Laboratory Research and Evaluation

Branch, CDC

Johan Luthman, D.D.S., Ph.D., Senior Program

Leader, Neuroscience & Ophthalmology

Research & Development Franchise

Integrator, Merck

Elaine Lyon, Ph.D., Medical Director, Molecular

Genetics, ARUP Laboratories

Ron Mazumder, Ph.D., MBA, Global Head,

Research and Product Development, Janssen

Diagnostics, Janssen Pharmaceutical Companies

of Johnson & Johnson

Duncan McHale, Ph.D., Vice President, Global

Exploratory Development at UCB Pharma

Alan Mertz, President, American Clinical

Laboratory Association

Yoshi Oda, Ph.D., President, Biomarkers and

Personalized Medicine Core Function Unit, Eisai

Lorraine O’Driscoll, Ph.D., Associate Professor,

Pharmacology; Director, Research, School of

Pharmacy and Pharmaceutical Sciences, Trinity

College Dublin

Carol S. Palackdharry, M.D., MS, Medical

Director, ActiveHealth Management; Clinical

Lead, Oncology Condition Analysis, Aetna

Saumya Pant, Ph.D., Research Fellow, Merck

Liron Pantanowitz, M.D., Associate Professor,

Pathology and Biomedical Informatics,

University of Pittsburgh Medical Center

Scott D. Patterson, Ph.D., Executive Director,

Medical Sciences, Amgen

Sonia Pearson-White, Ph.D., Scientific

Program Manager, Oncology, The Biomarkers

Consortium, Foundation for the National

Institutes of Health

Emanuel Petricoin III, Ph.D., Co-Director, The

Center for Applied Proteomics and Molecular

Medicine, George Mason University

Suso Platero, Ph.D., Director, Oncology

Biomarkers, Janssen Pharmaceuticals

Mark Priebe, MT(ASCP)SBB, Managing

Director, QualityStar Quality Consortium

Debra Rasmussen, MBA, Senior Director,

Regulatory Affairs, Johnson & Johnson

Hallgeir Rui, M.D., Ph.D., Professor, Cancer

Biology, Medical Oncology, and Pathology,

Thomas Jefferson University

Hakan Sakul, Ph.D., Executive Director and

Head, Diagnostics, Worldwide R&D, Clinical

Research and Precision Medicine, Pfizer

Kurt A. Schalper, M.D., Ph.D., Associate

Research Scientist, Pathology, Yale School

of Medicine

Stephen C. Schmechel, M.D., Ph.D., Associate

Professor, Pathology, University of Washington

School of Medicine

Robert Schupp, Ph.D., Executive Director,

Diagnostics Hematology/Oncology,

Celgene Corporation

Jason S. Simon, Ph.D., Director, Immuno-

Oncology Biomarkers, Discovery Medicine and

Clinical Pharmacology, Bristol-Myers Squibb

Sharon Sokolowski, Ph.D., Principal Scientist,

Pfizer Global Research & Development

Gyongyi Szabo, M.D., Ph.D., Professor,

Gastroenterology, University of Massachusetts

Medical School

Douglas D. Taylor, Ph.D., Professor, Obstetrics

and Gynecology, University of Louisville School

of Medicine

Meghna Das Thakur, Ph.D., Presidential

PostDoctoral Fellow, Novartis Institutes for

BioMedical Research

Emina Torlakovic, M.D., Ph.D., Associate

Professor, Laboratory Medicine and

Pathobiology, University of Toronto

Jessie Villanueva, Ph.D., Assistant Professor,

Molecular & Cellular Oncogenesis Program,

The Wistar Institute

Glen J. Weiss, M.D., Co-Head, Lung Cancer

Unit, The Translational Genomics Research

Institute (TGen); Director, Thoracic Oncology,

Virginia G. Piper Cancer Center Clinical Trials

at Scottsdale Healthcare; CMO, CRAB-Clinical

Trials Consortium

David Wholley, Director, Biomarkers

Consortium, Foundation for the NIH

David T.W. Wong, D.M.D., D.M.Sc., Professor,

Associate Dean of Research, UCLA

School of Dentistry and Director of Dental

Research Institute

Janghee Woo, M.D., Albert Einstein

Medical Center

Wen Jin Wu, M.D., Ph.D., Principal Investigator,

Division of Monoclonal Antibodies, Office

of Biotechnology Products, Center for Drug

Evaluation and Research, FDA

Brenda Yanak, Ph.D., Precision Medicine

Leader, Clinical Innovation, Pfizer

Tammie Yeh, Ph.D., Molecular Biomarkers,

Oncology Lead, Merck

Eunhee S. Yi, M.D., Consultant, Anatomic

Pathology, Mayo Clinic; Professor, Pathology,

Mayo Clinic College of Medicine

Malcolm York, MPhil, Director and Head,

Clinical Pathology and Safety Assessment,

GlaxoSmithKline R&D

Theresa Zhang, Ph.D., Associate Director,

Exploratory and Translational Sciences, Merck

Premier Sponsor Corporate

Sponsors

4 | Biomarkers & Diagnostics World Congress BiomarkerWorldCongress.com

Monday, May 6, 6:00-9:00 pm

Fit-for-Purpose Biomarker Assay Development

and Validation

Instructors:

John L. Allinson, FIBMS, Vice President, Biomarker Laboratory Services, ICON

Development Solutions

Viswanath Devanarayan, Ph.D., Global Head, Exploratory Statistics, AbbVie, Inc

This tutorial will provide recommendations on the “fit-for-purpose” best

practices in the development and validation of biomarker assays for

exploratory or advanced biomarker applications. Strategies for different

applications at various phases of biomarker development will be described.

Key elements in the method of development and validation will be illustrated

with examples, including reference to standard material, sample stability and

collection integrity, validation and QC samples, validity of reference standards,

calibration curve fitting methods, method optimization and feasibility studies.

Special challenges in protein biomarker assays will be discussed, including

strategies for moving from biomarker panels in the exploratory phase to the

few markers chosen to support clinical trials, cross-validation of biomarker

assays, etc.

Outline:

1. Introduction: Nomenclature, types of biomarker methods/assays, method

development and validation road-map, fundamental validity, similarity and

differences from PK assays and diagnostic applications

2. Pre-analytical and bioanalytical elements: Target range, standards,

validation and QC samples, stability, matrix effect, specificity and

relative selectivity

3. Calibration curve model selection, evaluation and weighting

4. Method feasibility and optimization with precision profiles

5. Evaluation of some pre-study validation characteristics such as precision,

bias, sensitivity and quantification limits

6. Use of sample controls for in-study performance monitoring and

conformance testing among laboratories

7. Special considerations for multiplex assays, cross-validation of assays, etc.

8. Method comparisons

Next-Generation Sequencing as a Clinical Test:

It Takes a Community

Instructors:

Nazneen Aziz, Ph.D., Director, Molecular Medicine, Transformation Program

Office, College of American Pathologists

Madhuri Hegde, Ph.D., Associate Professor, Human Genetics; Senior Director,

Emory Genetics Laboratory, Emory University

Next-Generation Sequencing (NGS) is used widely in clinical research for

the discovery of disease-associated genes and the clinical community

is beginning to embrace this technology for diagnostic testing. The rapid

evolution of NGS technologies presents significant opportunities and

challenges for researchers and clinicians for improving health outcomes,

particularly with respect to an increased emphasis on personalized and

preventive medicine. Adoption of NGS in the clinical laboratory setting

requires the adoption of many processes and procedures, such as

the analytic and clinical validation of the test, CLIA certification/CAP

accreditation, standards for reference materials, availability for proficiency

testing, and questions regarding reimbursement and informed consent.

The success of NGS as a viable diagnostic modality depends on many

branches of the health care community working together. This session will

be informative and practical for the researcher and laboratorians who are

considering launching NGS as a clinical test.

Tuesday, May 7, 6:00-9:00 pm

Laboratory-Developed Tests

Regulatory Issues Facing Laboratory-Developed Tests

Peter M. Kazon, General Counsel, American Clinical Laboratory Association

The development of molecular diagnostics has been accompanied by a host

of regulatory issues, including coding, billing and FDA issues. This session will

review recent changes affecting these codes as well as the position of Medicare

on how to pay for these tests and tests including an algorithm, also referred

to as MAAAs. It will review the latest developments from the FDA concerning

whether such tests will require FDA pre-market approval or clearance, and what

action FDA is likely to take in the future. It will also review other actions that affect

these tests, such as the new MolDx program being overseen by Palmetto GBA, a

Medicare contractor.

Laboratory-Developed Tests in the Genomic Medicine Era: Validation, Regulation

and Challenges Faced by New Technologies and Clinical Applications

Andrea Ferreira-Gonzalez, Ph.D., Professor and Chair, Division of Molecular

Diagnostics; Director, Molecular Diagnostics Laboratory, Department of

Pathology, Virginia Commonwealth University

Laboratory-developed tests are those tests developed, validated and

performed by clinical laboratories. There are standards and regulations in

place for the validation of these tests before they are introduced into clinical

practice. This presentation will discuss the process of validation under the

current regulatory framework, and regulatory challenges posed by new

technologies such as NGS and its clinical applications.

LDTs in the Context of CLIA: An NIH Experience

Daniel Edelman, Ph.D., Facility Head, Clinical Molecular Profiling Core, National

Cancer Institute, NIH

The mission of the Clinical Molecular Profiling Core (CMPC) of the National

Cancer Institute (NCI) is to provide state of the art genomic testing for specimens

obtained from NCI clinical trials. The greatest impact is effected where test results

have immediate clinical application for personalized cancer care for individual

patients enrolled in these trials. To that end, the CMPC is CLIA certified and

provides a growing set of clinical test modalities. In this talk we’ll discuss the

challenges of meeting CLIA regulations in this new age of genomics at NIH for

high-complexity assays that did not exist as diagnostic tests when the federal

guidelines were written.

LDT Regulation Guidance from the FDA: Where Does It Stand after Three Years?

Stephen P. Day, Ph.D., Director, Medical Affairs, Hologic

The FDA’s announced intent to further regulate laboratory developed tests

(LDTs) enters its third year without the issuance of the anticipated guidance.

This presentation will summarize what the FDA has made publicly available

on the subject up to this time, the positions and recommendations put

forward by medical and industry professional societies, and how it will

potentially affect clinical laboratories offering LDTs and the delivery of quality

medical care.

Next-Generation Sequencing Assays as Laboratory-Developed Tests

Elaine Lyon, Ph.D., Medical Director, Molecular Genetics; Co-Medical Director,

Pharmacogenomics, ARUP Laboratories; Associate Professor, University of Utah

As next-generation sequencing (NGS) technologies improve in accuracy

and cost effectiveness, they will become standard in clinical laboratories.

Multi-gene panels, exome or genome analysis are alternative approaches.

With the complexity of genomic scale sequencing, implementing NGS

assays into clinical laboratories requires expertise in laboratory techniques,

informatics and interpretation. CLIA-certified clinical laboratories are

developing NGS assays as laboratory-developed tests (LDTs). The

presentation will discuss how NGS assays are “procedures” involving input

from health care professionals, and how they fit under the category of high

complexity LDTs.

*Separate registration required

Dinner Courses*

BiomarkerWorldCongress.com Biomarkers & Diagnostics World Congress | 5

Sunday, May 5

5:00-6:00 pm Conference Pre-Registration

Monday, May 6

7:30-8:30 am Conference Registration and Morning Coffee

8:30-8:40 Welcome Remarks from Conference Director

Julia Boguslavsky, Executive Director, Conferences, Cambridge Healthtech Institute

Biomarkers in Translational Medicine

8:40-8:45 Chairperson’s Opening Remarks

8:45-9:10 Translating Biological Data into Predictive Biomarker

Development Strategies

Nicholas C. Dracopoli, Ph.D., Vice President, Janssen R&D, Johnson & Johnson

A decade after completion of the human genome sequence, the translation

of complex genomic data into widely used clinical tests has been slower

than anticipated. Three complex tests (in vitro diagnostic multiplex index

assays – IVDMIA) have been approved as prognostic tests, but there has

still not been a single approval of an IVDMIA to predict response to therapy.

Retrospective analyses of the development of predictive biomarkers for

first-in-class oncology drugs over the last ten years shows that 1) insufficient

patients have been exposed to an efficacious dose to support complex

statistical analyses to correlate high-content data against clinical endpoints,

and 2) biomarkers that correlate to response in Phase II studies are not

always good predictors of overall survival in Phase III trials. We will need to

modify the clinical development paradigm for first-in-class agents to support

the efficient co-development of predictive markers.

9:10-9:35 Application of Next-Generation Sequencing in Phase III

Oncology Trials

David Chen, Ph.D., Senior Director, Oncology Correlative Sciences, Novartis

Analysis of tumor samples by next-generation sequencing (NGS) has

increased dramatically in the last 2 years. Most of the reported results

are genetic landscapes generated on samples collected outside clinical

trials or from early phase trials. Application of this technology in large

global Phase III trials provides an excellent opportunity for treatment

efficacy predictive biomarker explorations. Study design considerations

and analysis strategies for the implementation of complex and resource

demanding NGS analysis in Phase III trials will be discussed.

9:35-10:00 Can Biomarkers Recover Drug Development from the Ditch?

