Funding, Deals & Partnerships: BIOLOGICS & MEDICAL DEVICES; BioMed e-Series; Medicine and Life Sciences Scientific Journal – http://PharmaceuticalIntelligence.com
June 22-24: Free Registration for AACR Members, the Cancer Community, and the Public
This virtual meeting will feature more than 120 sessions and 4,000 e-posters, including sessions on cancer health disparities and the impact of COVID-19 on clinical trials
This Virtual Meeting is Part II of the AACR Annual Meeting. Part I was held online in April and was centered only on clinical findings. This Part II of the virtual meeting will contain all the Sessions and Abstracts pertaining to basic and translational cancer research as well as clinical trial findings.
The Opening Ceremony will include the following presentations: Welcome from AACR CEO Margaret Foti, PhD, MD (hc)
CHIEF EXECUTIVE OFFICER
MARGARET FOTI, PHD, MD (HC)
American Association for Cancer Research
Philadelphia, Pennsylvania
Dr. Foti mentions that AACR is making progress in including more ethnic and gender equality in cancer research and she feels that the disparities seen in health care, and in cancer care, is related to the disparities seen in the cancer research profession
AACR is very focused now on blood cancers and creating innovation summits on this matter
In 2019 awarded over 60 grants but feel they will be able to fund more research in 2020
Government funding is insufficient at current levels
Remarks from AACR Immediate Past President Elaine R. Mardis, PhD, FAACR
involved in planning and success of the first virtual meeting (it was really well done)
# of registrants was at unprecedented numbers
the scope for this meeting will be wider than the first meeting
they have included special sessions including COVID19 and health disparities
70 educational and methodology workshops on over 70 channels
AACR Award for Lifetime Achievement in Cancer Research
How should we think about exceptional and super responders to cancer therapy? What biologic insights might ensue from considering these cases? What are ways in which considering super responders may lead to misleading conclusions? What are the pros and cons of the quest to locate exceptional and super responders?
Alice P Chen, Vinay K Prasad, Celeste Leigh Pearce
Medcity Converge 2018 Philadelphia: Live Coverage @pharma_BI
Stephen J. Williams: Reporter
3.3.3 Medcity Converge 2018 Philadelphia: Live Coverage @pharma_BI, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 2: CRISPR for Gene Editing and DNA Repair
MedCity CONVERGE is a two-day executive summit that gathers innovative thought leaders from across all healthcare sectors to provide actionable insight on where oncology innovation is heading.
On July 11-12, 2018 in Philadelphia, MedCity CONVERGE will gather technology disruptors, payers, providers, life science companies, venture capitalists and more to discuss how AI, Big Data and Precision Medicine are changing the game in cancer. See agenda.
The conference highlights innovation and best practices across the continuum—from research to technological innovation to transformations of treatment and care delivery, and most importantly, patient empowerment—from some of the country’s most innovative healthcare organizations managing the disease.
Meaningful networking opportunities abound, with executives driving the innovation from diverse entities: leading hospital systems, medical device firms, biotech, pharma, emerging technology startups and health IT, as well as the investment community.
Day 1: Wednesday, July 11, 2018
7:30 AM
2nd Floor – Paris Foyer
Registration + Breakfast
8:15 AM–8:30 AM
Paris Ballroom
Welcome Remarks: Arundhati Parmar, VP and Editor-in-Chief, MedCity News
8:30 AM–9:15 AM
Paris Ballroom
Practical Applications of AI in Cancer
We are far from machine learning dictating clinical decision making, but AI has important niche applications in oncology. Hear from a panel of innovative startups and established life science players about how machine learning and AI can transform different aspects in healthcare, be it in patient recruitment, data analysis, drug discovery or care delivery.
Opening Keynote: Dr. Joshua Brody, Medical Oncologist, Mount Sinai Health System
The Promise and Hype of Immunotherapy
Immunotherapy is revolutionizing oncology care across various types of cancers, but it is also necessary to sort the hype from the reality. In his keynote, Dr. Brody will delve into the history of this new therapy mode and how it has transformed the treatment of lymphoma and other diseases. He will address the hype surrounding it, why so many still don’t respond to the treatment regimen and chart the way forward—one that can lead to more elegant immunotherapy combination paths and better outcomes for patients.
Startups from diagnostics, biopharma, medtech, digital health and emerging tech will have 8 minutes to articulate their visions on how they aim to tame the beast.
Breakout: Biopharma Gets Its Feet Wet in Digital Health
In the last few years, biotech and pharma companies have been leveraging digital health tools in everything from oncology trials, medication adherence to patient engagement. What are the lessons learned?
