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Early Diagnosis

Reporter: Stephen J. Williams, Ph.D.

This post contains a curation of all Early Diagnosis posts on this site as well as a curation of the Early Detection Research Network.

Early Research Detection Network (EDRN)

Welcome to EDRN

The Early Detection Research Network (EDRN), an initiative of the National Cancer Institute (NCI), brings together dozens of institutions to help accelerate the translation of biomarker information into clinical applications and to evaluate new ways of testing cancer in its earliest stages and for cancer risk.

Getting Started…

Check out the EDRN Highlights — a listing of our accomplishments and milestones.

 

► Scientific Components ► For Public, Patients, Advocates
► Collaborative Opportunities (how to join EDRN) ► For Researchers

Highlights

Highlights of the accomplishments of the Early Detection Research Network.

A brief list of major EDRN-developed assays that have been adapted for clinical use is described in the table below:

Detection/Biomarker Assay Discovery Refine/Adapt for Clin Use Clinical Validation Clinical Translation
Blood proPSA FDA approved
Urine PCA3 FDA approved
OVA1™ for Ovarian Cancer FDA approved
ROMA Algorithm for CA125 and HE4 Tests for Pelvic Mass Malignancies FDA approved
Blood/DCP and AFP-L3 for Hepatocellular Carcinoma FDA approved
Blood GP73 Together with AFP-L3 used  for monitoring cirrhotic patients for HCC in China
MiPS (Mi Prostate Score Urine test), Multiplex analysis of T2-ERG gene fusion, PCA3 and serum PSA In CLIA Lab
FISH to detect T2S:Erg fusion for Prostate Cancer In CLIA Lab
GSTP1 methylation for repeat biopsies in prostate cancer In CLIA Lab
Mitochondrial deletion for detection of prostate cancer In CLIA Lab
Somalogic 12-marker panel for Lung Cancer In CLIA Lab
80-gene panel for Lung Cancer In CLIA Lab
Vimentin Methylation Marker for Colon Cancer In CLIA Lab
Galectin-3 ligand for detection of adenomas and colon cancer In CLIA Lab
8-gene panel for Barrett’s Esophagus In CLIA Lab
SOPs for Blood (Serum, Plasma), Urine, Stool Frequently used by biomarker research community
EDRN Pre/Validation Specimen Reference Sets (specimens from well characterized and matched cases and controls from specific disease spectra) Frequently used by biomarker research community

Since its inception in 1999 EDRN has achieved several key milestones, summarized below:

1998 through 2000: Inception and Inauguration of EDRN

2001 to 2003: Meeting the Challenges to Harness and Share Emerging Scientific Knowledge

  • EDRN Second Report, Translational Research to Identify Early Cancer and Cancer Risk, October 2002, http://edrn.nci.nih.gov/docs.) published.
  • EDRN joined the Gordon Research Conferences to co-host the New Frontiers in Cancer detection and Diagnosis in 2002.

 

  • Guidelines Set for Studies Measuring Biomarker Predictive Power Journal of National Cancer Institute (Vol. 93, No. 14, July 18, 2001).
  • EDRN Associate Membership Program Initiated: This novel approach to make EDRN inclusive has been extremely successful. EDRN has now more than 120 Associate Members who are significantly contributing to EDRN efforts in biomarker discovery, development and validation.

2003 to 2004: Network Surges Ahead in Real-time

  • Collaborative Discovery and Validation Projects:  More than 100 collaborative projects spanned the various organ sites. These projects are monitored through the EDRN’s electronic System Information System (eSIS).
  • EDRN Virtual Specimen Bank and Validation Management System Launched: The EDRN Virtual Specimen Bank, also known as ERNE knowledge system, was deployed to 10 institutions in early 2003, allowing a common web-based query to search for available specimens across the EDRN Clinical Epidemiology and Validation Centers https://ginger.fhcrc.org/edrn/imp/GateServlet?pwd. VSIMS was created to allow multiple studies to be administered efficiently by minimizing development time with standardization of information and data management across multiple activities and research sites. This system encompasses all the security features of Food and Drug Administration (FDA)-required auditing systems.
  • Partnership on the Plasma Proteome Project (PPP) Initiative of the Human Proteome Organization (HUPO): PPP project was initiated to evaluate multiple technology platforms, develop bioinformatic tools and standards for protein identification, and create a database of the plasma proteome. The entire study was published in the August issue of the journal Proteomics August 2005, Volume 4 (4), pp 1045-1450.

2005 to 2008: An Investment in Prevention

  • In late 2006, EDRN’s Program for Rapid, Independent Diagnostic Evaluation (PRIDE), was established (http://grants.nih.gov/grants/guide/notice-files/NOT-CA-07-003.html ) as an administrative means to assist extramural investigators in successfully conducting cross-laboratory validation of biomarkers. Ten applications have been reviewed and five are being supported.
  • EDRN underwent external reviews in 2007 and 2008.
  • The Canary Foundation, Palo Alto, CA signed a Memorandum of Understanding with EDRN, NCI on supporting prostate cancer surveillance network of investigators from seven institutions. The tissue and serum will be collected during a three-year period and will be made available to extramural scientists for discovery and validation research.
  • The Lustgarten Foundation, N.Y., funded 6 institutions to generate monoclonal antibodies and associated hybridoma cell lines for pancreatic cancer antigens (biomarkers) identified by EDRN and non-EDRN investigators. These resources will be stored at the NCI-Frederick Facility for distribution to extramural investigators.

2009 to 2011: Realizing Investment for Clinical Use

  • Two biomarker tests approved by FDA and two IVDs pending FDA review.
  • Six biomarker tests offered by CLIA labs.
  • One biomarker test approved for clinical use outside the USA

A Curation of Posts on Early Detection of Cancer and Other Early Detection Networks is Included Below

 

BRCA 1 and 2 and Early Detection of Cancer

Early Detection of Prostate Cancer: American Urological Association (AUA) Guideline

Mechanism involved in Breast Cancer Cell Growth: Function in Early Detection & Treatment

Warning signs may lead to better early detection of ovarian cancer

Cancer Detection

Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University

China, India, and Russia account for 46% of all new cancer cases globally, as well as 52% of cancer-related mortality per 4/2014 Lancet Oncology article

 

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New Generation of Platinated Compounds to Circumvent Resistance

Curator/Writer: Stephen J. Williams, Ph.D.

Resistance to chemotherapeutic drugs continues to be a major hurdle in the treatment of neoplastic disorders, irregardless if the drug is a member of the cytotoxic “older” drugs or the cytostatic “newer” personalized therapies like the tyrosine kinase inhibitors.  For the platinatum compounds such as cisplatin and carboplatin, which are mainstays in therapeutic regimens for ovarian and certain head and neck cancers, development of resistance is often regarded as the final blow, as new options for these diseases have been limited.

Although there are many mechanisms by which resistance to platinated compounds may develop the purpose of this posting is not to do an in-depth review of this area except to refer the reader to the book   Ovarian Cancer and just to summarize the well accepted mechanisms of cisplatin resistance including:

  • Decreased cellular cisplatin influx
  • Increased cellular cisplatin efflux
  • Increased cellular glutathione and subsequent conjugation, inactivation
  • Increased glutathione-S-transferase activity (GST) and subsequent inactivation, conjugation
  • Increased γ-GGT
  • Increased metallothionenes with subsequent conjugation, inactivation
  • Increased DNA repair: increased excision repair
  • DNA damage tolerance: loss of mismatch repair (MMR)
  • altered cell signaling activities and cell cycle protein expression

Williams, S.J., and Hamilton, T.C. Chemotherapeutic resistance in ovarian cancer. In: S.C. Rubin, and G.P. Sutton (eds.), Ovarian Cancer, pp.34-44. Lippincott, Wilkins, and Williams, New York, 2000.

Also for a great review on clinical platinum resistance by Drs. Maritn, Hamilton and Schilder please see the following Clinical Cancer Research link here.

This curation represents the scientific rationale for the development of a new class of platinated compounds which are meant to circumvent mechanisms of resistance, in this case the loss of mismatch repair (MMR) and increased tolerance to DNA damage.