Abdel Halim, Pharm.D., Ph.D., DABCC-MDx, DABCC-TOX, DABCC-CC, FACB,

Director, Clinical Biomarkers, Daiichi Sankyo Pharma Development

Despite all the potential benefits of using biomarkers to advance the

pharmaceutical industry, discrepant results can pose a threat to development

programs by triggering false decisions. This talk will highlight the following

topics: biomarkers and their potential utility in drug development, limitations,

major reasons behind discrepant results and possibility of its mitigation.

10:00-10:30 Networking Coffee Break

10:30-10:55 Advancing Biomarkers for Alzheimer’s Disease—From

Target Engagement to Diagnostics

Johan Luthman, D.D.S., Ph.D., Senior Program Leader, Neuroscience &

Ophthalmology Research & Development Franchise Integrator, Merck

Measuring pathophysiology associated factors, such as Aβ peptide

and tau protein in cerebrospinal fluid, and imaging brain function with

fluorodeoxyglucose PET or functional MRI, or pathology with amyloid

PET or MRI, allows us to detect and follow the progression of very early,

pre-dementia stages of AD. While the use of pathophysiology associated

biomarkers allows pharmacodynamics monitoring of putative disease

modifying therapeutics, further qualification efforts are paving the way for

diagnostic and prognostic readouts.

10:55-11:20 Perspectives of Target and Marker Discovery in Multiple Myeloma

Robert Schupp, Ph.D., Executive Director, Diagnostics Hematology/Oncology,

Celgene Corporation

While major advances in therapeutic treatments have almost quadrupled the

overall survival of patients with multiple myeloma (MM) within the last decade,

the clinical challenges are now to optimize clinical utility of drugs and their

therapeutic sequence. The immunomodulatory drugs (IMiDs) thalidomide,

lenalidomide, and pomalidomide comprise an essential treatment modality in

MM and have shown to needfully bind to a newly identified protein in order

to exert their antimyeloma activity. Since this potential new target protein

may qualify as a biomarker predicting clinical response and the emergence of

resistance, significant challenges remain with regards to validating a robust

assay. This talk will highlight key challenges in the methodology and further

development of measurements leading to establishing a new biomarker in MM.

11:20-11:35 Measure for Measure: Assaying the Sponsored by

Rise and Fall of Protein Biomarkers across the Proteome

Steve Williams, M.D., Ph.D., CMO, SomaLogic

Shakespeare’s proteome: “Oh what may man within him hide, though angel on

the outward side!” – Early disease markers. “Our doubts are traitors and make

us lose the good we oft might win, by fearing to attempt” – Now is proteomics’

time. “Truth is truth to the end of reckoning” – Truth standards and biomarkers.

“The miserable have no other medicine but only hope” – Proteomics applied.

“What’s mine is yours, and what is yours is mine.” – Working with us.

11:35-11:50 Sponsored Presentation

(Opportunity available. Contact Ilana Quigley at 781-972-5457

or iquigley@healthtech.com)

11:50-1:20 pm Luncheon Presentation Sponsored by

Obtaining NAT Sensitivity with ELISA: Results from

Application of Simoa to Blood Screening

David Wilson, Ph.D., Vice President, Product Development, Quanterix

Until recently, nucleic acid testing (NAT) represented the most sensitive

method for early acute HIV infection, when individuals are most

contagious. Using Single Molecule Arrays (Simoa), a digital ELISA

technique, researchers were able to demonstrate a 3000x sensitivity

improvement over conventional ELISA and equivalence with the NAT gold

standard but at a fraction of the cost. This ground-breaking research has

significant implications for blood banking, HIV detection and beyond.

Biomarker Utility in Clinical Development

1:20-1:25 Chairperson’s Remarks

1:25-1:50 Implementing Biomarkers in Clinical Trials

Suso Platero, Ph.D., Director, Oncology Biomarkers, Janssen Pharmaceuticals

Finding biomarkers is relatively easy nowadays. One has only to open

any journal and find dozens of articles showing the discovery of new

biomarkers. The bottleneck in the development of biomarkers is in the

correlation of the appropriate biomarkers to each specific drug. This is done

in the context of clinical trials. Several strategies will be presented of how to

better accomplish this task in an efficient and time sensitive manner.

1:50-2:15 Clinical Innovation in Precision Medicine

Brenda Yanak, Precision Medicine Leader, Clinical Innovation, Pfizer

This presentation will give examples of how Pfizer is innovating in the

clinical development space to aid in the advancement of precision medicine.

2:15-2:40 Discovering Oncology Biomarkers and Translating into

Clinical Trials

Theresa Zhang, Ph.D., Associate Director, Exploratory and Translational

Sciences, Merck

This talk will present a platform for discovering oncology response

biomarkers using a large panel of tumor cell lines, validating them in

selected in vivo models, and refining and estimating biomarker prevalence

in a large human tumor reference dataset. The predictive signature

will then be converted into an analytically validated assay that will be

performed in a CLIA- or CAP-certified laboratory in order to enroll patients

for clinical trials. The process will be illustrated by examples.

Track 1: Translational Biomarkers in Drug Development

6 | Biomarkers & Diagnostics World Congress BiomarkerWorldCongress.com

2:40-3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

3:40-4:05 Biomarker Discovery for Immuno-Oncology Agents

Jason S. Simon, Ph.D., Director, Immuno-Oncology Biomarkers, Discovery

Medicine and Clinical Pharmacology, Bristol-Myers Squibb

Tumor cells can use escape mechanisms to avoid or suppress the

natural immune response, ultimately resulting in tumor growth; in fact,

avoiding immune destruction is one of the emerging hallmarks of cancer.

Therefore, understanding and dismantling key immune escape mechanisms

(“checkpoints”) is a key focus of immuno-oncology research. In concert with

identifying agents to regulate the immune checkpoint is working to understand

which tumor types and patient characteristics will respond best to this

treatment approach. This talk will review our strategy to identify biomarkers

which help support clinical development and commercialization strategies.

4:05-4:30 Accelerating and Personalizing Clinical Trials with

Biomarkers and Adaptive Design, the I-SPY 2 Example

Sonia Pearson-White, Ph.D., Scientific Program Manager, Oncology, The

Biomarkers Consortium, Foundation for the National Institutes of Health

I-SPY 2 is a unique clinical trial managed as a public/private partnership

by the Foundation for the NIH (FNIH) Biomarkers Consortium. I-SPY

2 employs an innovative adaptive trial design testing multiple drugs in

high-risk breast cancers in the neoadjuvant setting, and will advance the

understanding of which drugs work best with tumor types with different

biomarker profiles, and the drive toward personalized medicine.

4:30 Metabolomic Profiling for NMR Based Clinical Sponsored by

Assay Development

Thomas O’Connell, Ph.D., Senior Director, Assay Research &

Development, LipoScience, Inc.

Metabolomic profiling yields a unique picture of the downstream phenotype

taking into account genetic influences as well as environmental factors such

as diet, lifestyle and the microbiome. In this presentation it will be shown how

NMR technology is used in both the discovery and translation of biomarkers

into the clinical laboratory. Applications include the prediction, diagnosis and

prognosis of disease as well as the guidance of pharmaceutical interventions.

5:00-6:00 Networking Reception in the Exhibit Hall with Poster Viewing

6:00-9:00 Dinner Courses

Fit-for-Purpose Biomarker Assay Development and Validation

Next-Generation Sequencing as a Clinical Test

(Separate registration required. See Page 4 for additional information.)

Tuesday, May 7

7:30-8:15 am Breakfast Presentation Sponsored by

Identifying Non-Invasive Biomarkers of Smoking-

Related Parenchymal Lung Disease (i.e. COPD and

IPF) to Detect Subclinical Lung Disease

Ivan O. Rosas, M.D., Assistant Professor, Medicine Division, Pulmonary &

Critical Care Medicine, Brigham & Women’s Hospital, Harvard Medical School

Biomarkers for Safety Assessment

8:25-8:30 Chairperson’s Opening Remarks

8:30-8:55 Pre-Clinical Safety Biomarkers and Translation to Clinical

Testing: Current Perspectives

Malcolm York, MPhil, Director and Head, Clinical Pathology and Safety

Assessment, GlaxoSmithKline R&D

Significant efforts have been conducted into the analytical validation,

characterization and qualification of safety biomarkers, notably for the

assessment and prediction of cardiac, kidney and liver safety. However,

significant challenges are still evident in the interpretation of toxicity

biomarker signals above defined thresholds, which report apparent injury

(but in the absence of the histopathology) and their relevance for clinical

safety testing. Current perspectives on the measurement and use of toxicity

biomarkers/multiple biomarkers, along with integration with other measures

of biological response, to improve definition of safety margins and riskbenefit

characterization of exploratory new medicines will be discussed.

8:55-9:20 Biomarkers of Acute Kidney Injury: From Pre-Clinical Species

to Human Patients

Jiri Aubrecht, Pharm.D., Ph.D., Senior Director, Safety Biomarker Group Lead,

Drug Safety Research & Development, Pfizer

Acute kidney injury provides a significant challenge to drug development.

Recently, new biomarkers of acute kidney injury have been developed. In this

presentation we will review the recent progress in applying emerging biomarkers

of acute kidney injury across pre-clinical species and human subjects.

9:20-9:45 Preparing for Safety Biomarkers to Support Clinical Trials

Stephen T. Furlong, Ph.D., Safety Science Lead, AstraZeneca Patient Safety

Many new biomarkers are being considered for use in clinical trials to

monitor drug-induced organ toxicity. However, deciding which biomarkers

to use, selecting a vendor to perform the assays, establishing sample

handling protocols, preparing for statistical analysis of the data and

deciding how to use the data all represent significant challenges. This talk

will review these topics, provide examples from specific biomarkers and

provide suggestions for overcoming some of these challenges.

9:45-10:10 Identifying Biomarkers of Kidney and Liver Toxicity by

Integrating Toxicogenomics Datasets with Biological Networks

Philip Hewitt, Ph.D., Head, Early Non-Clinical Safety (Liver and Kidney), Merck Serono

Candidate nephrotoxicity biomarkers were identified by interrogating

profiles from hundreds of publicly available toxicogenomics datasets,

including datasets from the EU PredTox and Japanese TG-GATEs

projects. Application of multiple bioinformatics approaches identified

43 significant candidates. These findings were corroborated by testing

model nephrotoxic compounds using whole genome expression profile

experiments both in vivo and in vitro. This in silico approach greatly

enriched candidates for those likely to be true biomarkers.

10:10-11:00 Coffee Break in the Exhibit Hall with Poster Viewing

Biomarker Collaborations and Consortia

11:00-11:25 From Promise to Progress: An Update on the Biomarkers

Consortium

David Wholley, Director, Biomarkers Consortium, Foundation for the NIH

11:25-11:50 Open Innovation in Biomarker Discovery: Experiences

from Our Grants for Targets and Biomarkers Initiative

Khusru Asadullah, M.D., Vice President and Head, Global Biomarkers, Bayer

HealthCare

To combine expertise Bayer Healthcare has set up a novel open innovation

approach called Grants4Targets. After a review process, grants are

provided to perform focused experiments to further validate the proposed

targets/biomarkers. In addition to financial support, specific know-how on

target validation and drug discovery is provided. Experienced scientists

are nominated as project partners and, depending on the project, tools

or specific models are provided. More than 600 applications have been

received and 77 projects granted so far.

11:50-12:15 pm Biomarker Discovery—The Power of Collaborative

Networks

Duncan McHale, Ph.D., Vice President, Global Exploratory Development, UCB

Pharma

Clinically useful, predictive biomarkers have been very elusive despite

the growth of Big Biology. Individual technology solutions are commonly

touted as being able to identify drug response biomarkers but are rarely

successful. It is likely that to be successful a network of collaborators will

be needed bringing together technology discipline experts with disease

biology experts. A case example is given in rheumatoid arthritis.

12:15-1:45 Enjoy Lunch on Your Own

Track 1: Translational Biomarkers in Drug Development

BiomarkerWorldCongress.com Biomarkers & Diagnostics World Congress | 7

Track 2: Clinical Assay Development

Sunday, May 5

5:00-6:00 pm Conference Pre-Registration

Monday, May 6

7:30-8:30 am Conference Registration and Morning Coffee

8:30-8:40 Welcome Remarks from Conference Director

Julia Boguslavsky, Executive Director, Conferences, Cambridge Healthtech Institute

From Research Biomarkers to Clinical Assays

8:40-8:45 Chairperson’s Opening Remarks

8:45-9:10 Biomarkers and the Quest for Clinical Utility—Obstacles,

Challenges and Opportunities

Steven Gutman, M.D., MBA, Strategic Advisor, Myraqa

Over the past ten years there has been an explosive increase in the number

of biomarker assays available for the study and evaluation of human

disease. To ensure stakeholders are able to use this growing menu of tests

responsibly, there is a compelling need to understand the clinical utility of

these assays. Unfortunately a surprising number of tests are plagued by

inadequate information on clinical utility. This talk will focus on obstacles,

challenges and opportunities for addressing this problem.

9:10-9:35 Clinical Assay Development—The Process and Considerations

Herbert A. Fritsche, Ph.D., Senior Vice President and CSO, Health Discovery Corporation

The process for successful development of a clinical laboratory test begins

with a strict definition of the test concept and its clinical utility; design of an

accurate and robust assay for the analyte; analytical validation followed by

clinical validation; and lastly, translation of the new test from the research

lab to routine clinical use, which includes validation of the new test outside

of the research setting. Success of development is defined as acceptance of

the new test by the medical community as the “standard-of-care.”