Moderator:Anthony Green, Ph.D., Vice President, Technology Commercialization Group, Ben Franklin Technology Partners Speakers: Derek Bowen, VP of Business Development & Strategy, Blackfynn, Inc. Gyan Kapur, Vice President, Activate Venture Partners Tom Kottler, Co-Founder & CEO, HealthPrize Technologies @HealthPrize
11:00 AM–11:45 AM
Paris Ballroom
Breakout: How to Scale Precision Medicine
The potential for precision medicine is real, but is limited by access to patient datasets. How are government entities, hospitals and startups bringing the promise of precision medicine to the masses of oncology patients
Building a Precision Medicine Business from the Ground Up: An Operating and Venture Perspective
Dr. Pellini has spent more than 20 years working on the operating side of four companies, each of which has pushed the boundaries of the standard of care. He will describe his most recent experience at Foundation Medicine, at the forefront of precision medicine, and how that experience can be leveraged on the venture side, where he now evaluates new healthcare technologies.
The randomized, controlled clinical trial is the gold standard, but it may be time for a new model. How can patient networks and new technology be leveraged to boost clinical trial recruitment and manage clinical trials more efficiently?
CONVERGEnce on Steroids: Why Comcast and Independence Blue Cross?
This year has seen a great deal of convergence in health care. One of the most innovative collaborations announced was that of Cable and Media giant Comcast Corporation and health plan Independence Blue Cross. This fireside chat will explore what the joint venture is all about, the backstory of how this unlikely partnership came to be, and what it might mean for our industry.
sponsored by Independence Blue Cross
Moderator:Tom Olenzak, Managing Director Strategic Innovation Portfolio, Independence Blue Cross @IBX Speakers: Marc Siry, VP, Strategic Development, Comcast Michael Vennera, SVP, Chief Information Officer, Independence Blue Cross
3:00 PM–3:15 PM
Paris Foyer
Networking Break + Showcase
3:15 PM–4:00 PM
Montpellier – 3rd Floor
Breakout: Charting the Way Forward in Gene and Cell Therapy
There is a boom underway in cell and gene therapies that are being wielded to tackle cancer and other diseases at the cellular level. FDA has approved a few drugs in the space. These innovations raise important questions about patient access, patient safety, and personalized medicine. Hear from interesting startups and experts about the future of gene therapy.
Moderator:Alaric DeArment, Senior Reporter, MedCity News Speakers: Amy DuRoss, CEO, Vineti Andre Goy, M.D., Chairman and Director of John Theurer Cancer Center , Hackensack University Medical Center
3:15 PM–4:00 PM
Paris Ballroom
Breakout: What’s A Good Model for Value-Based Care in Oncology?
How do you implement a value-based care model in oncology? Medicare has created a bundled payment model in oncology and there are lessons to be learned from that and other programs. Listen to two presentations from experts in the field.
Breakout: What Patients Want and Need On Their Journey
Cancer patients are living with an existential threat every day. A panel of patients and experts in oncology care management will discuss what’s needed to make the journey for oncology patients a bit more bearable.
sponsored by CEO Council for Growth
Moderator:Amanda Woodworth, M.D., Director of Breast Health, Drexel University College of Medicine Speakers: Kezia Fitzgerald, Chief Innovation Officer & Co-Founder, CareAline® Products, LLC Sara Hayes, Senior Director of Community Development, Health Union @SaraHayes_HU Katrece Nolen, Cancer Survivor and Founder, Find Cancer Help @KatreceNolen John Simpkins, Administrative DirectorService Line Director of the Cancer Center, Children’s Hospital of Philadelphia
5:00 PM–5:45 PM
Paris Ballroom
Early Diagnosis Through Predictive Biomarkers, NonInvasive Testing
Diagnosing cancer early is often the difference between survival and death. Hear from experts regarding the new and emerging technologies that form the next generation of cancer diagnostics.
Opening Remarks: Arundhati Parmar, VP and Editor-in-Chief, MedCity News
8:40 AM–9:25 AM
Paris Ballroom
The Davids vs. the Cancer Goliath Part 2
Startups from diagnostics, biopharma, medtech, digital health and emerging tech will have 8 minutes to articulate their visions on how they aim to tame the beast.
Liquid Biopsy and Gene Testing vs. Reimbursement Hurdles
Genetic testing, whether broad-scale or single gene-testing, is being ordered by an increasing number of oncologists, but in many cases, patients are left to pay for these expensive tests themselves. How can this dynamic be shifted? What can be learned from the success stories?
Moderator:Shoshannah Roth, Assistant Director of Health Technology Assessment and Information Services , ECRI Institute @Ecri_Institute Speakers: Rob Dumanois, Manager – reimbursement strategy, Thermo Fisher Scientific Eugean Jiwanmall, Senior Research Analyst for Medical Policy & Technology Evaluation , Independence Blue Cross @IBX Michael Nall, President and Chief Executive Officer, Biocept
10:15 AM–10:25 AM
Paris Foyer
Networking Break + Showcase
10:25 AM–11:10 AM
Paris Ballroom
Promising Drugs, Pricing and Access
The drug pricing debate rages on. What are the solutions to continuing to foster research and innovation, while ensuring access and affordability for patients? Can biosimilars and generics be able to expand market access in the U.S.?