An early step in the production of cytotoxicity by the important anticancer drug cisplatin and its analog carboplatin is the formation of intra- and inter-strand adducts with tumor cell DNA 1-3. This damage triggers a cascade of events, best characterized by activation of damage-sensing kinases (reviewed in 4), p53 stabilization, and induction of p53-related genes involved in apoptosis and cell cycle arrest, such as bax and the cyclin-dependent kinase inhibitor p21waf1/cip1/sdi1 (p21), respectively 5,6. DNA damage significantly induces p21 in various p53 wild-type tumor cell lines, including ovarian carcinoma cells, and this induction is responsible for the cell cycle arrest at G1/S and G2/M borders, allowing time for repair 7,8.  DNA lesions have the ability of  to result in an opening of chromatin structure, allowing for transcription factors to enter 56-58.  Therefore the anti-tumoral ability of cisplatin and other DNA damaging agents is correlated to their ability to bind to DNA and elicit responses, such as DNA breaks or DNA damage responses which ultimately lead to cell cycle arrest and apoptosis.  Therefore either repair of such lesions, the lack of recognition of such lesions, or the cellular tolerance of such lesions can lead to resistance of these agents.

resistmech2

Mechanisms of Cisplatin Sensitivity and Resistance. Red arrows show how a DNA lesion results in chemo-sensitivity while the beige arrow show common mechanisms of resistance including increased repair of the lesion, effects on expression patterns, and increased inactivation of the DNA damaging agent by conjugation reactions

 

 

 

 

 

 

 

 

 

 

 

 

 

 

mechPtresistance

 

 

Increased DNA Repair Mechanisms of Platinated Lesion Lead to ChemoResistance

 

DNA_repair_pathways

Description of Different Types of Cellular DNA Repair Pathways. Nucleotide Excision Repair is commonly up-regulated in highly cisplatin resistant cells

 

 

 

 

 

 

 

 

 

 

 

Loss of Mismatch Repair Can Lead to DNA Damage Tolerance

dnadamage tolerance

 

 

 

 

 

 

 

 

In the following Cancer Research paper Dr. Vaisman in the lab of Dr. Steve Chaney at North Carolina (and in collaboration with Dr. Tom Hamilton) describe how cisplatin resistance may arise from loss of mismatch repair and how oxaliplatin lesions are not recognized by the mismatch repair system.
Cancer Res. 1998 Aug 15;58(16):3579-85.

The role of hMLH1, hMSH3, and hMSH6 defects in cisplatin and oxaliplatin resistance: correlation with replicative bypass of platinum-DNA adducts.

Abstract

Defects in mismatch repair are associated with cisplatin resistance, and several mechanisms have been proposed to explain this correlation. It is hypothesized that futile cycles of translesion synthesis past cisplatin-DNA adducts followed by removal of the newly synthesized DNA by an active mismatch repair system may lead to cell death. Thus, resistance to platinum-DNA adducts could arise through loss of the mismatch repair pathway. However, no direct link between mismatch repair status and replicative bypass ability has been reported. In this study, cytotoxicity and steady-state chain elongation assays indicate that hMLH1 or hMSH6 defects result in 1.5-4.8-fold increased cisplatin resistance and 2.5-6-fold increased replicative bypass of cisplatin adducts. Oxaliplatin adducts are not recognized by the mismatch repair complex, and no significant differences in bypass of oxaliplatin adducts in mismatch repair-proficient and -defective cells were found. Defects in hMSH3 did not alter sensitivity to, or replicative bypass of, either cisplatin or oxaliplatin adducts. These observations support the hypothesis that mismatch repair defects in hMutL alpha and hMutS alpha, but not in hMutS beta, contribute to increased net replicative bypass of cisplatin adducts and therefore to drug resistance by preventing futile cycles of translesion synthesis and mismatch correction.

 

 

The following are slides I had co-prepared with my mentor Dr. Thomas C. Hamilton, Ph.D. of Fox Chase Cancer Center on DNA Mismatch Repair, Oxaliplatin and Ovarina Cancer.

edinborough2mmrtranslesion1

 

 

 

 

 

 

Multiple Platinum Analogs of Cisplatin (like Oxaliplatin )Had Been Designed to be Sensitive in MMR Deficient Tumors

edinborough2diffptanalogs

 

 

 

 

 

 

mmroxaliplatin

 

 

 

 

 

 

edinborough2ptanalogsresist

 

 

 

 

 

 

edinborough2relresistptanalogsdifflines

 

 

 

 

 

 

edinborough2msimlmh2refract

 

 

 

 

 

 

edinborough2gogoxaliplatintrial

 

 

 

 

 

 

 

Please see below video on 2015 Nobel Laureates and their work to elucidate the celluar DNA repair mechanisms.

Clinical genetics expert Kenneth Offit gives an overview of Lynch syndrome, a genetic disorder that can cause colon (HNPCC) and other cancers by defects in the MSH2 DNA mismatch repair gene. (View Video)

 

 

References

  1. Johnson, S. W. et al. Relationship between platinum-DNA adduct formation, removal, and cytotoxicity in cisplatin sensitive and resistant human ovarian cancer cells. Cancer Res 54, 5911-5916 (1994).
  2. Eastman, A. The formation, isolation and characterization of DNA adducts produced by anticancer platinum complexes. Pharmacology and Therapeutics 34, 155-166 (1987).
  3. Zhen, W. et al. Increased gene-specific repair of cisplatin interstrand cross-links in cisplatin-resistant human ovarian cancer cell lines. Molecular and Cellular Biology 12, 3689-3698 (1992).
  4. Durocher, D. & Jackson, S. P. DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme? Curr Opin Cell Biol 13, 225-231 (2001).
  5. el-Deiry, W. S. p21/p53, cellular growth control and genomic integrity. Curr Top Microbiol Immunol 227, 121-37 (1998).
  6. Ewen, M. E. & Miller, S. J. p53 and translational control. Biochim Biophys Acta 1242, 181-4 (1996).
  7. Gartel, A. L., Serfas, M. S. & Tyner, A. L. p21–negative regulator of the cell cycle. Proc Soc Exp Biol Med 213, 138-49 (1996).
  8. Chang, B. D. et al. p21Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cells. Oncogene 19, 2165-70 (2000).
  9. Davies, N. P., Hardman, L. C. & Murray, V. The effect of chromatin structure on cisplatin damage in intact human cells. Nucleic Acids Res 28, 2954-2958 (2000).
  10. Vichi, P. et al. Cisplatin- and UV-damaged DNA lure the basal transcription factor TFIID/TBP. Embo J 16, 7444-7456 (1997).
  11. Xiao, G. et al. A DNA damage signal is required for p53 to activate gadd45. Cancer Res 60, 1711-9 (2000).

Other articles in this Open Access Journal on ChemoResistance Include:

Cancer Stem Cells as a Mechanism of Resistance

An alternative approach to overcoming the apoptotic resistance of pancreatic cancer

Mutation D538G – a novel mechanism conferring acquired Endocrine Resistance causes a change in the Estrogen Receptor and Treatment of Breast Cancer with Tamoxifen

Can IntraTumoral Heterogeneity Be Thought of as a Mechanism of Resistance?

Nitric Oxide Mitigates Sensitivity of Melanoma Cells to Cisplatin

Heroes in Medical Research: Barnett Rosenberg and the Discovery of Cisplatin

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New Topoisomerase Inhibitors in Clinical Trials

Curator: Stephen J. Williams, Ph.D.

Below is a great review of topoisomerase in cancer, approved inhibitors as well as some in clinical trials.

Biomolecules 2015, 5, 1652-1670; doi:10.3390/biom5031652

OPEN ACCESS

biomolecules

ISSN 2218-273X

www.mdpi.com/journal/biomolecules/

Review

Inhibition of Topoisomerase (DNA) I (TOP1): DNA Damage Repair and Anticancer Therapy

Yang Xu and Chengtao Her *

School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Mail Drop 64-7520, Pullman, WA 99164, USA; E-Mail: davidxy22@vetmed.wsu.edu

* Author to whom correspondence should be addressed; E-Mail: cher@wsu.edu; Tel.: +1-509-335-7537; Fax: +1-509-335-4159.

Academic Editors: Wolf-Dietrich Heyer, Thomas Helleday and Fumio Hanaoka Received: 22 May 2015 / Accepted: 14 July 2015 / Published: 22 July 2015

Abstract: Most chemotherapy regimens contain at least one DNA-damaging agent that preferentially affects the growth of cancer cells. This strategy takes advantage of the differences in cell proliferation between normal and cancer cells. Chemotherapeutic drugs are usually designed to target rapid-dividing cells because sustained proliferation is a common feature of cancer [1,2]. Rapid DNA replication is essential for highly proliferative cells, thus blocking of DNA replication will create numerous mutations and/or chromosome rearrangements—ultimately triggering cell death [3]. Along these lines, DNA topoisomerase inhibitors are of great interest because they help to maintain strand breaks generated by topoisomerases during replication. In this article, we discuss the characteristics of topoisomerase (DNA) I (TOP1) and its inhibitors, as well as the underlying DNA repair pathways and the use of TOP1 inhibitors in cancer therapy.

Biomolecules 2015, 5                                                                                                                           1653

  1. Type IB Topoisomerases and Inhibitors
    1.1. TOP1

DNA topoisomerases resolve topological constraints that may arise from DNA strand separation and are therefore important for transcription and replication [4]. There are six topoisomerases in humans, classified as Type IA, IB and IIA. Type IA topoisomerases TOP3a and TOP3b cleave one DNA strand to relax only negative supercoiling. In addition, TOP3a forms the BTR complex with BLM and RMI1/2, which plays a role in the dissolution of double-Holliday junctions [5]. Type IIA topoisomerases TOP2a and TOP2b generate double-strand breaks on one DNA molecule to allow the passing of other DNA strands [6]. Topoisomerases are attractive drug targets in cancer therapy. For example, the commonly used anticancer agents doxorubicin and etoposide (VP-16) are TOP2 inhibitors [7]. Type IB topoisomerases include the nuclear TOP1 and mitochondrial TOP1mt [4]. TOP1 initiates the DNA relaxation by nicking one DNA strand. It then forms a TOP1-DNA cleavage complex (TOP1cc) by covalently linked to the 3′-phosphate end via its tyrosine residue Y723 (3′-P-Y). Following the resolution of topological entanglements and the removal of TOP1, the 5′-hydroxyl end is realigned with the 3′-end for religation. Each nicking-closing cycle enables the relaxation of one DNA supercoiling (Figure 1).