9:35-10:00 Bridging Research and “Clinical” Assays in Pharmaceutical

Research & Development

John L. Allinson, FIBMS, Vice President, Biomarker Laboratory Services, ICON

Development Solutions

Many biomarker assays used in drug development are research assays

(i.e., not accredited diagnostic devices). This presentation will look at the

following: basic validation experiments across assays in research and

diagnostics; differences and assay evolution as methods progress through

different uses of results data; the requirements for accreditation of assays to

be used in diagnostics; and a brief look at the development of a companion

diagnostic and its implications from the laboratory perspective.

10:00-10:30 Networking Coffee Break

10:30-10:55 Key Considerations for Choosing and Transitioning a

Research Grade Assay to the Clinical Setting

Tammie C. Yeh, Ph.D., Molecular Biomarkers, Oncology Lead, Merck

Developing a biomarker assay with the clinical perspective in mind is critical to

the success of the biomarker. Identifying/choosing a robust biomarker readout

is as important as developing a robust analytical assay to ensure clinical utility.

It is important to understand the inherent biological variability as well as the

clinical feasibility of a biomarker readout, both of which will depend on tissue

type, tissue processing and the specific clinical setting. Both patient selection

and pharmacodynamic biomarkers will be addressed in this presentation.

10:55-11:20 Clinical Assay Development for Cancer Protein Biomarkers:

What Works and What Does Not Work

Samir Hanash, Ph.D., Program Head, Molecular Diagnostics, Fred Hutchinson

Cancer Research Center

The breadth and depth of proteomics technologies for the discovery of

biomarkers has increased substantially over the past decade, covering

a dynamic range of more than 7 logs in protein abundance. As a result,

numerous cancer biomarker candidates have emerged from discovery

studies. There remains a need for the development of high-throughput

technologies that allow testing the utility of these biomarkers for their

intended clinical application to meet regulatory requirements. Current

opportunities and challenges will be presented.

11:20-11:45 Will Regulation of Laboratory-Developed Tests Stifle Innovation?

Alan Mertz, President, American Clinical Laboratory Association

Laboratory developed tests (LDTs) are regulated by Federal law (CLIA),

state law, and industry standards established by the College of American

Pathologists. For many years, FDA has maintained that LDTs are medical

devices. FDA’s legal authority has been questioned, however, and Congress,

in July 2011, considered legislation that would enhance the CLIA framework

for regulating LDTs. FDA’s work plan for 2013 does not mention new

guidance on LDTs, but remains a possibility. Closing the LDT pathway would

have substantial effects on clinical laboratories, health care providers, and

patients. This presentation will examine the role of LDTs in creating new

tests, diagnosing rare diseases, and including the most up-to-date clinical

information in diagnostic tests.

11:45-1:20 pm Enjoy Lunch on Your Own

NGS in Clinical Use

1:20-1:25 Chairperson’s Remarks

1:25-1:50 College of American Pathologists’ Standards and Proficiency

Testing for Next-Generation Sequencing for the Clinical Laboratory

Nazneen Aziz, Ph.D., Director, Molecular Medicine, Transformation Program

Office, College of American Pathologists

The rapid and ongoing advances in the genetic test market, spurred by the

opportunities of Next-Generation Sequencing (NGS), necessitate many facets

of the health care industry to work cohesively. Adoption of NGS as a clinical test

requires the adoption of many processes and procedures, such as the analytic

and clinical validation of the test, CLIA certification/CAP accreditation, standards

for reference materials, availability for proficiency testing, genetic counseling,

and questions regarding reimbursement, informed consent and incidental

findings. This talk will focus on the laboratory requirements developed at CAP

for CLIA/CAP accreditation and the plans for proficiency testing for NGS.

1:50-2:15 Assuring the Quality of Next-Generation Sequencing in

Clinical Laboratory Practice

Ira M. Lubin, Ph.D., Team Lead, Genetics Laboratory Research and Evaluation

Branch, Division of Laboratory Science and Standards, Laboratory Science,

Policy, and Practice Program Office, Office of Surveillance, Epidemiology, and

Laboratory Services, Centers for Disease Control and Prevention

Integration of next-generation sequencing (NGS) into the clinical laboratory

requires test validation, establishment of quality control procedures, and

the independent assessment of test performance by proficiency testing

or alternate approaches. Existing regulatory requirements and professional

guidance do not adequately address these quality issues for clinical NGS

testing. This talk will describe the outcomes of a national workgroup

organized by the Centers for Disease Control and Prevention tasked to

identify principles and develop guidance to promote good clinical laboratory

practices for NGS and meet regulatory and professional standards.

2:15-2:40 Clinical NGS: Validation, Reporting and Economics

Seth Crosby, M.D., Director, Partnerships & Alliances, Washington University

School of Medicine

As NGS enters the clinic, matters of analytic and clinical validation are just

the start of the medical director’s worries. How should results be quickly

generated and communicated to a physician in a meaningful and actionable

manner? What are the new rules for billing and reimbursement?

2:40-3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

3:40-4:05 Exome Sequencing in a Clinical Setting to Guide Patient Care

Madhuri Hegde, Ph.D., Associate Professor, Human Genetics; Senior Director,

Emory Genetics Laboratory, Emory University

8 | Biomarkers & Diagnostics World Congress BiomarkerWorldCongress.com

Track 2: Clinical Assay Development

Advances in genomic medicine have made it necessary for clinical laboratories

to rapidly implement new technologies to guide patient care. Exome

sequencing is rapidly being implemented across different specialties such as

inherited diseases, cancer and infectious diseases. This talk will focus on the

clinical utility of exome sequencing in patient care with real case examples.

4:05-4:30 Interpreting Clinical Next-Generation Sequencing Data:

Current Challenges and Hope for the Future

Elaine Lyon, Ph.D., Medical Director, Molecular Genetics; Co-Medical Director,

Pharmacogenomics, ARUP Laboratories; Associate Professor, University of Utah

With the complexity of genomic scale sequencing (next-generation

sequencing or NGS) and the massive amounts of data obtained, informatics

is essential. Two challenges in evaluating a variant are 1) is it real and 2)

is it clinically significant. Informatics allow alignment and variant calling

(differences from a reference sequence), and sifting of probable clinically

insignificant variants. More challenging is prioritizing variants that are likely

to be associated with the clinical symptoms. In addition to the symptomguided

analysis approach, NGS data can reveal variants in genes related to

drug metabolism that may affect efficacy or response. This presentation will

discuss approaches to prioritize symptom-related variants as well as the

potential of NGS data for companion diagnostics or therapeutics.

4:30-5:00 Sponsored Presentations

(Opportunities available. Contact Ilana Quigley at 781-972-5457

or iquigley@healthtech.com)

5:00-6:00 Networking Reception in the Exhibit Hall with Poster Viewing

6:00-9:00 Dinner Courses

Fit-for-Purpose Biomarker Assay Development and Validation

Next-Generation Sequencing as a Clinical Test

(Separate registration required. See Page 4 for additional information.)

Tuesday, May 7

7:30-8:15 am Breakfast Presentation Sponsored by

Identifying Non-Invasive Biomarkers of Smoking-

Related Parenchymal Lung Disease (i.e. COPD and

IPF) to Detect Subclinical Lung Disease

Ivan O. Rosas, M.D., Assistant Professor, Medicine Division, Pulmonary &

Critical Care Medicine, Brigham & Women’s Hospital, Harvard Medical School

Choosing a Platform for Companion Diagnostics

8:25-8:30 Chairperson’s Opening Remarks

8:30-8:55 Validating Biomarker Assays as a Prelude to Companion

Diagnostic Development: Emerging Platform-Specific Considerations

Michael Burczynski, Ph.D., Executive Director, Biomarker Technologies, Discovery

Medicine and Clinical Pharmacology, Bristol-Myers Squibb

Timely implementation of companion diagnostics alongside therapeutic

products has amplified the need to validate predictive biomarkers in earlier

phases of drug development. Today, biomarker strategies are more complex

and require more diverse platforms than ever before. Ensuring that analytical

validation strategies for these exploratory predictive biomarker assays

are aligned with the downstream requirements for full-blown companion

diagnostic development is a critical activity that ultimately helps determine

the efficiency with which targeted medicines can be brought to market.

8:55-9:20 Choosing a Platform for Companion Diagnostic Development

Ron Mazumder, Ph.D., MBA, Global Head, Research and Product Development,

Janssen Diagnostics, Janssen Pharmaceutical Companies of Johnson & Johnson

One of the early considerations in developing a companion diagnostic is

choice of platform. Several factors, such as technical performance, regulatory

and reimbursement path, and commercial access will be discussed in this

context. Examples from the literature and case studies will be presented.

9:20-9:45 Thoughts and Considerations for Choosing a Companion

Diagnostic Technology and Platform Delivery System

Patrick Groody, Ph.D., Divisional Vice President, Research & Development, Abbott

Choosing a diagnostic technology and testing platform for the

development of a companion diagnostic test can be a significant challenge.

A wide variety of factors including the development time, capabilities of

potential partners and the ability of laboratories and physicians to access

and perform the test routinely in a clinical setting are key factors in

developing a companion diagnostic program. This talk will focus on variety

of strategies for developing commercial companion diagnostic tests.

9:45-10:00 Sponsored Presentation

(Opportunity available. Contact Ilana Quigley at 781-972-5457

or iquigley@healthtech.com)

10:00-11:00 Coffee Break in the Exhibit Hall with Poster Viewing

Multiplexed Assays

11:00-11:25 Measurement of Telomere Repeats in Human Cancer Cell Lines

and Tissues Using a Monochrome Multiplex Quantitative PCR Assay

Daniel Edelman, Ph.D., Facility Head, Clinical Molecular Profiling Core, National

Cancer Institute, NIH

This talk will describe our efforts for the development and validation of a

QPCR multiplex assay to enable the quantitation of overall telomere length

(TL) in cancerous cell lines and tissues. A TL pattern between cancers

might provide valuable diagnostic or prognostic information to promote

a better understanding of the molecular or pathogenic characteristics of

specific cancer types.

11:25-11:50 Multiplexed Immunoassays on Formalin-Fixed, Paraffin-

Embedded Tissue Homogenates as Cancer Diagnostics

Geoffrey Stuart Baird, M.D., Ph.D., Assistant Professor, Laboratory Medicine,

University of Washington

Multiplex immunoassays (MIs) performed on formalin-fixed, paraffinembedded

(FFPE) tissue homogenates offer several advantages

over immunohistochemistry as cancer diagnostics. In contrast to

immunohistochemistry, MIs offer absolute quantitation and improved

sensitivity and specificity through the use of sandwich assay geometries.

Moreover, MI instrumentation has already been adopted in the clinical

laboratory, and is much less expensive than a mass spectrometer. MIs have

been validated as a clinical diagnostic for pituitary adenoma classification in

FFPE tissue, with current work focused on breast carcinoma.

11:50-12:05 pm Diagnostic Classifiers for the Detection Sponsored by

of Bladder Cancer

Mark Ruddock, Ph.D., Team Leader, Molecular Biology, Randox

Pharma Services

Patients presenting with hematuria require investigations, including

cystoscopy and imaging of their upper urinary tracts, to identify the source

of bleeding. This is a significant health burden, which is set to increase

because of our aging population. Using biochip array technology, we have

identified diagnostic classifiers for detecting bladder cancer.

12:05-12:30 Development of Multiplexed Protein Pathway Activation

Mapping Clinical Assays for Personalized Cancer Therapy

Emanuel Petricoin III, Ph.D., Co-Director, The Center for Applied Proteomics and

Molecular Medicine, George Mason University

Cellular signaling pathways are a protein-based network, and the intended

drug effect is to disrupt aberrant protein phosphorylation-based enzymatic

activity, and epigenetic phenomena. The reverse-phase protein microarray

platform provides detailed information about the state of the cellular

“circuitry” from small samples. Measurements of dozens to hundreds of

specific phosphorylated proteins that represent most of the targets for

targeted therapeutics can be obtained at once from only a few thousand

cells. This information helps select specific therapy(ies) tailored to the

patient’s tumor activated protein “circuitry.”

12:30-1:45 Enjoy Lunch on Your Own

BiomarkerWorldCongress.com Biomarkers & Diagnostics World Congress | 9

Track 3: Cancer Tissue Diagnostics

Sunday, May 5

5:00-6:00 pm Conference Pre-Registration

Monday, May 6

7:30-8:30 am Conference Registration and Morning Coffee

8:30-8:40 Welcome Remarks from Conference Director

Julia Boguslavsky, Executive Director, Conferences, Cambridge Healthtech Institute

Whole-Slide Imaging and Digital Pathology

8:40-8:45 Chairperson’s Opening Remarks

8:45-9:10 Validation of Whole Slide Imaging in Pathology

Liron Pantanowitz, M.D., Associate Professor, Pathology and Biomedical

Informatics, University of Pittsburgh Medical Center

Validation of whole slide imaging (WSI) is important to ensure that digitized

slides are at least equivalent to that of glass slides. The College of American

Pathologists (CAP) Pathology and Laboratory Quality Center convened a

panel to recommend validation requirements for WSI systems to be used

for clinical diagnostic purposes employing a combination of evidence-based

evaluation of the literature, expert consensus and public commentary. The

recommendations are comprehensive and address technical, interpretation

components and administrative issues related to WSI in pathology providing

practical guidance for all types of laboratories who are using or plan to

utilize WSI systems for diagnostic clinical work. This session will educate

participants about WSI in pathology, the regulatory issues surrounding digital

pathology, and review the validation guidelines developed by the CAP.