Moderator:Bunny Ellerin, Director, Healthcare and Pharmaceutical Management Program, Columbia Business School Speakers: Patrick Davish, AVP, Global & US Pricing/Market Access, Merck Robert Dubois M.D., Chief Science Officer and Executive Vice President, National Pharmaceutical Council Gary Kurzman, M.D., Senior Vice President and Managing Director, Healthcare, Safeguard Scientifics Steven Lucio, Associate Vice President, Pharmacy Services, Vizient
11:10 AM–11:20 AM
Networking Break + Showcase
11:20 AM–12:05 PM
Paris Ballroom
Breaking Down Silos in Research
“Silo” is healthcare’s four-letter word. How are researchers, life science companies and others sharing information that can benefit patients more quickly? Hear from experts at institutions that are striving to tear down the walls that prevent data from flowing.
Moderator:Vini Jolly, Executive Director, Woodside Capital Partners Speakers: Ardy Arianpour, CEO & Co-Founder, Seqster @seqster Lauren Becnel, Ph.D., Real World Data Lead for Oncology, Pfizer Rakesh Mathew, Innovation, Research, & Development Lead, HealthShareExchange David Nace M.D., Chief Medical Officer, Innovaccer
12:10 PM–12:40 PM
Paris Ballroom
Closing Keynote: Anne Stockwell, Cancer Survivor, Founder, Well Again
Finding Your Well Again
Anne Stockwell discusses her mission to help cancer survivors heal their emotional trauma and regain their balance after treatment. A multi-skilled artist as well as a three-time cancer survivor, Anne learned through experience that the emotional impact of cancer often strikes after treatment, isolating a survivor rather than lighting the way forward. Anne realized that her well-trained imagination as an artist was key to her successful reentry after cancer. Now she helps other survivors develop their own creative tools to help them find their way forward with joy.
AstraZeneca’s WEE1 protein inhibitor AZD1775 Shows Success Against Tumors with a SETD2 mutation
Stephen J. Williams, Ph.D., Curator
There have been multiple trials investigating the utility of cyclin inhibitors as anti-tumoral agents (see post) with the idea of blocking mitotic entry however another potential antitumoral mechanism has been to drive the cell into mitosis in the presence of DNA damage or a defective DNA damage repair capacity. A recent trial investigating an inhibitor or the cell cycle checkpoint inhibitor Wee1 showed positive results in select cohorts of patients with mutations in DNA repair, indicating the therapeutic advantage of hijacking the cell’s own DNA damage response, much like how PARP inhibitor Olaparib works in BRCA1 mutation positive ovarian cancer patients.
Investigators at Oxford University say that one of AstraZeneca’s ($AZN) pipeline drugs proved particularly effective in killing cancer cells with a particular genetic mutation.
The ex-Merck ($MRK) drug is AstraZeneca’s WEE1 protein inhibitor AZD1775, which proved particularly lethal to genes with a SETD2 mutation, which the researchers see as a potential ‘Achilles heel’ often found in kidney cancer and childhood brain tumors.
“When WEE1 was inhibited in cells with a SETD2 mutation, the levels of deoxynucleotides, the components that make DNA, dropped below the critical level needed for replication,” noted Oxford’s Andy Ryan. “Starved of these building blocks, the cells die. Importantly, normal cells in the body do not have SETD2 mutations, so these effects of WEE1 inhibition are potentially very selective to cancer cells.”
AstraZeneca landed rights to the drug back in 2013, when incoming Merck R&D chief Roger Perlmutter opted to spin it out while focusing an immense effort around the development of its PD-1 checkpoint inhibitor KEYTRUDA® (pembrolizumab). Since then, AstraZeneca has made it available to academic investigators through their open innovation program.