Figure 1. A schematic representation of strand passages catalyzed by three types of topoisomerases (adapted from ref. [8]).

fig1topto

TOP1 is essential for embryonic development in mammals [9]. Although TOP1 plays an important role in the deconvolution of supercoils arising amid DNA replication, the precise steps involved with

Biomolecules 2015, 5                                                                                                                         1654

the recruitment of TOP1 to topological constraints remains to be revealed. It appears that in yeast TOP1 travels at a distance of 600 bp ahead of the replication fork [10] and remains associated with the GINS-MCM complex [11]. However, the yeast TOP1 is distinct from its human counterpart in that it has little effect on fork progression or the firing of replication origin [12]. In humans, TOP1 binds to the regions of the pre-replicative complex in cells during the M, early G1, and G1/S phases of the cell cycle to control the firing of replication origins [12]. This difference may explain why yeast cells are viable in the absence of TOP1. In addition, TOP1 also has functions in transcription that are independent of its role in resolving DNA topological entanglements. First, TOP1 is known to repress transcription by binding to TFIID [13]. Second, inhibition of TOP1 can cause the induction of c-Jun in leukemia cells, suggesting its additional role in the control of transcription [14]. Furthermore, TOP1 interacts with the splicing factor ASF/SF2 by which it promotes the maturation of RNA—through suppressing the formation of R-loops (RNA-DNA hybrids)—and prevents collision between transcription bubble and replication fork [15,16]. It appears that the levels of TOP1 have to be dynamically regulated. In B cells, TOP1 is reduced by activation-induced cytidine deaminase (AID) to facilitate class-switch recombination (CSR) and somatic hypermutation (SHM) [17,18]. Although TOP1mt is important for mitochondrial integrity and metabolism, mice lacking mitochondrial TOP1mt are viable and fertile but they are associated with increased negative supercoiling of mtDNA [19,20].

1.2. TOP1 Inhibitors

Stabilization of TOP1cc by topoisomerase poison is detrimental to cells due to the disruption of DNA uncoiling, increased strand breaks, and unstable RNA transcripts as well as incomplete DNA replication [21]. The TOP1 inhibitor camptothecin (CPT), first isolated from the Chinese tree Camptotheca acuminate, was clinically used for cancer treatment long before it was identified as a TOP1 inhibitor [22]. Due to side effects, CPT is no longer used clinically and it has been replaced by more effective and safer TOP1 inhibitors [23]. Currently, CPT derivatives topotecan (trade name: Hycamtin) and irinotecan (CPT-11, trade name: Camptosar) are routinely used to treat colorectal, ovarian and lung cancers, while a few other TOP1 inhibitors are being tested in clinical trials.

CPT is a 5-ring alkaloid that is active in its closed E-ring (lactone) form but it is inactive with an open E-ring (carboxylate) at physiological and alkaline pH [24]. Therefore, CPT is not effective for inhibiting TOP1mt due to a higher pH mitochondrial environment. The inactive form of CPT tends to bind to serum albumin, which might be a reason for its side effects. CPT is highly specific for TOP1 and the binding is of relatively low affinity and can be reversed after drug removal. These features make the action of CPT controllable [24], and in fact CPT is widely used in studies of replication-associated DNA damage response. There are a few CPT derivatives and non-CPT TOP1 inhibitors [4,8,24]. For example, CPT derivatives Diflomotecan and S39625 were designed to stabilize the E-ring. Irinotecan has the bis-piperidine side chain to increase its water solubility, but it also contributes to some side effects. Non-CPTs—such as indolocarbazoles, phenanthrolines (e.g., ARC-111) and indenoisoquinolines—refer to drugs that have no typical CPT E-ring structures but they can still specifically target TOP1 and bind irreversibly to TOP1cc. Some of the CPT derivatives (i.e., Gimatecan and Belotecan) and non-CPTs (i.e., NSC 725776 and NSC 724998) are presently tested in clinical trials [23].

Biomolecules 2015, 5                                                                                                                           1655

How does CPT trap TOP1cc? Analysis of the crystal structure and modeling suggest that CPT-TOP1-DNA forms a ternary complex to prevent the two DNA ends from religation [25–27]. Although it is still controversial on how CPT is intercalated into DNA, it seems that CPT traps TOP1cc with a thymine (T) at the -1 position and a guanine (G) at the +1 position on the scissile strand, and it is therefore sequence-specific [28]. Three amino acid residues of the TOP1 enzyme, R364, D533 and N722, combined with DNA bases, contribute to the stabilization of the ternary complex by forming hydrogen bonds and hydrophobic interactions. It is of note that several point mutations, including N722S, in Camptotheca acuminata TOP1 confer resistance to CPT [29]. Interestingly, the same amino acids also contribute to the inhibition of TOP1 by non-CPT drugs [24].

  1. Repair of TOP1 Poison-Induced DNA Lesions

As aforementioned, CPT-induced trapping of TOP1cc creates a single strand break with a free 5′-hydroxyl group, whereas the 3′-phosphate is connected to Y723 of TOP1 (3′-P-Y). At least two pathways contribute to the repair of DNA lesions created by TOP1 poison [30]. The tyrosyl-DNA-phosphodiesterase (TDP1) pathway starts with the ubiquitination and proteasome-mediated degradation of TOP1 in the CPT-TOP1-DNA complex to generate a 3′-P end linked to a short peptide [31]. TDP1 then cleaves the P-Y bond to release the 3′-P end; however, the 3′-P end cannot be directly ligated to the 5′-OH end because of the requirements of DNA ligases. The human polynucleotide kinase (PNKP) can process the DNA ends by functioning as both a 3′-phosphatase and a kinase to generate the required 3′-OH and 5′-P termini for direct ligation. The rest of the repair events can be best described by the single-strand break (SSB) repair pathway, which will be discussed below. Indeed, TDP1 and PNKP are tightly associated with the SSB repair machinery [32,33].

The endonuclease pathway requires multiple endonucleases to excise the DNA—usually at a few nucleotides away from the 3′-P-TOP1 end – on the scissile strand to release the DNA-TOP1 complex [30]. Initial studies were carried out to identify genes that functioned in CPT repair in the absence of TDP1 in yeast [34,35]. These studies led to the identification of RAD1-RAD10, SLX1-SLX4, MUS81-MMS4, MRE11-SAE2 as well as genes involved in recombination. The RAD1-RAD10 (human XPF/ERCC4-ERCC1) complex is a DNA structure-specific endonuclease that can act on 5′ overhang structures [36]. Interestingly, the cleavage site of XPF-ERCC1 is in the non-protruding DNA strand, about 3–4 nucleotides away from the 3′ end [36]. Therefore, trapped TOP1ccs can be removed by this endonuclease activity. Likewise, MUS81-MMS4 (human MUS81-EME1) can also cleave nicked duplex at the 5′ of the nick [37]. The SLX1-SLX4 endonuclease, although not tested on nicked duplexes, is able to process 3′ flap and other DNA structures [38,39]. In human cells, SLX4 also associates with XPF-ERCC1 and MUS81-EME1 endonucleases to process specific DNA intermediates [39,40]. Moreover, MRE11-RAD50 cleaves the 3′-P-Y bond and resects DNA to produce a 3′-OH end [41]. A direct role of SAE2 (human CtIP) in processing 3′-P-TOP1 is unknown, and its endonuclease activity appears to be limited to the 5′ flap or DNA “hairpin” structures [42,43]. Nonetheless, the endonuclease activity of CtIP is essential for processing CPT adducts [42]. In addition, like CtIP, the 5′ flap endonuclease RAD27 (human FEN1) seems to be unable to directly process 3′-P-TOP1 ends [44]. However, the gap endonuclease activity of FEN1 is important for processing stalled replication forks and CPT-induced adducts [45]. The role of FEN1 in SSB repair will be discussed further in the next section.

Biomolecules 2015, 5                                                                                                                           1656

During DNA replication, SSBs created by CPT are most likely converted to double-strand breaks (DSBs) by replication fork runoff. This conversion appears to be dependent on the proteolysis of TOP1 [46]. The repair of one-ended DSBs, as will be discussed in the next section, is largely dependent on homologous recombination (HR). However, low doses of CPT may also induce PARP1 and/or RAD51 dependent replication fork regression—generating no or few DSBs [47,48]. The regressed fork leads to the formation of a “chicken foot” DNA structure by newly synthesized strands [3,49,50]. The formation of regressed fork can be largely suppressed by ATR, EXO1, and DNA2 [51–53]. However, fork reversal can also be beneficial as it provides time for the repair of TOP1-induced DNA lesions by TDP1, thereby preventing DSB formation and the activation of error-prone non-homologous end-joining (NHEJ) [30].