9:10-9:35 New Applications Utilizing Whole Slide Digital Imaging

for Anatomic Pathology Inter- and Intra-Lab Peer Review and

Benchmarking Quality Assurance

Mark Priebe, MT(ASCP)SBB, Managing Director, QualityStar Quality Consortium

Although application of Whole Slide Digital Imagining (WSI) for primary

diagnosis is limited by the FDA at this time, WSI is a significant enabling

technology for anatomic pathology (AP) quality assurance (QA) initiatives

both inter- and intra-laboratory. This presentation will review current AP/

QA programs and the application of WSI to a novel approach of gaining

longitudinal benchmarking data for quality review. The presentation

will focus on understanding design requirements for development and

implementation, investment requirements, confidentiality considerations

and methods to encourage pathologist participation and acceptance.

9:35-10:00 Label-Free Infrared Spectral Histopathology: Diagnostics and

Prognostics

Max Diem, Ph.D., Professor, Chemistry and Chemical Biology, Northeastern University

Infrared spectral histopathology is a method in which the biochemical

composition of a histopathological sample is used, rather than

morphometric criteria, to diagnose disease. To this end, thousands of

infrared spectra are collected from pixels about 10 μm on edge, and

analyzed to produce spectral images that detect abnormality based on

variations in composition. The accuracy of this method is comparable to

multi-panel immunohistochemistry.

10:00-10:30 Networking Coffee Break

10:30-10:55 Tumor Heterogeneity Assessed by Immunohistochemistry

of Multiplexed Protein Biomarkers

Steve Schmechel, M.D., Ph.D., Associate Professor, Pathology, University of

Washington School of Medicine

Intratumoral heterogeneity of protein expression may be linked to the

biological aggressiveness of tumors and selection of therapies. Analytical

and statistical methods to quantify heterogeneity are needed, particularly

for multiplexed assays. This presentation will discuss novel methods to

measure tumor heterogeneity.

10:55-11:20 Application of WSI in Consensus Review for Clinical Trials

Stephen M. Hewitt, M.D., Ph.D., Clinical Investigator, Laboratory of Pathology,

National Cancer Institute, NIH

Whole Slide Imaging is an enabling technology within pathology, altering all

aspects of current practice. Consensus review processes for clinical trials have

previously been expensive, slow, and complicated by issues of reproducibility.

Whole Slide Imaging and distributed review overcome many of these issues,

and provide new opportunities that have previously not been feasible.

11:20-11:50 Sponsored Presentations

(Opportunities available. Contact Ilana Quigley at 781-972-5457

or iquigley@healthtech.com)

11:50-1:20 pm Enjoy Lunch on Your Own

NGS in Clinical Use

1:20-1:25 Chairperson’s Remarks

1:25-1:50 College of American Pathologists’ Standards and Proficiency

Testing for Next-Generation Sequencing for the Clinical Laboratory

Nazneen Aziz, Ph.D., Director, Molecular Medicine, Transformation Program

Office, College of American Pathologists

The rapid and ongoing advances in the genetic test market, spurred by the

opportunities of Next-Generation Sequencing (NGS), necessitate many

facets of the health care industry to work cohesively. Adoption of NGS as

a clinical test requires the adoption of many processes and procedures,

such as the analytic and clinical validation of the test, CLIA certification/CAP

accreditation, standards for reference materials, availability for proficiency

testing, genetic counseling, and questions regarding reimbursement,

informed consent and incidental findings. This talk will focus on the

laboratory requirements developed at CAP for CLIA/CAP accreditation and

the plans for proficiency testing for NGS.

1:50-2:15 Assuring the Quality of Next-Generation Sequencing in

Clinical Laboratory Practice

Ira M. Lubin, Ph.D., Team Lead, Genetics Laboratory Research and Evaluation

Branch, Division of Laboratory Science and Standards, Laboratory Science,

Policy, and Practice Program Office, Office of Surveillance, Epidemiology, and

Laboratory Services, Centers for Disease Control and Prevention

Integration of next-generation sequencing (NGS) into the clinical laboratory

requires test validation, establishment of quality control procedures, and

the independent assessment of test performance by proficiency testing

or alternate approaches. Existing regulatory requirements and professional

guidance do not adequately address these quality issues for clinical NGS

testing. This talk will describe the outcomes of a national workgroup

organized by the Centers for Disease Control and Prevention tasked to

identify principles and develop guidance to promote good clinical laboratory

practices for NGS and meet regulatory and professional standards.

2:15-2:40 Clinical NGS: Validation, Reporting and Economics

Seth Crosby, M.D., Director, Partnerships & Alliances, Washington University

School of Medicine

As NGS enters the clinic, matters of analytic and clinical validation are just

the start of the medical director’s worries. How should results be quickly

generated and communicated to a physician in a meaningful and actionable

manner? What are the new rules for billing and reimbursement?

2:40-3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

3:40-4:05 Exome Sequencing in a Clinical Setting to Guide Patient Care

Madhuri Hegde, Ph.D., Associate Professor, Human Genetics; Senior Director,

Emory Genetics Laboratory, Emory University

Advances in genomic medicine have made it necessary for clinical

laboratories to rapidly implement new technologies to guide patient care.

Exome sequencing is being rapidly being implemented across different

specialties such as inherited diseases, cancer and infectious diseases. This

talk will focus on the clinical utility of exome sequencing in patient care

with real case examples.

10 | Biomarkers & Diagnostics World Congress BiomarkerWorldCongress.com

Track 3: Cancer Tissue Diagnostics

4:05-4:30 Interpreting Clinical Next-Generation Sequencing Data:

Current Challenges and Hope for the Future

Elaine Lyon, Ph.D., Medical Director, Molecular Genetics; Co-Medical Director,

Pharmacogenomics, ARUP Laboratories; Associate Professor, University of Utah

With the complexity of genomic scale sequencing (next-generation

sequencing or NGS) and the massive amounts of data obtained, informatics

is essential. Two challenges in evaluating a variant are 1) is it real and 2)

is it clinically significant. Informatics allow alignment and variant calling

(differences from a reference sequence), and sifting of probable clinically

insignificant variants. More challenging is prioritizing variants that are likely

to be associated with the clinical symptoms. In addition to the symptomguided

analysis approach, NGS data can reveal variants in genes related to

drug metabolism that may affect efficacy or response. This presentation will

discuss approaches to prioritize symptom-related variants as well as the

potential of NGS data for companion diagnostics or therapeutics.

4:30-5:00 Sponsored Presentations

(Opportunities available. Contact Ilana Quigley at 781-972-5457

or iquigley@healthtech.com)

5:00-6:00 Networking Reception in the Exhibit Hall with Poster Viewing

6:00-9:00 Dinner Courses

Fit-for-Purpose Biomarker Assay Development and Validation

Next-Generation Sequencing as a Clinical Test

(Separate registration required. See Page 4 for additional information.)

Tuesday, May 7

7:30-8:15 am Breakfast Presentation Sponsored by

Identifying Non-Invasive Biomarkers of Smoking-

Related Parenchymal Lung Disease (i.e. COPD and

IPF) to Detect Subclinical Lung Disease

Ivan O. Rosas, M.D., Assistant Professor, Medicine Division, Pulmonary &

Critical Care Medicine, Brigham & Women’s Hospital, Harvard Medical School

Advances in Immunohistochemistry:

Guiding Therapy Decisions

8:25-8:30 Chairperson’s Opening Remarks

8:30-8:55 Quality Assurance/Quality Control for Immunohistochemistry

in the Era of Personalized Medicine

Emina Torlakovic, M.D., Ph.D., Associate Professor, Laboratory Medicine and

Pathobiology, University of Toronto

Immunohistochemistry (IHC) enables in situ detection of protein expression

(right tissue, right cells, right cellular compartment) and evaluation of expression

levels. Biomarker discovery increases demands on biomarker testing by IHC.

IHC incorporates >20 parameters and requires expert interpretation. Key

challenges include clinical trial study design, tissue processing parameters

and parameters related to expert interpretation. IHC testing challenges remain

significant due to widely spread lack of awareness that IHC QA/QC needs to

evolve to match IHC intended use in personalized medicine.

8:55-9:20 Detection of ALK Gene Rearrangement (ALK+) in Non-Small

Cell Lung Cancers

Eunhee S. Yi, M.D., Consultant, Anatomic Pathology, Mayo Clinic; Professor,

Pathology, Mayo Clinic College of Medicine

Currently, ALK FISH is regarded as the gold standard to select the ALK+

patients eligible for crizotinib therapy, and FISH confirmation is required for

“on-label” crizotinib treatment. ALK IHC can be useful to limit the number

of patients to be tested for ALK FISH by identification of a high probability

population whose tumors are likely to be ALK+. Current status of ALK IHC will

be reviewed along with the data from a molecular study on discordant cases

for ALK status by ALK IHC and FISH in a Mayo Clinic Lung Cancer Cohort.

9:20-9:45 Molecular Profiling and Immunohistochemistry: The Interface

for Identification of Tissue of Origin in Occult Primary Cancers

Charles R. Handorf, M.D., Ph.D., Professor and Chair, Pathology and Laboratory

Medicine, University of Tennessee

Metastatic tumors with an uncertain primary site can be a difficult clinical

problem. In thousands of patients every year, no confident diagnosis is ever

issued making standard-of-care treatment difficult. Newer gene expression

profiling (GEP) tests currently available to analyze these difficult-to-diagnose

tumors are now being compared head-to-head with immunochemistry (IHC),

which has long been held as a gold standard. The interface between these

techniques will be discussed and practical approaches will be explored.

9:45-10:00 Sponsored Presentation

(Opportunity available. Contact Ilana Quigley at 781-972-5457

or iquigley@healthtech.com)

Tissue Biomarkers for Targeted Therapy

10:00-11:00 Coffee Break in the Exhibit Hall with Poster Viewing

11:00-11:25 In situ Measurement of Tissue Biomarkers for Companion

Diagnostics in Cancer

Kurt A. Schalper, M.D., Ph.D., Associate Research Scientist, Pathology, Yale

School of Medicine

Measurement of tissue biomarkers has been shown to be a valuable tool

for companion diagnostics and is an essential component of personalized

cancer medicine. Several technical limitations surround commonly used

testing methods. In situ measurement of protein and mRNA transcripts

using automated quantitative immunofluorescence and novel hybridization

techniques provides increased sensitivity, specificity and reproducibility.

More quantitative approaches could open new opportunities for biomarker

discovery and patient selection for anti-cancer treatments.

11:25-11:50 Biomarkers and Targeted Therapy for Kaposi Sarcoma

Liron Pantanowitz, M.D., Associate Professor, Pathology and Biomedical

Informatics, University of Pittsburgh Medical Center

Kaposi sarcoma (KS) is an enigmatic vascular neoplasm that arises from

the initial infection of an endothelial or progenitor cell by Kaposi Sarcoma

Herpesvirus/Human Herpesvirus-8 (KSHV/HHV8). KS represents an ideal

model to investigate the interplay between viral oncogenesis, angiogenesis

and host immunity. The discovery of KSHV and related data about the

pathogenesis of KS has resulted in the identification of multiple novel

therapeutic targets. This talk will educate participants about KS biomarkers

being applied for diagnostic work, and also address newer therapeutic

agents aimed at molecular targets being evaluated in clinical trials.

11:50-12:15 pm Access to Human Tissue in the Age of Targeted

Therapies—Impact on Patient Care and Drug Development

Carol Cheung, M.D., Ph.D., Department of Pathology, Canadian University Health

Network

Access to human tissue is paramount in this age of targeted therapies.

Demand for this biological substrate, which is necessary for development

of innovative new tests and potentially blockbuster new therapies, is ever

increasing. The distinction between the two broad classes of excised human

tissue, research tissue that resides in research biobanks and diagnostic

tissue that resides in the clinical archives of institutional departments of

pathology, is important because the rules governing access differ depending

on this fundamental classification.

12:15-1:45 Enjoy Lunch on Your Own

BiomarkerWorldCongress.com Biomarkers & Diagnostics World Congress | 11

Track 4: Executive Summit: Companion Diagnostics

Sunday, May 5

5:00-6:00 pm Conference Pre-Registration

Monday, May 6

7:30-8:30 am Conference Registration and Morning Coffee

8:30-8:40 Welcome Remarks from Conference Director

Julia Boguslavsky, Executive Director, Conferences, Cambridge Healthtech Institute

Commercialization of Companion Diagnostics

8:40-8:45 Chairperson’s Opening Remarks

8:45-9:10 Companion Diagnostic Success: Biomarker Discovery to

Global Commercialization

Chris Jowett, General Manager, Commercial Operations, Abbott Molecular

Developing a successful global commercialization strategy for a companion

diagnostic can be a significant challenge. Critical capability factors need

to be discussed prior to entering into the partnership to minimize risk.

Understanding the IVD manufacturers’ capabilities to develop, manage the

required clinical trials, navigate the regulatory environment for approval,

and drive sales and marketing efforts in all targeted countries for the

therapeutic launch is essential. This talk will focus on a variety of strategies

to support a successful launch of a companion diagnostic program.