Wee1, DNA damage checkpoint and cell cycle regulation
In fission yeast, Wee1 delays entry into mitosis by inhibiting the activity of Cdk1, the cyclin-dependent kinase that promotes entry into mitosis (Cdk1 is encoded by the cdc2+ gene in fission yeast and the CDC28 gene in budding yeast) (Russell and Nurse, 1987a). Wee1 inhibits Cdk1 by phosphorylating a highly conserved tyrosine residue at the N-terminus (Featherstone and Russell, 1991; Gould and Nurse, 1989; Lundgren et al., 1991; Parker et al., 1992; Parker and Piwnica-Worms, 1992). The phosphatase Cdc25 promotes entry into mitosis by removing the inhibitory phosphorylation (Dunphy and Kumagai, 1991; Gautier et al., 1991; Kumagai and Dunphy, 1991; Millar et al., 1991; Russell and Nurse, 1986; Strausfeld et al., 1991). Loss of Wee1 activity causes cells to enter mitosis before sufficient growth has occurred and cytokinesis therefore produces two abnormally small daughter cells (Fig. 1A) (Nurse, 1975). Conversely, increasing the gene dosage of wee1 causes delayed entry into mitosis and an increase in cell size, indicating that the levels of Wee1 activity determine the timing of entry into mitosis and can have strong effects on cell size (Russell and Nurse, 1987a). Similarly, cdc25– mutants undergo delayed entry into mitosis, producing abnormally large cells, and an increase in the gene dosage of cdc25 causes premature entry into mitosis and decreased cell size (Russell and Nurse, 1986). Despite these difficulties, early work in fission yeast suggested that the Wee1 kinase plays an important role in a checkpoint that coordinates cell growth and cell division at the G2/M transition (Fantes and Nurse, 1978; Nurse, 1975; Thuriaux et al., 1978). WEE1 is an evolutionarily conserved nuclear tyrosine kinase (Table 2) that is markedly active during the S/G2 phase of the cell cycle [24, 25]. It was first discovered 25 years ago as a cell division cycle (cdc) mutant-wee1– in the fission yeast, Schizosaccharomyces pombe [26]. Fission yeast lacking WEE1 are characterized by a smaller cell size, and this phenotype has been attributed to the ability of WEE1 to negatively regulate the activity of cyclin dependent kinase, Cdc2 (Cdc28 in budding yeast and CDK1 in human), in the Cdc2/CyclinB complex [27]. Recently, WEE1 was shown to directly phosphorylate the mammalian core histone H2B at tyrosine 37 in a cell cycle dependent manner. Inhibition of WEE1 kinase activity either by a specific inhibitor (MK-1775) or suppression of its expression by RNA interference abrogated H2B Y37-phosphorylation with a concurrent increase in histone transcription [17].
As shown in the Below figure Wee1 is a CDK cyclin kinase which results in an inactivating phosphorylation event on CDK/Cyclin complexes
Figure 1. Schematic representation of the effects of Chk1 and Wee1 inhibition on CDK-CYCLIN complex regulation, that gets more activated being unphosphorylated from Cell cycle, checkpoints and cancer by Laura Carrassa.
Figure 2. Schematic representation of the role of Chk1 and Wee1 in regulation of the CDK-cyclin complexes involved in S phase and M phase entry from Cell cycle, checkpoints and cancer by Laura Carrassa.
The following articles discuss how Wee1 can be a target and synergize with current chemotherapy
p53 mutation Frequency in Ovarian Cancer and contribution to chemo-resistance
The following is from the curated database TCGA and cBioPortal TCGA Data Viewer for mutations found in ovarian cancer sequencing studies in the literature
Confirmed that mutations in gene TP53 are present in more than 96 percent of ovarian cases (>57% mutation frequency) while SETD2 mutations are present in only 1% of cases (1.1% mutation frequency).
In general, ovarian cancers with TP53 are considered to have increased resistance to commonly used cytotoxic agents used for this neoplasm, for example cisplatin and taxol, as TP53 is a major tumor suppressor/transcription factor involved in cell cycle, DNA damage response, and other chemosensitivity mechanisms. One subtype of TP53 mutations, widely termed gain-of-function (GOF) mutations, surprisingly converts this protein from a tumor suppressor to an oncogene. We term the resulting change an oncomorphism. In this review, we discuss particular TP53 mutations, including known oncomorphic properties of the resulting mutant p53 proteins. For example, several different oncomorphic mutations have been reported, but each mutation acts in a distinct manner and has a different effect on tumor progression and chemoresistance.
Figure 1. The spectrum of protection against cancer provided by WT p53. As copies of WT p53 (TP53+/+) are lost, cancer protection decreases. When oncomorphic mutations are acquired, cancer susceptibility is increased.
Oncomorphic p53 proteins were first identified over two decades ago, when different TP53 mutants were introduced into cells devoid of endogenous p53 [38,39]. Among all cancers, the most common oncomorphic mutations are at positions R248, R273, and R175, and in ovarian cancers the most common oncomorphic TP53 mutations are at positions R273, R248, R175, and Y220 at frequencies of 8.13%, 6.02%, 5.53%, and 3.74%, respectively [33,34]. In in vitro studies, cells with oncomorphic p53 demonstrate increased invasion, migration, angiogenesis, survival, and proliferation as well as resistance to chemotherapy [35,37,40,41].
Figure 2. Hotspots for TP53 mutations. Mutations that occur at a frequency greater than 3% are highlighted. Certain p53 mutants have oncomorphic activity (denoted by *), functioning through novel protein interactions as well as novel transcriptional targets to promote cell survival and potentially chemoresistance. Codons in the “other” category include those that produce non-functional p53 or have not been characterized to date.
Osman AA, Monroe MM, Ortega Alves MV, Patel AA, Katsonis P, Fitzgerald AL, Neskey DM, Frederick MJ, Woo SH, Caulin C, Hsu TK, McDonald TO, Kimmel M, Meyn RE, Lichtarge O, Myers JN.
Mol Cancer Ther. 2015 Feb;14(2):608-19. doi: 10.1158/1535-7163.MCT-14-0735-T. Epub 2014 Dec 10.