  1. Pathways Involved in the Repair of CPT-Induced DNA Lesions

Normal cells use DNA damage response (DDR) pathways to maintain genomic stability [54]. As aforementioned, SSB and DSB repair mechanisms are the two major DDR pathways that repair TOP1-induced DNA lesions. Paradoxically, cancer cells exploit DDR pathways to accumulate necessary genomic alterations for promoting proliferation. Furthermore, altered DDR and apoptotic responses in cancer cells are the major obstacles to successful chemotherapy. Thus, the delineation of TOP1-related SSB and DSB repair mechanisms is of great importance for identifying drug targets that can selectively affect cancer cell survival.

3.1. Single-Strand Break (SSB) Repair

Trapping of TOP1cc results in a 3′-P-TOP1 end and a 5′-OH terminus. Because the two ends cannot be directly religated, the persisting SSB is likely to be detected by PARP1 in which activated PARP1 catalyzes the synthesis of poly(ADP-ribose) (PAR) chains for recruiting repair proteins [55]. This reaction can be rapidly reversed by PARG, which hydrolyzes the PAR chains. The PAR chains at the SSB sites are important for the recruitment of XRCC1 that functions as a loading dock for other SSB repair proteins including TDP1 and PNKP. TDP1 generates 3′-P and PNKP converts 3′-P to 3′-OH, and PNKP also converts 5′-OH to 5′-P, making ends compatible for religation with no base loss. The rejoining of the 3′-OH and 5′-P ends is mainly mediated by LIG3, in which XRCC1 mediates the recruitment of LIG3.

If the trapped TOP1cc intermediates are processed by endonucleases, the initial SSBs will be converted to 3′-OH and 5′-OH ends with a gap over a few nucleotides (in the case of XPF-ERCC1, the loss is in the range of 3–4 nt), leading to the activation of PARP1 and XRCC1 recruitment. Consequentially, Pol3 recruited by XRCC1 can catalyze the gap filling, and PCNA-Polö/E also plays a role in this process [55]. If the 5′-OH is not processed by PNKP, the 5′-flap resulted from gap filling is likely to be removed by FEN1, which explains why FEN1 deficiency also leads to an increased CPT sensitivity. The final ligation is catalyzed by LIG1 because of the presence of PCNA.

Biomolecules 2015, 5                                                                                                                           1657

3.2. Double-Strand Break (DSB) Repair

Successful DSB repair requires concerted actions of proteins involved in DNA damage signaling and repair [54]. To repair TOP1 poison-induced DNA lesions, ATR signaling is required due to the runoff of replication fork and the presence of long single-strand DNA (ssDNA) [56]. The full activation of ATR follows a “two-man” rule—the ssDNA-ATRIP-dependent recruitment of ATR kinase and the RAD17 clamp loader/9-1-1/TOPBP1 mediator loading at the ssDNA-dsDNA junction. ATR phosphorylates CHEK1 to harness cell cycle arrest. If one-ended DSB is formed, ATM will be activated through the action of the MRE11-RAD50-NBS1 (MRN) complex. ATM mainly phosphorylates CHEK2 to mediate cell cycle arrest. Both ATM and ATR are able to phosphorylate hundreds of proteins in response to DSB formation [57]. One remarkable substrate is the histone H2AX, which can be phosphorylated by both kinases to yield g-H2AX. It is conceived that the propagation of g-H2AX signaling along the chromatin facilitates MDC1 recruitment and BRCA1 signaling via the MDC1-RNF8-RNF168-RAP80 ubiquitin cascade—events that are essential for HR [58].

The repair of TOP1 poison-induced DNA lesions is in essence the repair of one-ended DSBs, which facilitates the restoration of replication forks to restart DNA replication. It is important to note that one-ended DSB repair occurs in the S phase and relies on HR rather than NHEJ [59]. The first step in HR is end resection to generate a 3′-overhang for homology searching. A TOP1 cleavage in the leading strand may require end resection by the MRN-CtIP-BRCA1 and BLM-EXO1-DNA2 complexes [60], whereas a cleavage in the lagging strand automatically forms a 3′-overhang. Rad51 then associates with the 3′-ssDNA to form a nucleofilament for strand invasion, which leads to the formation of a D-loop structure [61]. This process continues with DNA synthesis, branch migration and the resolution of Holliday junction structures to reconstitute a functional replication fork [62]. TOP1 poisons can also lead to the formation of two-ended DSB if two replication forks collide into each other at the site of SSB. The repair of this type of DSBs is not aimed for fork restoration and can be accomplished by the classical DSB repair mechanisms [61].

3.3. Genes Involved in CPT-Induced Damage Repair

A long list of genes, in which mutations confer sensitivity to CPT in yeast, chicken or mammalian cells, has been compiled [24,30,63]. With no surprise, many genes involved in SSB and DSB repair are on the list, such as PARP1, XRCC1, PNKP, TDP1 for SSB repair; MRN, ATM-CHK2, ATR-CHK1 for DSB signaling; BRCA1/2, XRCC2, XRCC3 for HR. Most recently, the hMSH5-FANCJ complex has also been implicated to play a role in CPT-induced DNA damage response and repair [64]. Mutations in the binding partners of these repair factors are also likely to sensitize cells to CPT treatment. For example, depletion of the MRN-binding partner hnRNPUL increases the sensitivity to CPT [65]; and deficiencies in ZRANB3 and SPIDR, binding partners of PCNA and RAD51, cause CPT hypersensitivity in cancer cells [66–68]. In addition, the two DNA helicases BLM and WRN have also been implicated in the repair of CPT-induced DNA lesions [69,70]. Early studies revealed that chicken BLM knockout cells and human BLM-deficient fibroblasts showed increased sensitivity to CPT [71,72]. On the contrary, mouse BLM knockout embryonic stem cells showed mild resistance to

Biomolecules 2015, 5                                                                                                                           1658

CPT [73]. This discrepancy is likely attributable to the complexity of CPT-induced DNA lesion repair as well as different treatment conditions and experimental systems.

Interstrand crosslinks (ICLs) resemble CPT-induced lesions in that they block both replication and transcription [74]. They may induce replication fork reversal and fork collapse, which require DNA incision for lesion processing and HR for repair. ICL repair is accomplished by the coordinated actions of 17 Fanconi anemia (FA) genes whose mutations contribute to FA in patients [75]. Depletion of FANCP/SLX4 or FANCQ/XPF causes cellular sensitivity to CPT because they form an endonuclease complex involved in the repair of trapped TOP1cc [38]. Likewise, depletion of FANCS/BRCA1, FANCD1/BRCA2, FANCN/PALB2 or FANCO/RAD51C sensitizes cells to CPT because of their involvement in HR [76]. Accordingly, depletion of the FA core complex except FANCM—involved in fork reversal—is not expected to increase CPT sensitivity because they are unable to recognize the trapped TOP1cc [76]. However, the roles of FANCI, D2, J and FAN1 in the process are elusive due to conflicting reports presumably reflecting different experimental systems [76–78]. For example, in a multicolor competition assay, loss of FANCI or FAN1 rendered cells sensitive to CPT treatment [77]. However, this observation could not be recapitulated in studies performed with FANCI-deficient lymphoblasts and FAN1-depleted HEK293 cells [76,79], indicating that the involvement of these two genes in CTP sensitivity might be cell type specific.

It is interesting to note that the MMS22L-TONSL complex plays a prominent role in mediating CPT sensitivity [80–83]. Depletion of this complex impairs RAD51 foci formation and triggers G2/M arrest, indicating that the MMS22L-TONSL complex participates in HR repair. Furthermore, this complex associates with MCM, FACT, ASF1 and histones. FACT and ASF1 are histone chaperones that function in H2A/H2B and H3/H4 chromatin assembly and disassembly, respectively [84]. They recycle parental histones from old DNA strands unwound by MCM and incorporate them into newly synthesized DNA strands. FACT and ASF1 also function in checkpoint signaling; therefore the involvement of MMS22L-TONSL in CPT response implies the existence of a close association between HR, DNA damage signaling and replication restart.

  1. TOP1 Inhibition in Cancer Treatment

The understanding of the function of TOP1 and the cellular effects of TOP1 inhibition has been a stepping-stone for the development of effective CPT derivatives in cancer therapy. Since TOP1 functions in normal and cancer cells, the use of low doses of TOP1 inhibitors are actively sought to treat cancers that heavily rely on the function of TOP1 for survival (e.g., highly malignant, rapid-dividing tumor cells). In fact, the FDA-approved CPT derivatives topotecan and irinotecan are currently used to treat ovarian and colorectal cancers, respectively [24].

Furthermore, the promising results from a Phase I trial have warranted further evaluation of the CPT derivative Diflomotecan in Phase II trials [85]. Other derivatives like Gimatecan, Lurtotecan and Exatecan are also being tested in clinical trials (Table 1). The non-CPT indolocarbazole BMS-250749 showed great anti-tumor activity against preclinical xenograft models [86], but no further evaluation beyond Phase I trials is presently available (Table 2). Another indolocarbazole compound Edotecarin has shown promising anti-tumor activity in xenograft models and it is now advanced to Phase II studies of patients with advanced solid tumors [87]. By contrast, Phenanthroline ARC-111 (topovale)

Biomolecules 2015, 5                                                                                                                             1659

was potently against human tumor xenografts and displayed anti-cancer activity in colon and Wilms’ tumors [88]; however, no result from Phase I clinical trials is available owing to profound bone marrow toxicity [89]. To date, indenoisoquinolines are the most promising non-CPT inhibitors in clinical trials. LMP400 (NSC 743400, indotecan) and LMP776 (NSC 725776, indimitecan) show significant anti-tumor activities in animal models and both are being evaluated in Phase I clinical trials for relapsed solid tumors and lymphomas [8,90].