9:10-9:35 The Payor’s Role in Personalized Medicine

Carol S. Palackdharry, M.D., MS, Medical Director, ActiveHealth Management;

Clinical Lead, Oncology Condition Analysis, Aetna

Targeted cancer treatment is already changing the standard of care for many

cancers. Personalized therapies are costly and generally have anti-tumor activity

only in patients with the specific targeted abnormality. Most targeted agents

require pre-certification, with coverage dependent on appropriate results on

approved companion diagnostic tests. Development of rigorous, evidencebased

recommendations for usage of such tests, as well as new contracting

strategies with high-quality laboratories, will avoid wasted expenditures and

assure access to personalized therapies for all qualified patients.

9:35-10:00 Meeting Evidence Demands for Diagnostics in an Evolving

Payment Environment

Andrew C. Fish, Executive Director, AdvaMedDx

Payer reimbursement of diagnostics is critical to ensuring a robust

market for innovation. As advanced molecular diagnostics proliferate, a

growing appreciation of the importance of these tests is tempered by

rising payer concerns about coding transparency, evidence of clinical

utility, and utilization of and payment for these tests. This talk will review

the reimbursement challenges faced by test developers and initiatives

underway by payers and in Congress to address those challenges.

10:00-10:30 Networking Coffee Break

10:30-10:55 Creating a Companion Diagnostic Regulatory Strategy:

Biomarker to Commercial Test

Debra Rasmussen, Senior Director, Regulatory Affairs, Johnson & Johnson

Validated biomarkers (diagnostic tests) that can serve as intermediate or

surrogate endpoints to acquire rapid regulatory approval are needed to

help move research into the clinic. This is especially true if such biomarkers

could be measured easily, rapidly and were generally accessible.

Pharmaceutical companies could gain from biomarkers and diagnostic

co-development efforts. In an increasingly challenging regulatory

environment, diagnostic led treatment can improve the chance that drugs

are reimbursed or approved in the first place. As companion diagnostics

these could also potentially identify patient benefits from a novel

therapeutic strategy earlier, assist in early discontinuation of ineffective

strategies, and identify active drugs more efficiently. New concerns could

include: 1) designing a definitive clinical study for a joint therapeutic–

diagnostic that allows for assessment of the therapeutic’s safety and

efficacy, as well as for validation of the clinical utility of the biomarker

guiding the therapeutic’s use or 2) regulatory bodies requiring a diagnostic

test before a prescription may be written for a patient.

10:55-11:25 Sponsored Presentations

(Opportunities available. Contact Ilana Quigley at 781-972-5457

or iquigley@healthtech.com)

11:25-11:50 Panel Discussion: Strategies for Regulatory and

Reimbursement Challenges in Commercialization of CDx

Panelists:

Chris Jowett, General Manager, Commercial Operations, Abbott Molecular

Carol S. Palackdharry, M.D., MS, Medical Director, ActiveHealth Management;

Clinical Lead, Oncology Condition Analysis, Aetna

Debra Rasmussen, Senior Director, Regulatory Affairs, Johnson & Johnson

Andrew C. Fish, Executive Director, AdvaMedDx

11:50-1:20 pm Enjoy Lunch on Your Own

Strategies for Rx-Dx Partnerships

1:20-1:25 Chairperson’s Remarks

1:25-1:50 Synchronizing Drug Development and Companion

Diagnostics: Challenges and Solutions

Hakan Sakul, Ph.D., Executive Director and Head, Diagnostics, Worldwide R&D,

Clinical Research and Precision Medicine, Pfizer

Last year witnessed simultaneous regulatory approvals of Rx and Dx and

it is expected that such approvals will be more commonplace in the near

future. Synchronizing the drug development phases with those for Dx

development presents many challenges. This talk will attempt to outline

these challenges and offer solutions based on the Xalkori Rx/Dx program.

1:50-2:15 Managing Pharma/Diagnostic Partnerships in Companion

Diagnostic Development

George A. Green IV, Ph.D., Director, Pharmacodiagnostics, Bristol-Myers Squibb

The development of CDx assays minimally requires a partnership between a

pharmaceutical and a diagnostic company. It is not uncommon for the drug

to be developed through an alliance of two pharmaceutical companies, and

diagnostic assay development programs may include separate companies

for design of the assay and development of the platform. To ensure effective

delivery of the CDx within this complex environment, highly matrixed teams

must be formed to address strategic and technical issues, and to deliver a

quality product coordinated with the drug development schedule.

2:15-2:40 Presentation to be Announced

2:40-3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

3:40-4:10 Key Considerations for Selecting a Diagnostic Sponsored by

Partner in Rx-Dx Program Commercialization

Jeremy Bridge-Cook, Ph.D., Senior Vice President, Research &

Development, Luminex

What are the optimal capabilities and expertise required of diagnostic

partners for the development and commercialization of companion

diagnostic devices? Key considerations include prototype assay

development, analytical and clinical validation, regulatory filing, approval

and market launch. The speaker will discuss how each of these elements

can impact the success of a companion diagnostic program.

4:10-4:25 Sponsored Presentation

(Opportunity available. Contact Ilana Quigley at 781-972-5457

or iquigley@healthtech.com)

12 | Biomarkers & Diagnostics World Congress BiomarkerWorldCongress.com

Track 4: Executive Summit: Companion Diagnostics

4:25-5:00 Panel Discussion: Strategies for Initiating and Managing

Successful Rx-Dx Partnerships

Panelists:

Hakan Sakul, Ph.D., Executive Director and Head, Diagnostics, Worldwide R&D,

Clinical Research and Precision Medicine, Pfizer

George A. Green IV, Ph.D., Director, Pharmacodiagnostics, Bristol-Myers Squibb

Panelist to be Announced

5:00-6:00 Networking Reception in the Exhibit Hall with Poster Viewing

6:00-9:00 Dinner Courses

Fit-for-Purpose Biomarker Assay Development and Validation

Next-Generation Sequencing as a Clinical Test

(Separate registration required. See Page 4 for additional information.)

Tuesday, May 7

7:30-8:15 am Breakfast Presentation Sponsored by

Identifying Non-Invasive Biomarkers of Smoking-

Related Parenchymal Lung Disease (i.e. COPD and

IPF) to Detect Subclinical Lung Disease

Ivan O. Rosas, M.D., Assistant Professor, Medicine Division, Pulmonary &

Critical Care Medicine, Brigham & Women’s Hospital, Harvard Medical School

Choosing a Platform for Companion Diagnostics

8:25-8:30 Chairperson’s Opening Remarks

8:30-8:55 Validating Biomarker Assays as a Prelude to Companion

Diagnostic Development: Emerging Platform-Specific Considerations

Michael Burczynski, Ph.D., Executive Director, Biomarker Technologies,

Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb

Timely implementation of companion diagnostics alongside therapeutic

products has amplified the need to validate predictive biomarkers in earlier

phases of drug development. Today, biomarker strategies are more complex

and require more diverse platforms than ever before. Ensuring that analytical

validation strategies for these exploratory predictive biomarker assays

are aligned with the downstream requirements for full-blown companion

diagnostic development is a critical activity that ultimately helps determine

the efficiency with which targeted medicines can be brought to market.

8:55-9:20 Choosing a Platform for Companion Diagnostic Development

Ron Mazumder, Ph.D., MBA, Global Head, Research and Product Development,

Janssen Diagnostics, Janssen Pharmaceutical Companies of Johnson &

Johnson

One of the early considerations in developing a companion diagnostic

is choice of platform. Several factors, such as technical performance,

regulatory and reimbursement path, and commercial access will be

discussed in this context. Examples from the literature and case studies

will be presented.

9:20-9:45 Thoughts and Considerations for Choosing a Companion

Diagnostic Technology and Platform Delivery System

Patrick Groody, Ph.D., Divisional Vice President, Research & Development,

Abbott

Choosing a diagnostic technology and testing platform for the

development of a companion diagnostic test can be a significant challenge.

A wide variety of factors including the development time, capabilities of

potential partners and the ability of laboratories and physicians to access

and perform the test routinely in a clinical setting are key factors in

developing a companion diagnostic program. This talk will focus on variety

of strategies for developing commercial companion diagnostic tests.

9:45-10:00 Sponsored Presentation

(Opportunity available. Contact Ilana Quigley at 781-972-5457

or iquigley@healthtech.com)

10:00-11:00 Coffee Break in the Exhibit Hall with Poster Viewing

11:00-12:00 pm Panel Discussion: Next-Generation CDx Platforms

Panelists:

Michael Burczynski, Ph.D., Executive Director, Biomarker Technologies,

Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb

Ron Mazumder, Ph.D., MBA, Global Head, Research and Product Development,

Janssen Diagnostics, Janssen Pharmaceutical Companies of Johnson & Johnson

Elaine Lyon, Ph.D., Medical Director, Molecular Genetics; Co-Medical Director,

Pharmacogenomics, ARUP Laboratories; Associate Professor, University of Utah

Patrick Groody, Ph.D., Divisional Vice President, Quality Assurance and

Operations, Abbott

12:00-1:45 Enjoy Lunch on Your Own

Biomarkers to Diagnostics

1:45-1:50 Chairperson’s Remarks

1:50-2:15 Investing in Biomarkers and Turning Them into Diagnostics

Felix Frueh, Entrepreneur-in-Residence, Third Rock Ventures

The translation of biomarkers into useful clinical diagnostics requires the

demonstration of clinical benefit and cost effectiveness. Investing in new

technology is not sufficient without the realization that discovery and

development of a new biomarker needs to include the demonstration that

the biomarker makes a difference in clinical outcomes or decision-making,

preferably tested in the environment in which ultimately a diagnostic will

be used.

2:15-2:40 From Biomarker Research to Diagnostic Development—Our

Challenges

Yoshi Oda, Ph.D., President, Biomarkers and Personalized Medicine Core

Function Unit, Eisai

Biomarkers play important roles for drug development as a part of

translational research. Several examples about biomarkers for 1) the

evidence of target engagement, 2) patient stratification, 3) drug efficacy

and 4) disease diagnostics will be discussed.

2:40-3:45 Refreshment Break in the Exhibit Hall with Poster Viewing

Timeline for CDx Development

3:45-3:50 Chairperson’s Remarks

3:50-4:15 Timeline Considerations for Incorporating a Companion

Diagnostic into the Drug Development Process

Luigi Catanzariti, Ph.D., Executive Director and Global Program Director,

Diagnostics, Novartis

Rx/Dx co-development provides new opportunities for Pharma with respect to

targeted therapeutics. It also comes with considerable clinical, technical and

regulatory challenges. While both drug and diagnostic development processes

have their own rules and regulations, this new codependency requires

significant adjustments in what can be considered quintessentially clinical

(Rx) and technical (Dx) development cultures. Mutual understanding and

integration of both cultures early in the development process is an important

aspect for minimizing development timelines and achieving success.

4:15-4:40 Nothing Ventured, Nothing Gained: The Timeline Challenge

for Companion Diagnostics

Scott Patterson, Ph.D., Executive Director, Medical Sciences, Amgen

The identification of patients who are most likely to benefit from therapy

is an important component of any drug development strategy. Other

than when the target of the therapeutic is also the diagnostic for patient

selection, the generation of evidence to test a biomarker patient selection

hypothesis occurs during the drug development process. That data may

not become available until late in the development process. Strategies that

could be pursued to address this issue, with examples, will be presented.

BiomarkerWorldCongress.com Biomarkers & Diagnostics World Congress | 13

Track 4: Executive Summit: Companion Diagnostics

4:40-5:05 Strategic and Computational Considerations in

Development of Complex Companion Diagnostics

Amir Handzel, Ph.D., Associate Director, Translational and Clinical Sciences, OSI

Pharma (Astellas)

Successful development of CDx requires special attention to diverse

factors, as well as to their seamless integration. These challenges in

developing validated complex diagnostic biomarkers have been highlighted

by several failures in the last decade. The universe of molecular entities

from which markers can be chosen is rich, comprising genetic mutations,

the transcriptome, proteins and emerging non-coding RNA and epigenetic

entities. Their extremely large numbers present difficult problems of

selection and validation in a statistically robust and consistent way.

In order to address them, an array of technical, as well as operational

and organizational approaches must be employed. For example, the

characteristics of the experimental platforms used to acquire data

influence biomarker selection and design and these in turn necessitate a

multidisciplinary team structure. I will discuss these strategic and technical

elements while pointing to pitfalls and how to avoid them to reach the

desired goal.

5:05-5:30 Companion Diagnostics: Challenges in Bridging the Chasm

between Diagnostics and Drugs

Steven Gutman, M.D., MBA, Strategic Advisor, Myraqa

An IVD companion diagnostic device is an in vitro diagnostic device

that provides information essential for the safe and effective use of a

corresponding therapeutic product. This pairing of products has generated

intense interest because 1) it offers a clear model for the implementation

of personalized health care and 2) it may contribute to more informed

choices about how to manage the pipeline for new drugs. This talk will

focus on potential roadmaps for use in drug-diagnostic co-development.

6:00-9:00 Dinner Course

Laboratory-Developed Tests

(Separate registration required. See Page 4 for additional information.)