Mol Cancer Ther. 2015 Jan;14(1):90-100. doi: 10.1158/1535-7163.MCT-14-0496. Epub 2014 Nov 5.
Mol Cancer Ther. 2013 Aug;12(8):1442-52. doi: 10.1158/1535-7163.MCT-13-0025. Epub 2013 May 22.
1Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
2Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
3Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland.
4Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland. mgottesman@nih.gov.
Abstract
Despite early positive response to platinum-based chemotherapy, the majority of ovarian carcinomas develop resistance and progress to fatal disease. Protein phosphatase 2A (PP2A) is a ubiquitous phosphatase involved in the regulation of DNA-damage response (DDR) and cell-cycle checkpoint pathways. Recent studies have shown that LB100, a small-molecule inhibitor of PP2A, sensitizes cancer cells to radiation-mediated DNA damage. We hypothesized that LB100 could sensitize ovarian cancer cells to cisplatin treatment. We performed in vitro studies in SKOV-3, OVCAR-8, and PEO1, -4, and -6 ovarian cancer lines to assess cytotoxicity potentiation, cell-death mechanism(s), cell-cycle regulation, and DDR signaling. In vivo studies were conducted in an intraperitoneal metastatic mouse model using SKOV-3/f-Luc cells. LB100 sensitized ovarian carcinoma lines to cisplatin-mediated cell death. Sensitization via LB100 was mediated by abrogation of cell-cycle arrest induced by cisplatin. Loss of the cisplatin-induced checkpoint correlated with decreased Wee1 expression, increased cdc2 activation, and increased mitotic entry (p-histone H3). LB100 also induced constitutive hyperphosphorylation of DDR proteins (BRCA1, Chk2, and γH2AX), altered the chronology and persistence of JNK activation, and modulated the expression of 14-3-3 binding sites. In vivo, cisplatin sensitization via LB100 significantly enhanced tumor growth inhibition and prevented disease progression after treatment cessation. Our results suggest that LB100 sensitizes ovarian cancer cells to cisplatin in vitro and in vivo by modulation of the DDR pathway and cell-cycle checkpoint abrogation.
So Why SETD2 Mutations?
SETD2 is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active chromatin and chromatin remodeling.
Kanu N, Grönroos E, Martinez P, Burrell RA, Yi Goh X, Bartkova J, Maya-Mendoza A, Mistrík M, Rowan AJ, Patel H, Rabinowitz A, East P, Wilson G, Santos CR, McGranahan N, Gulati S, Gerlinger M, Birkbak NJ, Joshi T, Alexandrov LB, Stratton MR, Powles T, Matthews N, Bates PA, Stewart A, Szallasi Z, Larkin J, Bartek J, Swanton C.
Oncogene. 2015 Mar 2. doi: 10.1038/onc.2015.24. [Epub ahead of print]
Ahn JW, Kim HS, Yoon JK, Jang H, Han SM, Eun S, Shim HS, Kim HJ, Kim DJ, Lee JG, Lee CY, Bae MK, Chung KY, Jung JY, Kim EY, Kim SK, Chang J, Kim HR, Kim JH, Lee MG, Cho BC, Lee JH, Bang D.
Genome Med. 2014 Feb 27;6(2):18. doi: 10.1186/gm535. eCollection 2014.
#2. Gemcitabine Hydrochloride With or Without WEE1 Inhibitor MK-1775 in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
This randomized phase II clinical trial studies how well gemcitabine hydrochloride and WEE1 inhibitor MK-1775 work compared to gemcitabine hydrochloride alone in treating patients with ovarian, primary peritoneal, or fallopian tube cancer that has come back after a period of time. Gemcitabine hydrochloride may prevent tumor cells from multiplying by damaging their deoxyribonucleic acid (DNA, molecules that contain instructions for the proper development and functioning of cells), which in turn stops the tumor from growing. The protein WEE1 may help to repair the damaged tumor cells, so the tumor continues to grow. WEE1 inhibitor MK-1775 may block the WEE1 protein activity and may increase the effectiveness of gemcitabine hydrochloride by preventing the WEE1 protein from repairing damaged tumor cells without causing harm to normal cells. It is not yet known whether gemcitabine hydrochloride with or without WEE1 inhibitor MK-1775 may be an effective treatment for recurrent ovarian, primary peritoneal, or fallopian tube cancer.