Table 1. CPT derivatives in clinical trials [91].

Name                            Structure                     Clinical Trial            Malignancy        Reference

Biomolecules 2015, 5                                                                                                                           1660

Given the observation that CPT-mediated TOP1 inhibition provokes DNA repair activities, a synergistic effect is then anticipated on cancer cells by inhibition of TOP1 and downregulation of DNA repair activities. The rationale for this approach is to accelerate the accumulation of DNA breaks and trigger cellular apoptosis, probably through mitotic catastrophe [92]. Which DNA repair pathways can we exploit? Currently, the major interests are in SSB and DSB repair mechanisms. Indeed, PARP inhibitors can enhance the cytotoxicity of TOP1 inhibitors in cancer cell lines as well as in mouse models [93–96]. Phase I studies of combination therapy using PARP inhibitors veliparib or olaparib (FDA-approved) together with topotecan were carried out in patients with advanced solid tumors but showed some dose-dependent side effects [97,98]. TDP1 can be another potential target because it functions directly downstream of PARP1 in the repair of TOP1 poison-induced DNA lesions [99]. TDP1 inhibitors sensitize cells to CPT treatment in vitro [100,101], however in vivo evaluation is presently unavailable due to unsuitable properties of the compounds [102].

Table 2. Non-CPT derivatives in preclinical and clinical trials [91].

Name                       Structure               Clinical Trial            Malignancy             Reference

Indolocarbazoles
(Edotecarin,
BMS-250749)
Phase II

(Edotecarin, Pfizer)

Stomach, breast
neoplasms
Preclinical
(BMS-250749)
Anti-tumor activity
in preclinical
xenograft models
[86,87,103]
Phenanthridines
(ARC-111/topovale)
Anti-tumor activity

Preclinical                    in preclinical            [88,89,103]
xenograft models

Indenoisoquinolines
(LMP400, LMP776)
Phase I                              Lymphomas             [8,90,103]

DSB repair can be targeted by either inhibition of DSB signaling or inhibition of HR. ATM and ATR inhibitors can largely increase the sensitivity to CPT in cancer cells [104,105]. This can be explained by the fact that abrogation of the cell cycle arrest will allow cells with unreplicated or unrepaired chromosomes to enter mitosis thereby triggering mitotic catastrophe and cell death. Similarly, CHEK1 and CHEK2 inhibitors are tested in Phase I studies in combination with irinotecan [106,107]. Inhibitors that can directly block HR proteins are very limited [108]. This is partially attributed to the fact that HR genes are often mutated in cancer cells, thus diminishing the enthusiasm for developing HR inhibitors. One diterpenoid compound, however, was found to be able to inhibit the function of BRCA1 and render cytotoxicity in human prostate cancer cells [109]. Several RAD51 inhibitors have also been

Biomolecules 2015, 5                                                                                                                           1661

identified but have not been tested in cell lines [110]. Inhibition of BRCA1 and RAD51 can be also achieved indirectly by harnessing corresponding kinases [106]. Clearly, defective hMRE11 sensitizes colon cancer cells to CPT treatment [111]. Although MRE11-deficeint tumor xenografts failed to display significant growth inhibition by irinotecan alone, combining thymidine with irinotecan caused a dramatic growth delay [112].

TOP1 inhibitors might be also useful for treating cancers with BRCA1/2 mutations. The successful use of PARP inhibitors in treating BRCA1/2-deficient tumors has ignited a broad interest in searching for synthetic lethality among DNA damage response and repair genes [113,114]. In the PARP-BRCA1/2 example, the accumulation of SSBs by PARP inhibition would lead to the formation of DSBs during replication. In HR-deficient cells, DSBs can only be repaired by illegitimate (toxic) NHEJ—joining one-ended DSBs from different locations—leading to cell death [115,116]. However, resistance to PARP inhibitors can arise in BRCA1-deficient tumors during treatment from either genetic reversion of BRCA1 mutations or the loss of NHEJ [117–122]. Therefore, it would be beneficial to explore the possibility of developing a similar synthetic lethal strategy to use TOP1 inhibitors in the treatment of BRCA1/2-deficient tumors.

Figure 2. An overview of the effects of TOP1 inhibition is provided. Inhibitors and key DNA repair factors are highlighted.

Biomolecules 2015, 5                                                                                                                         1662

  1. Conclusions

Trapping of TOP1 by inhibitors generates SSBs and DSBs that are repaired by their corresponding repair pathways (Figure 2). Therefore, developing effective TOP1 inhibitors not only provides powerful tools to study DNA replication and repair but also establishes a foundation to devise new synthetic lethal strategies for efficient cancer treatments. The accumulation of DNA strand breaks (SSBs and DSBs) by TOP1 inhibition in HR-deficient tumor cells is expected to enhance cytotoxicity. However, increased DNA repair activities in cancer cells can make TOP1 inhibitors less effective, so silencing of repair pathways in conjunction with the use of TOP1 inhibitors offers an attractive new means for cancer control. Since each tumor is unique, it would be advantageous to identify the individualities of DNA repair pathways or biomarkers reflecting the changes of DNA repair activities in tumor cells [92,123]. This will make it possible to achieve better and predictable prognosis through tailored therapeutic regimens. Given that TOP1 is essential for transcription and DNA replication, future design of novel TOP1 inhibitors and combinational therapy strategies should aim to increase therapeutic efficacy of the inhibitors, thus reducing side effects.

Acknowledgments

The work in the Her laboratory is supported by the NIH grant GM084353.

Author Contributions

Yang Xu and Chengtao Her wrote and revised the article.

Conflicts of Interest

The authors declare that they have no conflicts of interest with the contents of this article.

Please see the following file for the referencesReferences for top paper

From a 2015 Clinical Cancer Research paper:

Phase 1 clinical pharmacology study of F14512, a new polyamine-vectorized anti-cancer drug, in naturally occurring canine lymphoma

Dominique Tierny1, Francois Serres1, Zacharie Segaoula1, Ingrid Bemelmans1, Emmanuel Bouchaert1,

Aurelie Petain2, Viviane Brel3, Stephane Couffin4, Thierry Marchal5, Laurent Nguyen6, Xavier Thuru7,

Pierre Ferre2, Nicolas Guilbaud8, and Bruno Gomes9,*

Abstract

Purpose: F14512 is a new topoisomerase II inhibitor containing a spermine moiety that facilitates selective uptake by tumor cells and increases topoisomerase II poisoning. F14512 is currently in Phase I/II clinical trial in patients with acute myeloid leukemia. The aim of this study was to investigate F14512 potential in a new clinical indication. Because of the many similarities between human and dog lymphomas, we sought to determine the tolerance, efficacy, PK/PD relationship of F14512 in this indication, and potential biomarkers that could be translated into human trials. Experimental design: Twenty-three dogs with stage III-IV naturally occurring lymphomas were enrolled in the Phase 1 dose-escalation trial which consisted of three cycles of F14512 intravenous injections. Endpoints included safety and therapeutic efficacy. Serial blood samples and tumor biopsies were obtained for PK/PD and biomarker studies. Results: Five dose levels were evaluated in order to determine the recommended dose. F14512 was well tolerated, with the expected dose-dependent hematological toxicity. F14512 induced an early decrease of tumoral lymph node cells, and a high response rate of 91% (21/23) with 10 complete responses, 11 partial responses, 1 stable disease and 1 progressive disease. Phosphorylation of histone H2AX was studied as a potential pharmacodynamic biomarker of F14512. Conclusions: This trial demonstrated that F14512 can be safely administered to dogs with lymphoma resulting in strong therapeutic efficacy. Additional evaluation of F14512 is needed to compare its efficacy with standards of care in dogs, and to translate biomarker and efficacy findings into clinical trials in humans.

AND From ASCO 2015 Annual Meeting

Survival impact of switching to different topoisomerase I or II inhibitors-based regimens (topo-I or topo-II) in extensive-disease small cell lung cancer (ED-SCLC): supplemental analysis from JCOG0509.