Wednesday, May 8

7:30-8:15 am Breakfast Presentation or Morning Coffee

(Sponsorship opportunity available. Contact Ilana Quigley at 781-972-5457

or iquigley@healthtech.com)

Advancing Personalized Medicine

8:25-8:30 Chairperson’s Opening Remarks

8:30-8:55 Personalized Health Care: ‘One Size Does Not Fit All’ Applies

to Patients and Products

M.J. Finley Austin, Ph.D., Personalized Healthcare & Biomarker Strategy

Director, AstraZeneca

The essence of Personalized Health Care (PHC) is identifying,

understanding and partioning drug response variation to improve clinical

outcomes. Existing PHC examples demonstrate diversity in source of

variation, path to market as well as market delivery and uptake. Current

examples will be used to elucidate the implications of differing sources

and degrees of variation, clinical utility, and timing of discovery all have for

clinical trial design, regulatory strategy and market delivery.

8:55-9:20 Molecular Subtyping of Patients for Drug Development

Eric Lai, Ph.D., Senior Vice President and Head, Pharmacogenomics, Takeda

Pharmaceuticals International

While the concept of drug-diagnostic co-development (CDx) has been

around for awhile, most companion diagnostics are still an afterthought

and not an integrated component of drug development. To benefit from

the full potential of CDx, we have to change the strategy of drug target

identification from the single target approach to systematic understanding

of a patient’s disease phenotypes. I will discuss some of the potentials

steps that we have made to the drug development process.

9:20-9:45 Co-Diagnostics in Autoimmune Disorders: Improving

Outcomes in RA and IBD

Mark E. Curran, Ph.D., Vice President, Immunology Biomarkers, Janssen

Research & Development

Rheumatoid arthritis and inflammatory bowel disease are severe immune

diseases with significantly reduced quality of life for patients. Despite

advances in treatment with the evolution of antibody and recombinant

protein based therapeutics, there remains a significant unmet clinical need

for new therapies and integrated treatment solutions. At Janssen we are

focused on transforming therapy in these diseases by applying systems

pharmacology, precision medicine principles and developing companion

diagnostics to create new treatment paradigms. Our objective is to

provide for higher response rates, deeper remission, early interception and

eventually prevention of these diseases. Progress toward these objectives

will be discussed.

9:45-10:15 Complex microRNA Signatures of Response Sponsored by

and Resistance as Powerful Biomarkers

E. Robert Wassman, M.D., CMO, Rosetta Genomics

10:15-10:30 Sponsored Presentation

(Opportunity available. Contact Ilana Quigley at 781-972-5457

or iquigley@healthtech.com)

10:30-11:30 Coffee Break in the Exhibit Hall with Poster Viewing

11:30-11:55 Precision Medicine: Triumphs and Tribulations

Claudio Carini, M.D., Global Clinical Immunology and Biomarkers Lead,

Bioenhancement Development Unit, Pfizer

The current model for drug development is failing. Failures often occur

either during the phase II trials, where either the candidate drug did not

meet the expected pharmacological requirements or the targeted drug

mechanism did not play a role in the patients population studied. Thus,

a new “personalized medicine” strategy is needed to develop predictive

biomarkers to assist in the decision making process during the pre-clinical

phase of drug development and use biomarkers as companion diagnostics

for stratifying patients in hypothesis-driven clinical trials.

11:55-12:20 pm Towards Personalized Medicine in Metabolic Diseases

Mark Broenstrup, Ph.D., Director, Biomarker and Diagnostics, R&D Diabetes

Division, Sanofi

Currently, more than 346 million people worldwide have diabetes. The

identification of the most effective drug(s) for the individual patient

is guided by a few selection criteria and a trial-and-error approach.

Consequently, the introduction of personalized approaches, accounting

for the heterogeneity of the disease, is regarded as a key enabler for

improved health care. An overview on biomarkers for assessing risk,

monitoring disease progression and predicting response to drugs is

provided, with a focus on beta cell imaging and systems biology solutions.

Finally, major public-private partnerships aiming at personalized solutions in

diabetes will be highlighted.

12:20-12:45 Translating Molecular Targets for Cancer Therapeutics

Glen J. Weiss, M.D., Co-Head, Lung Cancer Unit, The Translational Genomics

Research Institute (TGen); Director, Clinical Research, Cancer Treatment

Centers of America; CMO, CRAB-Clinical Trials Consortium

The presentation will focus on why there is a push to individualize cancer

therapy, past failures and successes, and how to define the tumor context

of vulnerability (COV). The talk will also describe the steps from pre-clinical

to new drug application and show how to optimize the drug development

path with knowledge of biomarker-based COV.

12:45 Close of Conference

14 | Biomarkers & Diagnostics World Congress BiomarkerWorldCongress.com

Track 5: Biomarkers for Patient Selection

tuesday, May 7

12:15-1:45 Conference Registration

Biomarkers to Diagnostics

1:45-1:50 Chairperson’s Opening Remarks

1:50-2:15 Investing in Biomarkers and Turning Them into Diagnostics

Felix Frueh, Entrepreneur-in-Residence, Third Rock Ventures

The translation of biomarkers into useful clinical diagnostics requires the

demonstration of clinical benefit and cost effectiveness. Investing in new

technology is not sufficient without the realization that discovery and

development of a new biomarker needs to include the demonstration that the

biomarker makes a difference in clinical outcomes or decision-making, preferably

tested in the environment in which ultimately a diagnostic will be used.

2:15-2:40 From Biomarker Research to Diagnostic Development—Our

Challenges

Yoshi Oda, Ph.D., President, Biomarkers and Personalized Medicine Core

Function Unit, Eisai

Biomarkers play important roles for drug development as a part of

translational research. Several examples about biomarkers for 1) the

evidence of target engagement, 2) patient stratification, 3) drug efficacy

and 4) disease diagnostics will be discussed.

2:40-3:45 Refreshment Break in the Exhibit Hall with Poster Viewing

Molecular Profiling of Tumor Heterogeneity to

Guide Therapy

3:45-3:50 Chairperson’s Remarks

3:50-4:15 Liquid Biopsies to Monitor Response and Resistance to

Targeted Therapies

Luis Alberto Diaz, M.D., Associate Professor of Oncology, Johns Hopkins

Sidney Kimmel Comprehensive Cancer Center

The simplest hypothesis to account for the development of resistance

to EGFR blockade is that rare cells with KRAS mutations pre-exist at low

levels in tumors with ostensibly wild-type KRAS genes. Although this

hypothesis would seem readily testable, there is no evidence in preclinical

models to support it, nor is there data from patients. To test this

hypothesis, we determined whether mutant KRAS DNA could be detected

in the circulation of 28 patients receiving monotherapy with panitumumab,

a therapeutic anti-EGFR antibody. The results suggest that the emergence

of KRAS mutations is a mediator of acquired resistance to EGFR blockade

and that these mutations can be detected in a non-invasive manner. They

explain why solid tumors develop resistance to targeted therapies in a

highly reproducible fashion.

4:15-4:40 Application of Clinical Tumor Genotyping in Targeted Cancer

Therapy

Darrell R. Borger, Ph.D., Co-Director, Translational Research Laboratory,

Massachusetts General Hospital Cancer Center

Multiplexed tumor genotyping has been offered as a physician-ordered

clinical test at a major U.S. cancer center. Over 3,000 patients have been

evaluated and these new capabilities have fostered a genotype-directed

approach to clinical trial design. By testing a broad spectrum of tumor

types, new molecular signatures have been revealed and mechanisms

of de novo and acquired resistance to targeted therapies have been

uncovered. This has provided the foundation for expanding clinical cancer

genotyping approaches for personalizing cancer care.

4:40-5:05 Quantitative Tumor Protein Profiling for Therapy-Relevant

Stratification of Breast Cancer Patients

Hallgeir Rui, M.D., Ph.D., Professor, Cancer Biology, Medical Oncology and

Pathology; Scientific Director, Jefferson Breast Care Center; Program Leader,

Biology of Breast Cancer, Kimmel Cancer Center; Co-Director, Pathology

Translational Research Core, Thomas Jefferson University

Breast cancer is a heterogeneous group of malignancies driven by diverse

oncogenic pathways. Ongoing consortium efforts are to map breast cancer

subtypes at high resolution based on quantitative immunofluorescence

(QIF) profiling of druggable target proteins within carcinoma cells of a

panel of 5,000 untreated primary breast cancer specimens. Progress

with prolactin-receptor-Jak-Stat pathway profiling will be highlighted using

complementary QIF technologies. Utility of resulting protein-based breast

cancer subclassification maps for rational recruitment of patients into

biomarker-driven, adaptive clinical trials will be discussed.

5:05-5:30 Clinical Validation of Predictive Biomarkers and Next-

Generation Personalized Medicine Treatment Strategies Incorporating

Genetic Dynamics

Robert A. Beckman, M.D., External Faculty, Center for Evolution and Cancer,

Helen Diller Family Cancer Center, University of California at San Francisco;

Executive Director, Clinical Development Oncology, Daiichi Sankyo Pharma

Development

The future of oncology drug development lies in personalized therapy

using predictive biomarkers. However, examples of the failure of predictive

biomarkers also exist. In these cases the use of biomarkers increased

the costs, complexity and duration of clinical trials, and narrowed the

treated population unnecessarily. We present methods to adaptively

integrate predictive biomarkers into clinical programs in a data-driven

manner, wherein these biomarkers are emphasized in exact proportion

to the evidence supporting their clinical predictive value. Next-generation

personalized treatment strategies, which emphasize tumor heterogeneity,

evolutionary dynamics and possible future tumor states, will also

be presented.

6:00-9:00 Dinner Course

Laboratory-Developed Tests

(Separate registration required. See Page 4 for additional information.)

Wednesday, May 8

7:30-8:15 am Breakfast Presentation or Morning Coffee

(Sponsorship opportunity available. Contact Ilana Quigley at 781-972-5457

or iquigley@healthtech.com)

Advancing Personalized Medicine

8:25-8:30 Chairperson’s Opening Remarks

8:30-8:55 Personalized Health Care: ‘One Size Does Not Fit All’ Applies

to Patients and Products

M.J. Finley Austin, Ph.D., Personalized Healthcare & Biomarker Strategy

Director, AstraZeneca

The essence of Personalized Health Care (PHC) is identifying,

understanding and partioning drug response variation to improve clinical

outcomes. Existing PHC examples demonstrate diversity in source of

variation, path to market as well as market delivery and uptake. Current

examples will be used to elucidate the implications of differing sources

and degrees of variation, clinical utility, and timing of discovery all have for

clinical trial design, regulatory strategy and market delivery.

8:55-9:20 Molecular Subtyping of Patients for Drug Development

Eric Lai, Ph.D., Senior Vice President and Head, Pharmacogenomics, Takeda

Pharmaceuticals International

While the concept of drug-diagnostic co-development (CDx) has been

around for awhile, most companion diagnostics are still an afterthought

and not an integrated component of drug development. To benefit from

the full potential of CDx, we have to change the strategy of drug target

identification from the single target approach to systematic understanding

of a patient’s disease phenotypes. I will discuss some of the potentials

steps that we have made to the drug development process.

BiomarkerWorldCongress.com Biomarkers & Diagnostics World Congress | 15

Track 5: Biomarkers for Patient Selection

9:20-9:45 Co-Diagnostics in Autoimmune Disorders: Improving

Outcomes in RA and IBD

Mark E. Curran, Ph.D., Vice President, Immunology Biomarkers, Janssen

Research & Development

Rheumatoid arthritis and inflammatory bowel disease are severe immune

diseases with significantly reduced quality of life for patients. Despite

advances in treatment with the evolution of antibody and recombinant

protein based therapeutics, there remains a significant unmet clinical need

for new therapies and integrated treatment solutions. At Janssen we are

focused on transforming therapy in these diseases by applying systems

pharmacology, precision medicine principles and developing companion

diagnostics to create new treatment paradigms. Our objective is to

provide for higher response rates, deeper remission, early interception and

eventually prevention of these diseases. Progress toward these objectives

will be discussed.

9:45-10:15 Complex microRNA Signatures of Response

Sponsored by

and Resistance as Powerful Biomarkers

E. Robert Wassman, M.D., CMO, Rosetta Genomics

10:15-10:30 Sponsored Presentation

(Opportunity available. Contact Ilana Quigley at 781-972-5457

or iquigley@healthtech.com)

10:30-11:30 Coffee Break in the Exhibit Hall with Poster Viewing

11:30-11:55 Precision Medicine: Triumphs and Tribulations

Claudio Carini, M.D., Global Clinical Immunology and Biomarkers Lead,

Bioenhancement Development Unit, Pfizer

The current model for drug development is failing. Failures often occur

either during the Phase II trials, where either the candidate drug did not

meet the expected pharmacological requirements or the targeted drug

mechanism did not play a role in the patients population studied. Thus,

a new “personalized medicine” strategy is needed to develop predictive

biomarkers to assist in the decision making process during the pre-clinical

phase of drug development and use biomarkers as companion diagnostics

for stratifying patients in hypothesis-driven clinical trials.

11:55-12:20 pm Towards Personalized Medicine in Metabolic Diseases

Mark Broenstrup, Ph.D., Director, Biomarker and Diagnostics, R&D Diabetes

Division, Sanofi

Currently, more than 346 million people worldwide have diabetes. The

identification of the most effective drug(s) for the individual patient

is guided by a few selection criteria and a trial-and-error approach.

Consequently, the introduction of personalized approaches, accounting

for the heterogeneity of the disease, is regarded as a key enabler for

improved health care. An overview on biomarkers for assessing risk,

monitoring disease progression and predicting response to drugs is

provided, with a focus on beta cell imaging and systems biology solutions.

Finally, major public-private partnerships aiming at personalized solutions in

diabetes will be highlighted.