Primary Outcome Measures:
PFS evaluated using RECIST version 1.1 [ Time Frame: Time from start of treatment to time to progression or death, whichever occurs first, assessed up to 1 year ] [ Designated as safety issue: No ]
Secondary Outcome Measures:
GCIG CA125 response rate [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
Incidence of grade 3 or 4 serious adverse events, graded according to the National Cancer Institute CTCAE version 4.0 [ Time Frame: Up to 1 year ] [ Designated as safety issue: Yes ]
Objective response by RECIST version 1.1 [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
Overall survival [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
Survival estimates will be computed using the Kaplan-Meier method.
p53 protein expression in archival tumor tissue by immunohistochemistry (IHC) [ Time Frame: Baseline ] [ Designated as safety issue: No ]
TP53 mutations (presence and type of mutation) by Sanger sequencing [ Time Frame: Baseline ] [ Designated as safety issue: No ]
These Trials Are Not Investigating TP53 Status of Patient Cohorts
To establish the safety and tolerability of single-agent MK-1775 in patients with refractory solid tumors
To determine the pharmacokinetics of MK-1775 in patients with refractory solid tumors
SECONDARY OBJECTIVES:
To determine the effect of MK-1775 on markers of DNA damage and apoptosis in tumor tissue and circulating tumor cells
To evaluate the antitumor activity of MK-1775 in patients with refractory solid tumors
Note: A further expansion cohort of 6 additional patients with documented tumors harboring BRCA-1 or -2 mutations will lso be enrolled at the MTD to further explore the safety of the agent and obtain preliminary evidence of activity in this patient population
To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose of MK-1775 (WEE1 inhibitor MK-1775) administered on days 1 through 5 every 21 days, in combination with oral irinotecan (irinotecan hydrochloride), to children with recurrent or refractory solid tumors.
To define and describe the toxicities of MK-1775 in combination with oral irinotecan administered on this schedule.
III. To characterize the pharmacokinetics of MK-1775 in children with refractory cancer.
SECONDARY OBJECTIVES:
To preliminarily define the antitumor activity of MK-1775 and irinotecan within the confines of a Phase 1 study.
To obtain initial Phase 2 efficacy data on the anti-tumor activity of MK-1775 in combination with irinotecan administered to children with relapsed or refractory neuroblastoma and in children with relapsed or refractory medulloblastoma/CNS PNET (central nervous system primitive neuroectodermal tumor).
III. To investigate checkpoint over-ride by MK-1775 via the mechanism-based pharmacodynamic (PD) biomarker of decreased cyclin-dependent kinase 1 (CDK1) phosphorylation in correlative and exploratory studies.
To evaluate potential predictive biomarkers of MK-1775 sensitivity, including v-myc avian myelocytomatosis viral oncogene homolog (MYC), v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), phosphorylated-WEE1 G2 checkpoint kinase (p-Wee1), enhancer of zeste homolog 2 (Drosophila) (EZH2) and gamma-H2A histone family, member X (H2AX) in tumor tissues in correlative and exploratory studies.
Live Notes From AACR TownHall on Precision Medicine January 21, 2016 in Philadelphia, PA: Background Information on Speakers
Reporter: Stephen J. Williams, Ph.D.
The Speakers:
Chief Executive Officer Margaret Foti, PhD, MD (hc)
American Association for Cancer Research
Philadelphia, Pennsylvania
Margaret Foti, PhD, MD (hc), is the chief executive officer of the American Association for Cancer Research (AACR), the oldest cancer research organization in the world. Under her visionary leadership, membership has grown from about 3,000 members to 35,000 in 101 countries and the AACR’s portfolio of peer-reviewed scientific journals has increased from one to eight.
Chi Van Dang, MD, PhD
John H. Glick, M.D. Abramson Cancer Center Director’s Professor
Director, Abramson Cancer Center, University of Pennsylvania
Selected Publications:
Koppenol WH, Bounds PL, Dang CV: Otto Warburg’s contributions to current concepts of cancer metabolism. Nature Reviews Cancer 11 (5): 325-337,2011.
Dang CV, Hamaker M, Sun P, Le A, Gao P: Therapeutic targeting of cancer cell metabolism Journal of Molecular Medicine 89 (3): 205-212,2011.
Seltzer MJ, Bennett BD, Joshi AD, Gao P, Thomas AG, Ferraris DV, Tsukamoto T, Rojas C, Slusher BS, Rabinowitz JD, Dang CV, Riggins GJ: Inhibition of Glutaminase Preferentially Slows Growth of Glioma Cells with Mutant IDH1. Cancer Research 70 (22): 8981-8987,2010.
Otto AE, Hurd TW, Airik R, Chaki M, Zhou W, Stoetzel C, Patil SB, Levy S, Ghosh A K, Murga-Zamalloa CA, van Reeuwijk J, Letteboer SJF, Sang L, Giles RH, Liu Q, Coene KLM, Estrada-CuzcanA, Collin RWJ, McLaughlin HM, Held S, Kasanuki JM, Ramaswami G, Conte J, Lopez I, Washburn J, MacDonald J, Hu J, Yamashita Y, Maher ER, Guay-Woodford L, Neumann HPH, Obermüller N, Koenekoop RK, Bergmann C, Bei X, Lewis RA, Katsanis N, Lopes V, Williams DS, Lyons RH, Dang CV, Brito DA, Zhang X, Dias MB, Nürnberg G, Nürnberg P: Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nature Genetics 42 (10): 840-50,2010.
Dang CV: Glutaminolysis Supplying carbon or nitrogen or both for cancer cells? Cell Cycle 9 (19): 3884-3886,2010.
Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, Wilson KF, Ambrosio ALB, Dias SMG, Dang CV, Cerione RA: Targeting Mitochondrial Glutaminase Activity Inhibits Oncogenic Transformation. Cancer Cell 18 (3): 207-219,2010.
Koh, CM, Bierberich CJ, Dang CV, Nelson WG, Yegnaubramanian S, De Marzo A: Myc and prostate cancer. Genes & Cancer 1 (6): 617-628,2010.
Fan J, Zeller K, Chen YC, Watkins T, Barnes KC, Becker KG, Dang CV, Cheadle C: Time-Dependent c-Myc Transactomes Mapped by Array-Based Nuclear Run-On Reveal Transcriptional Modules in Human B Cells. Plos One 5 (3): e9691,2010.
Dang CV: p32 (C1QBP) and Cancer Cell Metabolism: Is the Warburg Effect a Lot of Hot Air? Molecular And Cellular Biology 30 (6): 1300-1302,2010.
Stephan A. Grupp, MD, PhD, is director of the Cancer Immunotherapy Frontier Program, director of Translational Research for the Center for Childhood Cancer Research at CHOP and medical director of the Stem Cell Laboratory.
Areas of Expertise: Development of engineered T cell therapies such as CTL019, Novel leukemia therapy, Stem cell transplants, Treatment of high-risk neuroblastoma
Working with our colleagues at the University of Pennsylvania, we have recently opened a phase I clinical trial called CART19. We’re using genetically modified T cells in this trial to treat patients with B cell cancers such as ALL, B cell non-Hodgkin lymphoma (NHL), the adult disease chronic lymphocytic leukemia and other B cell malignancies. T cells have the potential to kill cancer cells, but in patients with cancer, they’re not doing their job. By modifying them we can make the cells behave differently so they’ll attack cancer cells, using an engineered targeting protein called a chimeric antigen receptor (CAR). Initial results show that this could be an effective therapy for patients with B cell cancers. Indeed, our initial results show some of the most powerful activity against cancer of any clinical trial testing engineered cell therapy to date. This has received international attention, and some of this work has been published recently in Science Translational Medicine and the New England Journal of Medicine.
Prostate cancer is the most commonly diagnosed malignancy in the Unites States and the second leading cause of cancer death in men. Early prostate cancers require androgen to survive and proliferate; this dependence is exploited in treatment for disseminated disease. Wherein androgen ablation in the first line of therapeutic intervention. Although these regimens are initially effective, tumors ultimately recur due to reactivation of androgen receptor (AR) signaling, causing treatment failure and patient morbidity.
Despite the importance of understanding androgen action in the prostate, little is understood about the mechanisms underlying androgen dependence, and the means by which the androgen requirement is bypassed in relapsed tumors. My lab is dedicated to delineating the molecular mechanisms that govern these events. We currently have four main projects in the lab:
1. Regulation of AR dependent gene expression and cellular proliferation by cell cycle crosstalk in prostate cancer
2. Impact of SWI/SNF chromatin remodeling factors on AR function and prostate tumorigenesis
3. Impact of cell cycle deregulation on therapeutic efficacy
4. Role of endocrine disrupting compounds in circumventing the androgen requirement
By studying disease modifier genes we seek to develop new principles to treat cancer, diabetes, autoimmune disorders and cardiovascular disease. Currently most biomedical research focuses on understanding disease pathways. We seek to understand general disease modifier pathways that determine disease severity, an understudied area from which many useful drugs such as NSAIDs and statins are based. A major thrust of our present work focuses on modifiers of inflammatory processes which contribute significantly to the severity of many age-associated diseases. In our main project, we have developed a new class of drugs that recruit the immune system to eradicate a broad spectrum of advanced cancers, including breast, lung, skin, and pancreas tumors that are often refractory to chemotherapy. These drugs, called IDO inhibitors, are presently in Phase II clinical trials. In other projects, with our Lankenau colleagues we are developing new agents to treat autoimmune disorders, reduce risks of cardiovascular disease, and ameliorate diabetes.
Scientific Description
Our laboratory is interested primarily in cancer genes, cancer immunology and molecular therapeutics. We use transgenic mouse models and preclinical drug strategies to learn new ways to suppress cancer, focusing on long-term goals of improving strategies for cancer prognosis and treatment.
Localized tumors are often curable if they are detected before progression to invasive status, but many patients diagnosed with cancer already have invasive disease. What factors dictate malignant progression and how might they be therapeutically exploited? Molecular therapeutics that target key oncogene and tumor suppressor pathways show some clinical promise, but they have shown limited efficacy to date. Cancer modifier pathways that influence the immune microenvironment of tumor cells may strongly influence clinical course. Accordingly, new therapies we are developing are based on blocking enzymes that limit the ability of immune cells to destroy cancer cells or drive disease.