Abstract:

Background: The J0509 (phase III study for chemotherapy-naive ED-SCLC) demonstrated amrubicin plus cisplatin (AP) was inferior to irinotecan plus cisplatin (IP). However, median overall survival (OS) of both AP and IP (15 and 17 mo) was more favorable than those of previous trials (9-12 mo), probably because switching to different topo-I or topo-II in the second-line therapy, especially the use of topo-II in IP arm, was frequent. This analysis aimed to investigate whether observed survival benefit of IP arm can be explained by the treatment switching, and how post-protocol chemotherapy affected the result of J0509. Methods: Two analysis sets from J0509 were used: all randomized 283 pts and 250 pts who received post-protocol chemotherapy. One pt without initiation date of second-line therapy was excluded. A rank-preserving structural failure time (RPSFT) model was used to estimate “causal survival benefit” that would have been observed if all pts had been followed with the same type of regimen as randomized throughout the follow-up period. Additionally, to assess the survival impact of second-line use of topo-II, OS after initiating second-line therapy (OS2) was analyzed by multivariate Cox models. Results: %treatment switching in IP arm and AP arm was 65.2% (92/141) and 43.7% (62/142). By RPSFT model, estimated OS excluding the effect of the treatment switching was 2.7-fold longer in IP (topo-I) arm than AP (topo-II) arm. This causal survival benefit was stronger than the original report of J0509 (nearly 1.4-fold extension by Cox model), indicating that re-challenging topo-I in IP arm appeared beneficial. The multivariate Cox analysis for OS2 (n = 250) revealed second-line use of topo-II was detrimental (hazard ratio, 1.5; 95%CI, 1.1-2.1). Among sensitive relapsed pts in IP arm, OS2 was favorable in the following order: irinotecan-based regimen > the other topo-I > topo-II. Conclusions: IP remains the standard therapy. Re-challenging topo-I, especially irinotecan-based topo-I, seemed beneficial for IP-sensitive pts. This result should be confirmed in further investigations with large sample size. Clinical trial information: 000000720.

 

 

 

 

Below is actively recruiting clinical trials evaluating topoisomerase inhibitors. Shown are only a few trials for a complete list from CancerTrials.gov please see this link:

https://clinicaltrials.gov/ct2/results?term=topoisomerase+inhibitor&recr=Open#wrapper

A service of the U.S. National Institutes of Health

897 studies found for:    topoisomerase inhibitor | Open Studies

Include only open studies Exclude studies with Unknown status

Status Study
Recruiting A Study of Standard Treatment +/- Enoxaparin in Small Cell Lung Cancer

Condition: Small Cell Lung Cancer
Interventions: Drug: cisplatinum or carboplatin and e.g.etoposide.;   Drug: cisplatinum or carboplatin and e.g.etoposide+enoxaparin
Recruiting A Phase I Study of Indenoisoquinolines LMP400 and LMP776 in Adults With Relapsed Solid Tumors and Lymphomas

Conditions: Neoplasms;   Lymphoma
Interventions: Drug: LMP 400;   Drug: LMP 776
Recruiting A Dose-Ranging Study Evaluating the Efficacy, Safety, and Tolerability of GSK2140944 in the Treatment of Uncomplicated Urogenital Gonorrhea Caused by Neisseria Gonorrhoeae

Condition: Gonorrhea
Intervention: Drug: GSK2140944
Recruiting Selinexor in Combination With Irinotecan in Adenocarcinoma of Stomach and Distal Esophagus

Conditions: Esophageal Cancer;   Gastric Cancer
Interventions: Drug: Selinexor;   Drug: Irinotecan
Recruiting Multimodal Molecular Targeted Therapy to Treat Relapsed or Refractory High-risk Neuroblastoma

Condition: Neuroblastoma Recurrent
Interventions: Drug: Dasatinib;   Drug: Rapamycin;   Drug: Irinotecan;   Drug: Temozolomide
Unknown  Study of the Farnesyl Transferase Inhibitor, R115777, in Combination With Topotecan (NYU 99-32)

Condition: Cancer
Interventions: Drug: R115777 (farnesyl transferase inhibitor);   Drug: Topotecan
Recruiting Pegylated Irinotecan NKTR 102 in Treating Patients With Relapsed Small Cell Lung Cancer

Condition: Recurrent Small Cell Lung Carcinoma
Interventions: Other: Laboratory Biomarker Analysis;   Drug: Pegylated Irinotecan;   Other: Pharmacological Study
Recruiting Selinexor and Chemotherapy in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

Conditions: Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities;   Adult Acute Myeloid Leukemia With Del(5q);   Adult Acute Myeloid Leukemia With Inv(16)(p13;q22);   Adult Acute Myeloid Leukemia With t(15;17)(q22;q12);   Adult Acute Myeloid Leukemia With t(16;16)(p13;q22);   Adult Acute Myeloid Leukemia With t(8;21)(q22;q22);   Recurrent Adult Acute Myeloid Leukemia;   Secondary Acute Myeloid Leukemia
Interventions: Drug: mitoxantrone hydrochloride;   Drug: etoposide;   Drug: cytarabine;   Drug: selinexor;   Other: laboratory biomarker analysis;   Other: pharmacological study
Recruiting WEE1 Inhibitor MK-1775 and Irinotecan Hydrochloride in Treating Younger Patients With Relapsed or Refractory Solid Tumors

Conditions: Childhood Solid Neoplasm;   Recurrent Childhood Medulloblastoma;   Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor;   Recurrent Neuroblastoma
Interventions: Drug: Irinotecan Hydrochloride;   Other: Laboratory Biomarker Analysis;   Other: Pharmacological Study;   Drug: WEE1 Inhibitor AZD1775
Recruiting PARP Inhibitor BMN-673 and Temozolomide or Irinotecan Hydrochloride in Treating Patients With Locally Advanced or Metastatic Solid Tumors

Conditions: Metastatic Cancer;   Unspecified Adult Solid Tumor
Interventions: Drug: PARP inhibitor BMN-673;   Drug: temozolomide;   Drug: irinotecan hydrochloride;   Other: pharmacological study;   Other: laboratory biomarker analysis
Recruiting A Phase II Multicenter, Randomized, Placebo Controlled, Double Blinded Clinical Study of KD018 as a Modulator of Irinotecan Chemotherapy in Patients With Metastatic Colorectal Cancer

Condition: Colorectal Neoplasms
Interventions: Drug: KD018;   Drug: Irinotecan;   Drug: Placebo
Recruiting The Efficacy of the 7 Days Tailored Therapy as 2nd Rescue Therapy for Eradication of H. Pylori Infection

Condition: Helicobacter Infection
Interventions: Procedure: H. pylori culture and antimicrobial susceptibility testing;   Drug: 14 days empirical bismuth quadruple therapy (Proton pump inhibitor);   Drug: Metronidazole;   Drug: Tetracycline;   Drug: tripotassium dicitrate bismuthate;   Drug: 7 days tailored therapy Proton Pump Inhibitor;   Drug: Moxifloxacin;   Drug: Amoxicillin
Recruiting G1T28 (CDK 4/6 Inhibitor) in Combination With Etoposide and Carboplatin in Extensive Stage Small Cell Lung Cancer (SCLC)

Condition: Small Cell Lung Cancer
Interventions: Drug: G1T28 + carboplatin/ etoposide;   Drug: Placebo + carboplatin/ etoposide
Recruiting Trial of Topotecan With VX-970, an ATR Kinase Inhibitor, in Small Cell Lung Cancer

Conditions: Carcinoma, Non-Small -Cell Lung;   Ovarian Neoplasms;   Small Cell Lung Carcinoma;   Uterine Cervical Neoplasms;   Carcinoma, Neuroendocrine
Interventions: Drug: Topotecan;   Drug: VX-970
Recruiting Prospective Analysis of UGT1A1 Promoter Polymorphism for Irinotecan Dose Escalation in Metastatic Colorectal Cancer Patients Treated With Bevacizumab Combined With FOLFIRI as the First-line Setting

Condition: Metastatic Colorectal Cancer
Interventions: Genetic: UGT1A1 genotyping (6,6);   Genetic: UGTIA1 genotyping (6,7);   Genetic: UGTIA1 genotyping (7,7);   Genetic: UGT1A1 non-genotyping;   Drug: bevacizumab (Avastin);   Drug: irinotecan;   Drug: Leucovorin;   Drug: 5-FU
Recruiting A Study of the Bruton’s Tyrosine Kinase Inhibitor, PCI-32765 (Ibrutinib), in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma

Condition: Lymphoma
Interventions: Drug: Ibrutinib;   Drug: Placebo;   Drug: Rituximab;   Drug: Cyclophosphamide;   Drug: Doxorubicin;   Drug: Vincristine;   Drug: Prednisone (or equivalent)
Recruiting Irinotecan Combination Chemotherapy for Refractory or Relapsed Brain Tumor in Children and Adolescents

Condition: Brain Tumor
Intervention: Drug: Irinotecan combination chemotherapy
Recruiting A Study To Evaluate PF-04449913 With Chemotherapy In Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome

Condition: Acute Myeloid Leukemia
Interventions: Drug: PF-04449913;   Drug: Low dose ARA-C (LDAC);   Drug: Decitabine;   Drug: Daunorubicin;   Drug: Cytarabine
Recruiting Veliparib and Pegylated Liposomal Doxorubicin Hydrochloride in Treating Patients With Recurrent Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer or Metastatic Breast Cancer

Conditions: Estrogen Receptor Negative;   HER2/Neu Negative;   Male Breast Carcinoma;   Progesterone Receptor Negative;   Recurrent Breast Carcinoma;   Recurrent Fallopian Tube Carcinoma;   Recurrent Ovarian Carcinoma;   Recurrent Primary Peritoneal Carcinoma;   Stage IV Breast Cancer;   Triple-Negative Breast Carcinoma
Interventions: Other: Laboratory Biomarker Analysis;   Drug: Pegylated Liposomal Doxorubicin Hydrochloride;   Other: Pharmacological Study;   Drug: Veliparib
Recruiting A Study To Evaluate Ara-C and Idarubicin in Combination With the Selective Inhibitor Of Nuclear Export (SINE) Selinexor (KPT-330) in Patients With Relapsed Or Refractory AML

Condition: Acute Myeloid Leukemia (Relapsed/Refractory)
Interventions: Drug: Selinexor;   Drug: Idarubcin;   Drug: Cytarabine

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Can IntraTumoral Heterogeneity Be Thought of as a Mechanism of Resistance?