12:20-12:45 Translating Molecular Targets for Cancer Therapeutics

Glen J. Weiss, M.D., Co-Head, Lung Cancer Unit, The Translational Genomics

Research Institute (TGen); Director, Thoracic Oncology, Virginia G. Piper Cancer

Center Clinical Trials at Scottsdale Healthcare; CMO, CRAB-Clinical Trials

Consortium

The presentation will focus on why there is a push to individualize cancer

therapy, past failures and successes, and how to define the tumor context

of vulnerability (COV). The talk will also describe the steps from pre-clinical

to new drug application and show how to optimize the drug development

path with knowledge of biomarker-based COV.

12:45 Close of Conference

SPONSORSHIP, EXHIBIT & LEAD GENERATION OPPORTUNITIES

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opportunities, exhibit space and branding, as well as the use of the pre and postshow

delegate lists. Customizable sponsorship packages allow you to achieve

your objectives before, during, and long after the event. Signing on early will

allow you to maximize exposure to hard-to-reach decision makers!

Agenda Presentations

Showcase your solutions to a guaranteed, highly-targeted audience. Package

includes a 15- or 30-minute podium presentation within the scientific agenda,

exhibit space, on-site branding and access to cooperative marketing efforts

by CHI.

Breakfast & Luncheon Presentations

Opportunity includes a 30-minute podium presentation. Boxed lunches are

delivered into the main session room, which guarantees audience attendance

and participation. A limited number of presentations are available for sponsorship

and they will sell out quickly. Sign on early to secure your talk!

Invitation-Only VIP Dinner/Hospitality Suite

Sponsors will select their top prospects from the conference pre-registration

list for an evening of networking at the hotel or at a choice local venue. CHI will

extend invitations and deliver prospects. Evening will be customized according to

sponsor’s objectives i.e.:

• Purely social

• Focus group

• Reception style

• Plated dinner with specific

conversation focus

Exhibit

Exhibitors will enjoy facilitated networking opportunities with high-level

conference delegates. Speak face-to-face with prospective clients and showcase

your latest product, service, or solution.

*Inquire about additional branding opportunities!

Looking for additional ways to drive leads to your sales team?

Cambridge Healthtech Institute can help!

We offer clients numerous options for custom lead generation programs to

address their marketing and sales needs, including:

• Live Webinars

• White Papers

• Market Surveys

• Podcasts

• And More!

Benefits of working with Cambridge Healthtech Institute for your lead

generation needs:

• Your campaign will receive targeted promotion to Cambridge Healthtech

Institute’s unparalleled database of over 800,000 individuals, all of which are

involved in all sectors of the life sciences – lists can be segmented based on

geography, research area, title and industry.

• All custom lead generation programs are promoted through our experienced

marketing team that will develop and drive targeted campaigns to drive

awareness and leads to your lead generation program.

• For our webinar programs, we offer assistance in procuring speakers for

your web symposia through our extensive roster of industry recognized

speakers across multiple disciplines within life sciences, as well as provide

an experienced moderator and dedicated operations team who will

coordinate all efforts.

• If choosing a white paper program, we can offer editorial experience and

provide an industry recognized author to write your white paper.

To customize your participation at this event, please contact:

Ilana Quigley – Business Development Manager

781-972-5457 | iquigley@healthtech.com

16 | Biomarkers & Diagnostics World Congress BiomarkerWorldCongress.com

Track 6: Cancer Drug Resistance

Tuesday, May 8

12:15-1:45 Conference Registration

Biomarkers to Diagnostics

1:45-1:50 Chairperson’s Opening Remarks

1:50-2:15 Investing in Biomarkers and Turning Them into Diagnostics

Felix Frueh, Entrepreneur-in-Residence, Third Rock Ventures

The translation of biomarkers into useful clinical diagnostics requires the

demonstration of clinical benefit and cost effectiveness. Investing in new

technology is not sufficient without the realization that discovery and

development of a new biomarker needs to include the demonstration that the

biomarker makes a difference in clinical outcomes or decision-making, preferably

tested in the environment in which ultimately a diagnostic will be used.

2:15-2:40 From Biomarker Research to Diagnostic Development—Our

Challenges

Yoshi Oda, Ph.D., President, Biomarkers and Personalized Medicine Core

Function Unit, Eisai

Biomarkers play important roles for drug development as a part of

translational research. Several examples about biomarkers for 1) the

evidence of target engagement, 2) patient stratification, 3) drug efficacy

and 4) disease diagnostics will be discussed.

2:40-3:45 Refreshment Break in the Exhibit Hall with Poster Viewing

Molecular Profiling of Tumor Heterogeneity to

Guide Therapy

3:45-3:50 Chairperson’s Opening Remarks

3:50-4:15 Liquid Biopsies to Monitor Response and Resistance to

Targeted Therapies

Luis Alberto Diaz, M.D., Associate Professor of Oncology, Johns Hopkins

Sidney Kimmel Comprehensive Cancer Center

The simplest hypothesis to account for the development of resistance

to EGFR blockade is that rare cells with KRAS mutations pre-exist at low

levels in tumors with ostensibly wild-type KRAS genes. Although this

hypothesis would seem readily testable, there is no evidence in preclinical

models to support it, nor is there data from patients. To test this

hypothesis, we determined whether mutant KRAS DNA could be detected

in the circulation of 28 patients receiving monotherapy with panitumumab,

a therapeutic anti-EGFR antibody. The results suggest that the emergence

of KRAS mutations is a mediator of acquired resistance to EGFR blockade

and that these mutations can be detected in a non-invasive manner. They

explain why solid tumors develop resistance to targeted therapies in a

highly reproducible fashion.

4:15-4:40 Application of Clinical Tumor Genotyping in Targeted Cancer

Therapy

Darrell R. Borger, Ph.D., Co-Director, Translational Research Laboratory,

Massachusetts General Hospital Cancer Center

Multiplexed tumor genotyping has been offered as a physician-ordered

clinical test at a major U.S. cancer center. Over 3,000 patients have been

evaluated and these new capabilities have fostered a genotype-directed

approach to clinical trial design. By testing a broad spectrum of tumor

types, new molecular signatures have been revealed and mechanisms

of de novo and acquired resistance to targeted therapies have been

uncovered. This has provided the foundation for expanding clinical cancer

genotyping approaches for personalizing cancer care.

4:40-5:05 Quantitative Tumor Protein Profiling for Therapy-Relevant

Stratification of Breast Cancer Patients

Hallgeir Rui, M.D., Ph.D., Professor, Cancer Biology, Medical Oncology and

Pathology; Scientific Director, Jefferson Breast Care Center; Program Leader,

Biology of Breast Cancer, Kimmel Cancer Center; Co-Director, Pathology

Translational Research Core, Thomas Jefferson University

Breast cancer is a heterogeneous group of malignancies driven by diverse

oncogenic pathways. Ongoing consortium efforts are to map breast cancer

subtypes at high resolution based on quantitative immunofluorescence

(QIF) profiling of druggable target proteins within carcinoma cells of a

panel of 5,000 untreated primary breast cancer specimens. Progress

with prolactin-receptor-Jak-Stat pathway profiling will be highlighted using

complementary QIF technologies. Utility of resulting protein-based breast

cancer subclassification maps for rational recruitment of patients into

biomarker-driven, adaptive clinical trials will be discussed.

5:05-5:30 Clinical Validation of Predictive Biomarkers and Next-

Generation Personalized Medicine Treatment Strategies Incorporating

Genetic Dynamics

Robert A. Beckman, M.D., External Faculty, Center for Evolution and Cancer,

Helen Diller Family Cancer Center, University of California at San Francisco;

Executive Director, Clinical Development Oncology, Daiichi Sankyo Pharma

Development

The future of oncology drug development lies in personalized therapy

using predictive biomarkers. However, examples of the failure of predictive

biomarkers also exist. In these cases the use of biomarkers increased

the costs, complexity and duration of clinical trials, and narrowed the

treated population unnecessarily. We present methods to adaptively

integrate predictive biomarkers into clinical programs in a data-driven

manner, wherein these biomarkers are emphasized in exact proportion

to the evidence supporting their clinical predictive value. Next-generation

personalized treatment strategies, which emphasize tumor heterogeneity,

evolutionary dynamics and possible future tumor states, will also

be presented.

6:00-9:00 Dinner Course

Laboratory-Developed Tests

(Separate registration required. See Page 4 for additional information.)

Wednesday, May 8

7:30-8:05 am Morning Coffee

Secondary Resistance to Targeted Cancer Therapy

8:05-8:30 Biomarkers and Trastuzumab Resistance

Wen Jin Wu, M.D., Ph.D., Principal Investigator, Division of Monoclonal Antibodies,

Office of Biotechnology Products, Center for Drug Evaluation and Research, FDA

Trastuzumab is an anti-HER2 antibody indicated for the treatment of

HER2-positive breast cancer. Approximately two-thirds of HER2-positive

breast cancers show primary resistance to trastuzumab treatment, and

a majority of patients who achieve an initial response to trastuzumab

acquire resistance to trastuzumab within one year. However, there are

no clinically useful predictive biomarkers that can be used in conjunction

with HER2 expression to predict the outcome of trastuzumab treatment

in the HER2-positive breast cancer patients. We recently found that the

phosphorylation of HER2-Y1248 was associated with the sensitivity of

trastuzumab treatment, suggesting that the phosphorylation status of

HER2-Y1248 may be a predictive biomarker for trastuzumab treatment.

8:30-8:55 Resistance to MAPK Pathway Inhibitors in Melanoma:

Insights and Future Challenges

Jessie Villanueva, Ph.D., Assistant Professor, Molecular and Cellular

Oncogenesis Program, The Wistar Institute

The mitogen-activated protein kinase (MAPK) pathway is a key

therapeutic target for melanoma due to its activation in the majority of

tumors. Numerous small molecule inhibitors aimed at controlling MAPK

activity, such as BRAF and MEK inhibitors, are currently undergoing

clinical investigation. However, their therapeutic success is limited by

the development of drug resistance. To develop effective therapies for

melanoma patients, it is critical to uncover the mechanisms of resistance

to BRAF and MEK inhibitors. This presentation will discuss recent studies

on the molecular mechanisms of resistance to inhibitors of the MAPK

pathway and potential strategies to treat drug-resistant melanomas.

BiomarkerWorldCongress.com Biomarkers & Diagnostics World Congress | 17

8:55-9:20 A Pre-Clinical Model of BRAF Inhibitor Resistance in

Melanoma Reveals a Novel Approach to Forestall Drug Resistance

Meghna Das Thakur, Ph.D., Presidential Postdoctoral Fellow, Novartis Institutes

for BioMedical Research

BRAF inhibitors such as vemurafenib have shown promising effects in

patients with mutant BRAF(V600E) melanomas, but the tumors generally

develop resistance. Interestingly, the vemurafenib-resistant melanomas

become drug dependent for their continued proliferation, such that

cessation of drug administration leads to regression of established drugresistant

tumors. Thus, a discontinuous dosing strategy exploiting the

fitness disadvantage shown by drug-resistant cells in the absence of the

drug forestalls the onset of lethal drug-resistant disease.

9:20-9:45 Non Cell-Autonomous Mechanisms of Resistance against

Anti-EGFR Therapy

Janghee Woo, M.D., Albert Einstein Medical Center; Recipient of AACRGlaxoSmithKline

Clinical Cancer Research Scholar Award and Dana-Farber/

Harvard Cancer Center Award

Our findings suggest that stroma-derived MMP9 may help tumors bypass

common mutational mechanisms for constitutive growth factor pathway

activation and confer resistance to anti-EGFR therapy through activation of

the ERBB2/ERK/JUN pathway. Stromal MMP9 expression may therefore

have value as a predictive marker for cetuximab response and in stratifying

patients before treatment.

9:45-10:30 Sponsored Presentations

(Opportunities available. Contact Ilana Quigley at 781-972-5457 or

iquigley@healthtech.com)

10:30-11:30 Coffee Break in the Exhibit Hall with Poster Viewing

11:30-11:55 Managing Secondary Drug Resistance in the Clinic: The

Memorial Sloan-Kettering Approach

Maria E. Arcila, M.D., Department of Pathology, Memorial Sloan-Kettering

Cancer Center

Resistance to Various Therapies:

Cancer Does Not Discriminate

11:55-12:00 Chairperson’s Remarks

12:00-12:25 A20 Ubiquitin E3 Ligase is a Biomarker of the Cancer

Stem Cell Resistance to Apoptotic Drugs

Chunhai “Charlie” Hao, M.D., Ph.D., Associate Professor, Neuropathology

Attending, Department of Pathology and Laboratory Medicine, Emory

University School of Medicine

The TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)

apoptosis pathway has emerged as a cancer therapeutic target; however,

Phase II trials recently completed have showed limited if any antitumor

activities of TRAIL pathway-targeted therapies. Molecular and functional

examination of patients’ glioblastoma tissues and derived cancer stem

cells reveals the resistance mechanism by which the ubiquitin E3 ligase

A20 mediated poly-ubiquitination inhibits the cleavage of apoptosisinitiating

caspase-8 and the initiation of TRAIL-induced apoptosis. The

study suggests that the full characterization of patients’ cancer tissues

and derived cancer stem cells can predict the cancer responsiveness

to treatment and thus should be a critical pre-clinical trial step in

drug development.