RhoB studies derive from our long-standing research on this member of the Ras/Rho superfamily in cancer cell signaling. Recent work in collaboration with Drs. Lisa Laury-Kleintop and Laura Mandik-Nayak at Lankenau has opened exciting new directions in studies of the role of RhoB in autoimmune and cardiovascular disease. A start-up company has been created to fund and advance the preclinical and clinical work needed to explore a provocative new therapy emerging from these novel directions, which in principle may be useful to treat one or more diseases in important areas of medicine.
Bin1 studies originating in cancer cell studies led us to discover that it regulates the immune modulatory enzyme indoleamine 2,3-dioxygenase (IDO). Bin1 modifies inflammation in a variety of settings including cancer. Recently, in preclinical studies we found that its genetic blockade can limit the development of inflammatory bowel disease (colitis). Based on this finding, we are now investigating the use of Bin1 antibodies we have developed to treat this disorder.
IDO is a tryptophan catabolic enzyme that blocks T cell activation in physiological settings such as pregnancy and in many pathophysiological settings like cancer. IDO is very widely activated as a mechanism of immune escape by cancer cells. Genetic studies reveal that IDO is essential for inflammation-driven cancers, not only supporting immune escape but also angiogenesis and metastasis. We pioneered preclinical studies of IDO inhibitory drugs that can arrest tumor growth and enhance chemotherapeutic efficacy. Mechanistic studies of one clinical lead inhibitor, D-1MT (indoximod), will greatly assist ongoing Phase II studies of this drug. Translational studies including on an IDO-related gene called IDO2 discovered at Lankenau are currently a major focus of the laboratory.
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Given the following speakers, this event will have a large focus on use of cancer immunotherapy as well as new targets in the precision medicine arena.
Register today: Philly.com/CancerEvent – Use the promo code “AACR” for discounted $45 tickets.
The genetic tests help refine diagnoses with greater precision than standard imaging tests and blood work by spotting known mutations that can inform the treatment plan. Since it launched in February 2013, the CPD has performed more than 4,000 advanced diagnostics, representing a wide range of cancers. It’s also producing actionable findings: Of those tests, 75 percent found disease-associated mutations, revealing possible new treatment pathways.
ACC’s role as a national leader in personalized cancer care was also reinforced with the opening of the Center for Rare Cancers and Personalized Therapy in 2015.
Directed by Marcia Brose, MD, PhD, this virtual center enrolls patients into clinical trials based on genetic markers rather than tumor origin. Patients with the same mutation, BRAF for instance, but different cancers, are part of the same clinical study investigating a targeted therapy. A story, set to air on TV news affiliates across the country in the upcoming weeks, will feature a patient with a rare salivary tumor who ran out of treatment options, until a HRAS mutation identified through the CPD put him back on track, after switching to the drug tipifarnib. The patient responded well, and a recent scan revealed that his disease has stabilized.
“Philadelphia is a hotbed for healthcare innovation and groundbreaking scientific research—which becomes even more apparent as the ACC continues to move the needle in the precision medicine world,”Abramson Cancer Center (ACC) director Chi Van Dang, MD, PhD, said. “Quickly evolving diagnostics and genetic tests, cancer vaccines, and powerful personalized therapies that use the body’s own immune system to fight off cancer: These are just a few of the medical advances being utilized today that are giving patients the greatest chance.”
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Kite and Alpine Immune Sciences Join Forces to Deliver Personalised Cancer Treatments
Curator: Rosalind Codrington, PhD
This curation was attributed to Stephen J. Williams, PhD as a result of 12/7/2022 e-mail:
From: Rosalind Codrington <rcods@hotmail.co.uk> Date: Wednesday, December 7, 2022 at 8:32 AM To: Aviva Lev-Ari <aviva.lev-ari@comcast.net> Subject: Website
Hello Aviva,
How are you? I hope that you remember me. I used to be a content writer (Rosalind Codrington) at LPBI. Would you be able to remove my profile from your website, please because I am not in science anymore.
Thank you, best regards
Rosalind
Kite Pharma is joining forces with Alpine Immune Sciences to target the immune synapse, the communications area between the antigen presenting cell and the T lymphocyte (FierceBiotech). Their approach is to specifically modify the T cells in the patient’s peripheral blood so that these T cells will target the patient’s tumour. Their engineered Autologous Cell Therapy (eACT) platform, allows them to modify in vitro the patient’s T cells so that they will express either chimeric antigen receptors (CAR) or T cell receptors (TCR).
They have devised single chain antibodies linked to intracellular T-cell activating domains and TCR to specifically target the tumour antigen in the patient. These modifications are introduced into the T-cells via a viral vector to express the CAR and TCR on these cells.
The CAR products are specifically engineered to target cell membrane antigens on the tumour cells, whilst the TCR products are able to target both the cell membrane and the intracellular antigens, giving these products a well rounded approach to targeting both solid tumours and haemtalogical malignancies.
Kite and Alpine Immune Science’s potential for delivering personalised tumour therapy is now being tested in clinical trials.
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