Curator/Reporter: Stephen J. Williams, Ph.D.

Therapeutic resistance remains one of the most challenging problems for the oncologist, despite the increase of new therapeutics in the oncologist’s toolkit. As new targeted therapies are developed, and new novel targets are investigated as potential therapies, especially cytostatic therapies which it has become evident our understanding of chemoresistance is expanding beyond mechanisms to circumvent a drug’s pharmacologic mechanism of action (i.e. increased DNA repair and cisplatin) or pharmacokinetic changes (i.e. increased efflux by acquisition of a MDR phenotype).

In a talk at the 2015 AACR National Meeting, Dr. Charles Swanton discusses the development of tumor heterogeneity in the light of developing, or acquired, drug resistance. Chemoresistance is either categorized as acquired resistance (where resistance develops upon continued exposure to drug) or inherent resistance (related to a tumor being refractory or unresponsive to drug). Dr Swanton discusses findings where development of this heterogeneity (discussed here in a posting on Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing) and here (Notes On Tumor Heterogeneity: Targets and Mechanisms, from the 2015 AACR Meeting in Philadelphia PA) on recent findings on Branched Chain Heterogeneity) is resulting in clones resistant to the initial drug treatment.

To recount a bit of background I list the overall points of the one of previous posts on tumor heterogeneity (and an interview with Dr. Charles Swanton) are as follows:

Multiple biopsies of primary tumor and metastases are required to determine the full mutational landscape of a patient’s tumor

The intratumor heterogeneity will have an impact on the personalized therapy strategy for the clinician

Metastases arising from primary tumor clones will have a greater genomic instability and mutational spectrum than the tumor from which it originates

Tumors and their metastases do NOT evolve in a linear path but have a branched evolution and would complicate biomarker development and the prognostic and resistance outlook for the patient

 

The following is a curation of various talks and abstracts from the 2015 AACR National Meeting in Philadelphia on effects of clonal evolution and intratumoral heterogeneity of a tumor with respect to development of chemoresistance. As this theory of heterogeneity and clonal evolution is particularly new I attempted to present all works (although apologize for the length upfront) to forgo bias and so the reader may extract any information pertinent to their clinical efforts and research. However I will give a brief highlight summary below:

 

From the 2015 AACR National Meeting in Philadelphia

 

 

 

 

PresentationNumber:NGO2

Presentation Title: Polyclonal and heterogeneous resistance to targeted therapy in leukemia
Presentation Time: Monday, Apr 20, 2015, 10:40 AM -10:55 AM
Location: Room 201, Pennsylvania Convention Center
Author Block: Catherine C. Smith, Amy Paguirigan, Chen-Shan Chin, Michael Brown, Wendy Parker, Mark J. Levis, Alexander E. Perl, Kevin Travers, Corynn Kasap, Jerald P. Radich, Susan Branford, Neil P. Shah. University of California, San Francisco, CA, Fred Hutchinson Cancer Research Center, Seattle, WA, Pacific Biosciences, Menlo Park, CA, Royal Adelaide Hospital, Adelaide, Australia, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, University of California, San Francisco, CA
Abstract Body: Genomic studies in solid tumors have revealed significant branching intratumoral clonal genetic heterogeneity. Such complexity is not surprising in solid tumors, where sequencing studies have revealed thousands of mutations per tumor genome. However, in leukemia, the genetic landscape is considerably less complex. Chronic myeloid leukemia (CML) is the human malignancy most definitively linked to a single genetic lesion, the BCR-ABL gene fusion. Genome wide sequencing of acute myeloid leukemia (AML) has revealed that AML is the most genetically straightforward of all extensively sequenced adult cancers to date, with an average of 13 coding mutations and 3 or less clones identified per tumor.
In CML, tyrosine kinase inhibitors (TKIs) of BCR-ABL have resulted in high rates of remission. However, despite excellent initial response rates with TKI monotherapy, patients still relapse, including virtually all patients with Philadelphia-positive acute lymphoblastic leukemia and blast crisis CML. Studies of clinical resistance highlight BCR-ABL as the sole genetic driver in CML as secondary kinase domain (KD) mutations that prevent drug binding are the predominant mechanism of relapse on BCR-ABL TKIs.
In AML, a more diverse panel of disease-defining genetic mutations has been uncovered. However, in individual patients, a single oncogene can still drive disease. This is the case in FLT3 mutant AML, in which the investigational FLT3 TKI quizartinib achieved an initial response rate of ~50% in relapsed/refractory AML patients with activating FLT3 internal tandem duplication (ITD) mutations, though most patients eventually relapsed. Confirming the importance of FLT3 in disease maintenance, we showed that 8 of 8 patients who relapsed on quizartinib did so due to acquired drug-resistant FLT3 KD mutations.
Studies in CML have revealed that sequential TKI therapy is associated with additional complexity where multiple mutations can coexist separately in an individual patient (“polyclonality”) or in tandem on a single allele (“compound mutations”). In AML, we observed polyclonal FLT3-ITD KD mutations in 2 of 8 patients examined in our initial study of quizartinib resistance.
In light of the polyclonal KD mutations observed in CML and AML at the time of TKI relapse, we undertook next generation sequencing studies to determine the true genetic complexity in CML and AML patients at the time of relapse on targeted therapy. We used Pacific Biosciences RS Single Molecule Real Time (SMRT) third generation sequencing technology to sequence the entire ABL KD or the entire FLT3 juxtamembrane and KD on a single strand of DNA. Using this method, we assessed a total of 103 samples from 79 CML patients on ABL TKI therapy and 36 paired pre-treatment and relapse samples from 18 FLT3-ITD+ AML patients who responded to investigational FLT3 TKI therapy.
In CML, using SMRT sequencing, we detected all mutations previously detected by direct sequencing. Of samples in which multiple mutations were detectable by direct sequencing, 85% had compound mutant alleles detectable in a variety of combinations. Compound mutant alleles were comprised of both dominant and minor mutations, some which were not detectable by direct sequencing. In the most complex case, 12 individual mutant alleles comprised of 7 different mutations were identified in a single sample.
For 12 CML patients, we interrogated longitudinal samples (2-4 time points per patient) and observed complex clonal relationships with highly dynamic shifts in mutant allele populations over time. We detected compound mutations arising from ancestral single mutant clones as well as parallel evolution of de novo polyclonal and compound mutations largely in keeping with what would be expected to cause resistance to the second generation TKI therapy received by that patient.
We used a phospho-flow cytometric technique to assesses the phosphorylation status of the BCR-ABL substrate CRKL in as a method to test the ex vivo biochemical responsiveness of individual mutant cell populations to TKI therapy and assess functional cellular heterogeneity in a given patient at a given timepoint. Using this technique, we observed co-existing cell populations with differential ex vivo response to TKI in 2 cases with detectable polyclonal mutations. In a third case, we identified co-existence of an MLL-AF9 containing cell population that retained the ability to modulate p-CRKL in response to BCR-ABL TKIs along with a BCR-ABL containing only population that showed biochemical resistance to all TKIs, suggesting the co-existence of BCR-ABL independent and dependent resistance in a single patient.
In AML, using SMRT sequencing, we identified acquired quizartinib resistant KD mutations on the FLT3-ITD (ITD+) allele of 9 of 9 patients who relapsed after response to quizartinib and 4 of 9 patients who relapsed after response to the investigational FLT3 inhibitor, PLX3397. In 4 cases of quizartinib resistance and 3 cases of PLX3397 resistance, polyclonal mutations were observed, including 7 different KD mutations in one patient with PLX3397 resistance. In 7 quizartinib-resistant cases and 3 PLX3397-resistant cases, mutations occurred at the activation loop residue D835. When we examined non-ITD containing (ITD-) alleles, we surprisingly uncovered concurrent drug-resistant FLT3 KD mutations on ITD- alleles in 7 patients who developed quizartinib resistance and 4 patients with PLX3397 resistance. One additional PLX3397-resistant patient developed a D835Y mutation only in ITD- alleles at the time of resistance, suggesting selection for a non-ITD containing clone. All of the individual substitutions found on ITD- alleles were the same substitutions identified on ITD+ alleles for each individual patient.
Given that the same individual mutations found on ITD- alleles were also found on ITD+ alleles, we sought to determine whether these mutations were found in the same cell or were indicative of polyclonal blast populations in each patient. To answer this question, we performed single cell sorting of viably frozen blasts from 3 quizartinib-resistant patients with D835 mutations identified at the time of relapse and genotyped single cells for the presence or absence of ITD and D835 mutations. This analysis revealed striking genetic heterogeneity. In 2/3 cases, polyclonal D835 mutations were found in both ITD+ and ITD- cells. In all cases, FLT3-ITD and D835 mutations were found in both heterozygous and homozygous combinations. Most surprisingly, in all 3 patients, approximately 30-40% of FLT3-ITD+ cells had no identified quizartinib resistance-causing FLT3 KD mutation to account for resistance, suggesting the presence of non-FLT3 dependent resistance in all patients.
To determine that ITD+ cells lacking FLT3 KD mutations observed in patients relapsed on quizartinib are indeed consistent with leukemic blasts functionally resistant to quizartinib and do not instead represent a population of differentiated or non-proliferating cells, we utilized relapse blasts from another patient who initially achieved clearance of bone marrow blasts on quizartinib and developed a D835Y mutation at relapse. We performed a colony assay in the presence of 20nM quizartinib. As expected, this dose of quizartinib was unable to suppress the colony-forming ability of blasts from this relapsed patient when compared to DMSO treatment. Genotyping of individual colonies grown from this relapse sample in the presence of 20nM quizartinib again showed remarkable genetic heterogeneity, including ITD+ and ITD- colonies with D835Y mutations in homozygous and heterozygous combinations as well as ITD+ colonies without D835Y mutations, again suggesting the presence of blasts with non-FLT3 dependent resistance. Additionally, 4 colonies with no FLT3 mutations at all were identified in this sample, suggesting the presence of a quizartinib-resistant non-FLT3 mutant blast population. To see if we could identify specific mechanisms of off-target resistance, we performed targeted exome sequencing 33-AML relevant genes from relapse and pre-treatment DNA from all four patients and detected no new mutations in any genes other than FLT3 acquired at the time of disease relapse. Clonal genetic heterogeneity is not surprising in solid tumors, where multiple driver mutations frequently occur, but in CML and FLT3-ITD+ AML, where disease has been shown to be exquisitely dependent on oncogenic driver mutations, our studies suggest a surprising amount of clonal diversity. Our findings show that clinical TKI resistance in these diseases is amazingly intricate on the single allele level and frequently consists of both polyclonal and compound mutations that give rise to an complicated pool of TKI-resistant alleles that can change dynamically over time. In addition, we demonstrate that cell populations with off-target resistance can co-exist with other TKI-resistant populations, underscoring the emerging complexity of clinical TKI resistance. Such complexity argues strongly that monotherapy strategies in advanced CML and AML may be ultimately doomed to fail due to heterogeneous cell intrinsic resistance mechanisms. Ultimately, combination strategies that can address both on and off target resistance will be required to effect durable therapeutic responses.
Session Title: Tumor Heterogeneity and Evolution
Session Type: Educational Session
Session Start/End Time: Saturday, Apr 18, 2015, 1:00 PM – 3:00 PM
Location: Terrace Ballroom II-III (400 Level), Pennsylvania Convention Center
CME: CME-Designated
CME/CE Hours: 2
Session Description: One of the major challenges for both the measurement and management of cancer is its heterogeneity. Recent studies have revealed both extensive inter- and intra-tumor heterogeneity at the genotypic and phenotypic levels. Leaders in the field will discuss this challenge, its origins, dynamics and clinical importance. They will also review how we can best measure and deal with tumor heterogeneity, particularly intra-tumor heterogeneity.
Presentations:
Chairperson
Saturday, Apr 18, 2015, 1:00 PM – 3:00 PM
Carlo C. Maley. UCSF Helen Diller Family Comp. Cancer Center, San Francisco, CA
Universal biomarkers: How to handle tumor heterogeneity
Saturday, Apr 18, 2015, 1:00 PM – 1:25 PM
Carlo C. Maley. UCSF Helen Diller Family Comp. Cancer Center, San Francisco, CA
Discussion
Saturday, Apr 18, 2015, 1:25 PM – 1:30 PM
Heterogeneity of resistance to cancer therapy
Saturday, Apr 18, 2015, 1:30 PM – 1:55 PM
Ivana Bozic. HARVARD UNIV., Cambridge, MA
Discussion
Saturday, Apr 18, 2015, 1:55 PM – 2:00 PM
Determinants of phenotypic intra-tumor heterogeneity: integrative approach
Saturday, Apr 18, 2015, 2:00 PM – 2:25 PM
Andriy Marusyk, Michalina Janiszewska, Doris Tabassum. Dana-Farber Cancer Institute, Boston, MA, Dana-Farber Cancer Institute, Boston, MA
Discussion
Saturday, Apr 18, 2015, 2:25 PM – 2:30 PM
Cancer clonal complexity and evolution at the macro- and microheterogeneity scale
Saturday, Apr 18, 2015, 2:30 PM – 2:55 PM
Marco Gerlinger. Institute of Cancer Research, London, United Kingdom
Discussion
Saturday, Apr 18, 2015, 2:55 PM – 3:00 PM