12:25-12:50 pm Molecular Determinants of Hormone-Refractory

Prostate Cancer

Atish Choudhury, M.D., Instructor in Medicine, Medical Oncology, Dana-Farber

Cancer Institute

To identify novel genes that can confer androgen independence to

prostate cancer cells in vivo, we performed an unbiased screen for kinases

conferring androgen-independent tumor formation to androgen-dependent

transformed prostate epithelial cells in vivo. These kinases are likely

to activate signaling pathways that are relevant for conferring castrate

resistance in patients with advanced prostate cancer, and inhibiting these

genes is likely to result in inhibition of cancer cell proliferation and/or

restoration of hormone sensitivity. Integration of our ambitious functional

studies with gene expression and sequencing data in CRPC from tumor

samples being generated through collaborations between DFCI and the

Broad Institute will provide us a more comprehensive understanding of the

development of castrate resistance and novel targets for therapy.

12:50-1:15 Impact of microRNAs in Chemoresistance

Jingfang Ju, Ph.D., Co-Director, Translational Research, Pathology, Stony Brook

University

Non-coding miRNAs contribute to both intrinsic and extrinsic

chemoresistance mechanism, particularly in colon cancer stem cells.

We first discovered several miRNAs suppressing the expression of both

thymidylate synthase and dihydrofolate reductase to impact 5-FU and MTX

sensitivity. The expression of miR-215 was significantly associated with

colorectal cancer patient survival. Our recent studies also show miRNAs

impact intrinsic apoptotic pathways and autophagy. We believe miRNA

based therapeutics, diagnosis and prognosis may emerge in the near

future to benefit patients.

1:15 Close of Conference

Track 6: Cancer Drug Resistance

Lead Media Partners

Media Partners Web Partner

Lead Sponsoring Publications

Sponsoring Publications

18 | Biomarkers & Diagnostics World Congress BiomarkerWorldCongress.com

Track 7: Exosomes and Microvesicles as Biomarkers and Diagnostics

Tuesday, May 8

12:15-1:45 Conference Registration

Exosome Biomarkers in Drug Development

1:45-1:50 Chairperson’s Opening Remarks

1:50-2:15 Exosomes as Biomarkers for Translational Medicine

Holly Hilton, Ph.D., Head, Disease and Translational Genomics, Hoffmann-La

Roche; Adjunct Professor, Graduate School of Biomedical Sciences, University

of Medicine and Dentistry New Jersey

The need for new, relevant biomarkers for translational drug discovery

research is critical. Exosomes are small microvesicles secreted by a wide

range of mammalian cell types under normal and pathological conditions.

The unique signature of exosomal membrane and cytoplasmic proteins as

well as mRNAs and miRNAs can reveal the cell of origin and the condition

of those cells. Isolation and profiling of exosomes from accessible patient

biofluids, such as urine, blood, BALF and CSF, make them ideal candidates

as biomarkers. Examples of their utility as disease biomarkers of chronic

kidney disease and Alzheimer’s as well as possible applications of patient

stratification will be discussed. The current state of challenges to the

widespread use of fluid-based biomarkers will be explored.

2:15-2:40 Investigation of Microparticles as Potential Translatable

Biomarkers of Vascular Injury

Sharon Sokolowski, Ph.D., Principal Scientist, Pfizer Global Research &

Development

Endothelial cells (EC) are thin, flattened cells that line blood and lymph vessel

walls. Endothelial microparticles (EMPs) are small vesicles (0.1-1 mm) that are

released into circulating blood from activated, injured or apoptotic endothelial

cells and are found at elevated levels in a number of diseases associated with

vascular/endothelial dysfunction. The EMPs are being investigated as potential

translatable biomarkers of drug-induced vascular injury.

2:40-3:45 Refreshment Break in the Exhibit Hall with Poster Viewing

3:45-4:10 Utilization of Next-Gen Genomics Technologies for

Unraveling Exosomal Biomarker Potential

Saumya Pant, Ph.D., Research Fellow, Merck

4:10-4:35 CNS Exosomes and the Art of Eavesdropping

Reyna Favis, Ph.D., Scientific Director, Janssen Pharmaceutical Companies of

Johnson & Johnson

Gaining insight into both genomic changes and differences in the central

nervous system of living humans is currently pursued via investigation of

post mortem brain tissue and lymphocytes from living donors. Analyses

of both tissue types suffer from numerous caveats. There is an urgent

need to develop non-invasive methods that can accurately report temporal

changes, as well as inter-individual differences, in the CNS that may

elucidate neurological and neuropsychiatric disease and drug response.

4:35-5:00 Technology Assessment for Evaluation of Exosomal

microRNA as Novel Biomarkers

Shidong Jia, Ph.D., Scientist, Oncology Biomarker Development, Genentech

Dr. Jia’s lab has developed working procedures to evaluate exosomal

microRNA as novel biomarkers for cancer prognosis, prediction and patient

stratification. In particular, their work has refreshed current practice and

demonstrated a new approach for studying microRNA signature in patient

blood samples.

5:00-5:25 The Exosome Factor in Cancer

Lorraine O’Driscoll, Ph.D., Associate Professor, Pharmacology; Director, Research,

School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin

Our research at Trinity College Dublin supports exosomes cargo having

relevance as diagnostic, prognostic and predictive biomarkers. Evidence

indicates they are also causative in cancer spread and drug resistance.

Here we will discuss examples of this research in relation to breast cancer

and prostate cancer.

6:00-9:00 Dinner Course

Laboratory-Developed Tests

(Separate registration required. See Page 4 for additional information.)

Wednesday, May 8

7:30-8:15 am Breakfast Presentation or Morning Coffee

(Sponsorship opportunity available. Contact Ilana Quigley at 781-972-5457

or iquigley@healthtech.com).

Exosomes as Disease Markers

8:25-8:30 Chairperson’s Opening Remarks

8:30-8:55 Salivary Exosomes and Biomarkers Development

David T.W. Wong, D.M.D., D.M.Sc., Professor, Associate Dean, Research, UCLA

School of Dentistry and Director of Dental Research Institute

Extracellular RNA is an emerging concept in cellular communication

and biomarker development. Salivary extracellular RNA, microRNA and

snoRNA have recently been shown to be contained within exosomes

and can be developed to be discriminatory biomarkers for oral as well as

systemic diseases.

8:55-9:20 Circulating Exosomes in Liver Disease

Gyongyi Szabo, M.D., Ph.D., Professor, Gastroenterology, University of

Massachusetts Medical School

microRNAs (miRNAs) are fine tuners of diverse biological responses and

are expressed in various cell types of the liver. They can also serve as

biomarkers of liver damage and inflammation. We studied miRNA-122 that

is abundant in hepatocytes and miR-155, -146a and -125b that regulate

inflammation in immune cells in mouse models of various types of liver

diseases and found that serum/plasma miR-122 correlated with ALT

increases in the liver damage. miR-155, a regulator of inflammation, was

increased in serum/plasma liver injury associated with inflammation.

Depending on the type of liver injury, circulating miRNAs showed

association either with the exosome-rich or protein-rich compartments.

Our results suggest that circulating miRNAs may serve as biomarkers

to differentiate between hepatocyte injury and inflammation and the

exosome versus protein association of miRNAs may provide further

specificity to mechanisms of liver pathology.

9:20-9:45 Microvesicles: Linking the Bone Marrow and Endothelium in

Pulmonary Vascular Disease

Jason M. Aliotta, M.D., Assistant Professor, Medicine, Warren Alpert Medical

School, Brown University

Extracellular vesicles (EVs) represent potentially important mediators of

cell-to-cell communication and, depending on their source, facilitate tissue

repair or remodeling. We’ve demonstrated that EVs isolated from mice

with monocrotaline-induced pulmonary hypertension (PH) induce features

of PH in normal mice. This may be due to EV-induced apoptosis resistance

of pulmonary vascular endothelial cells or EV-induced differentiation

of marrow cells into progenitor cells which, in turn, induce vascular

remodeling. Conversely, we have found that mesenchymal stem cellderived

EVs may reverse monocrotaline-induced PH.

9:45-10:30 Sponsored Presentations

(Opportunities available. Contact Ilana Quigley at 781-972-5457 or

iquigley@healthtech.com)

10:30-11:30 Coffee Break in the Exhibit Hall with Poster Viewing

BiomarkerWorldCongress.com Biomarkers & Diagnostics World Congress | 19

Track 7: Exosomes and Microvesicles as Biomarkers and Diagnostics

Exosomes as Novel Cancer Biomarkers

11:30-11:35 Chairperson’s Remarks

11:35-12:00 pm The Exosome Platform as a Real-Time Tumor Status Monitor

Douglas D. Taylor, Ph.D., Professor, Obstetrics and Gynecology, University of

Louisville School of Medicine

12:00-12:25 Customized Heterogeneity of Breast Cancer Microvesicles

Dominik Duelli, Ph.D., Assistant Professor, Cellular and Molecular

Pharmacology, Rosalind Franklin University of Medicine & Science, Chicago

Medical School

Breast cancer cells, unlike normal cells, release a heterogeneous

population of circulating microvesicles. Resolving this heterogeneity

suggests that individual microvesicle subclasses have different subcellular

origin, different contents, and different destinations. Each subclass

contains mutually exclusive, functional marker microRNA species, and

some proteins with different functions in docking and lysis resistance in

blood plasma. Additionally, organ-site of metastasis influences the ratio of

these proteins, suggesting that these differences could be used to detect

the presence of malignant cells in the body.

12:25-12:50 Tumor-Derived Microvesicles: Biology and Clinical Potential

Crislyn D’Souza-Schorey, Ph.D., Professor, Biological Sciences, University of

Notre Dame

Tumor-derived microvesicles (TMVs) are heterogeneous membrane-bound

sacs that are shed from tumor cells into the extracellular environment.

The formation of these shed vesicles likely involves the vertical trafficking

of intracellular cargo to the cell surface. The complexity of bioactive

cargo contained in TMVs suggests multi-pronged mechanisms by which

shed TMVs can condition the extracellular milieu to facilitate disease

progression. It also demonstrates the potential to translate this knowledge

into innovative approaches for cancer diagnostics and therapy.

12:50-1:15 Exosome Biomarkers of Brain Tumors

Fred H. Hochberg, M.D., Associate Professor, Neurology, Massachusetts

General Hospital

We explore technology for detection of plasma and CSF exosomal

mutations specific to brain tumors. The analytics for mutations EGFrvIII

and IDH1.132 offer the potential to provide a diagnostic biomarker for

low grade and high grade gliomas. An eighteen member consortium,

collaborating with the ABC2 Foundation and the company Exosome

Diagnostics, will validate the sensitivity of these biomarker assays. The

presentation will include discussion of pre-clinical detection, SOPs for

specimen handling and the rationale for use of these biomarkers.

1:15 Close of Conference

Conference Hotel :

Loews Philadelphia Hotel

1200 Market Street

Philadelphia, PA 19107

Phone: 215-627-1200

HOTEL & TRAVEL

INFORMATION

Discounted Room Rate: $229 s/d

Discounted Room Rate Cut-off Date:

April 8, 2013

Please visit our conference website

to make your reservation online or

call the hotel directly to reserve your

sleeping accommodations. You will need

to identify yourself as a Cambridge

Healthtech Institute conference attendee

to receive the discounted room rate with

the host hotel. Reservations made after

the cut-off date or after the group room

block has been filled (whichever comes

first) will be accepted on a space and

rate-availability basis. Rooms are limited,

so please book early.

Flight Discounts:

Special discount rentals have been established with American Airlines

for this conference.

• Call American Airlines 1-800-433-1790 and use Conference code 8353BL.

• Go to http://www.aa.com/group and enter Conference code 8353BL in promotion

discount box.

• Contact our dedicated travel agents at 1-877-559-5549 or chi@protravelinc.com.

Car Rental Discounts:

Special discount rentals have been established with Hertz for this conference.

• Call Hertz 1-800-654-3131 and use our Hertz Convention Number (CV): 04KL0003

• Go to http://www.hertz.com and use our Hertz Convention Number (CV): 04KL0003

Top Reasons to Stay at The Loews Philadelphia

• Minutes from Amtrak 30th Street Station and 20 minutes from

Philadelphia Airport

• Complimentary wireless internet in your guest room

• Close to many of Philadelphia’s historical sites, including the Liberty

Bell and Independence Hall

• Steps from Reading Terminal Market, which offers an exhilarating selection

of baked goods, meats, poultry, seafood, produce, flowers and more

• Pet-friendly accommodations including specialty pet menus, gifts

upon arrival and dog-walking services

• Located in the historic PSFS Building: A 20th Century Masterpiece

BIOMARKERS & DIAGNOSTICS

world congress 2013

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DINNER courses

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Single Dinner Course Pricing $595 $295

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May 6, 2013 May 7, 2013

Fit-for-Purpose Biomarker Assay Development and Validation Laboratory-Developed Tests

Next-Generation Sequencing as a Clinical Test: It Takes a Community

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ALL ACCESS Executive Pricing: Includes access to entire 3-days of Congress programs, including Executive Summit. (Does not include

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May 6-7, 2013 May 7-8, 2013

Track 1: Translational Biomarkers in Drug Development Track 5: Biomarkers for Patient Selection

Track 2: Clinical Assay Development Track 6: Cancer Drug Resistance

Track 3: Cancer Tissue Diagnostics Track 7: Exosomes and Microvesicles as Biomarkers and Diagnostics

Track 4: Executive Summit: Companion Diagnostics (May 6-8, 2013)

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