From Ivana Bozic:

A spatial model predicts that dispersal and cell turnover limit intratumour heterogeneity.

Waclaw B, Bozic I, Pittman ME, Hruban RH, Vogelstein B, Nowak MA.

Nature. 2015 Sep 10;525(7568):261-4. doi: 10.1038/nature14971. Epub 2015 Aug 26.

PMID:

26308893

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Timing and heterogeneity of mutations associated with drug resistance in metastatic cancers.

Bozic I, Nowak MA.

Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):15964-8. doi: 10.1073/pnas.1412075111. Epub 2014 Oct 27.

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Session Title: Mechanisms of Cancer Therapy Resistance
Session Type: Educational Session
Session Start/End Time: Saturday, Apr 18, 2015, 1:00 PM – 3:00 PM
Location: Room 204, Pennsylvania Convention Center
CME: CME-Designated
CME/CE Hours: 2
Session Description: Despite dramatic advances in the treatment of cancer, therapy resistance remains the most significant hurdle in improving the outcome of cancer patients. In this session, we will discuss many different aspects of therapy resistance, including a summary of our current understanding of therapy resistant tumor cell populations as well as analyses of the challenges associated with intratumoral heterogeneity and adaptive responses to targeted therapies.
Presentations:
Chairperson
Saturday, Apr 18, 2015, 1:00 PM – 3:00 PM
Charles Swanton. Cancer Research UK London Research Institute, London, United Kingdom
Tumor heterogeneity and drug resistance
Saturday, Apr 18, 2015, 1:00 PM – 1:30 PM
Charles Swanton. Cancer Research UK London Research Institute, London, United Kingdom
Discussion

Saturday, Apr 18, 2015, 1:30 PM – 1:40 PM
Discussion Discussion, Discussion

Principles of resistance to targeted therapy
Saturday, Apr 18, 2015, 1:40 PM – 2:10 PM
Levi A. Garraway. Dana-Farber Cancer Institute, Boston, MA
Discussion

Saturday, Apr 18, 2015, 2:10 PM – 2:20 PM
Discussion Discussion, Discussion

Adaptive re-wiring of signaling pathways driving drug resistance to targeted therapies
Saturday, Apr 18, 2015, 2:20 PM – 2:50 PM
Taru E. Muranen. Harvard Medical School, Boston, MA
Discussion

Saturday, Apr 18, 2015, 2:50 PM – 3:00 PM
Discussion Discussion, Discussion

Presentation Abstract  

 

 

 

Abstract Number: 737
Presentation Title: Clonal evolution of the HER2 L755S mutation as a mechanism of acquired HER-targeted therapy resistance
Presentation Time: Sunday, Apr 19, 2015, 1:00 PM – 5:00 PM
Location: Section 30
Poster Board Number: 29
Author Block: Xiaowei Xu1, Agostina Nardone1, Huizhong Hu1, Lanfang Qin1, Sarmistha Nanda1, Laura Heiser2, Nicholas Wang2, Kyle Covington1, Edward Chen1, Alexander Renwick1, Tamika Mitchell1, Marty Shea1, Tao Wang1, Carmine De Angelis1, Alejandro Contreras1, Carolina Gutierrez1, Suzanne Fuqua1, Gary Chamness1, Chad Shaw1, Marilyn Li1, David Wheeler1, Susan Hilsenbeck1, Mothaffar Fahed Rimawi1, Joe Gray2, C.Kent Osborne1, Rachel Schiff1. 1Baylor College of Medicine, Houston, TX; 2Oregon Health & Science University, Portland, OR
Abstract Body: Background: Targeting HER2 with lapatinib (L), trastuzumab (T), or the LT combination, is effective in HER2+ breast cancer (BC), but acquired resistance commonly occurs. In our 12-week neoadjuvant
trial (TBCRC006) of LT without chemotherapy in HER2+ BC, the overall pathologic complete response (pCR) rate was 27%. To investigate resistance mechanisms, we developed 10 HER2+ BC cell line
models resistant (R) to one or both drugs (LR/TR/LTR). To discover potential predictive markers/therapeutic targets to circumvent resistance, we completed genomic profiling of the cell lines and a
subset of pre-treatment specimens from TBCRC006.
Methods: Parental (P) and LR/TR/LTR lines of 10 cell line models were profiled with whole exome/RNA sequencing. Mutations detected in R lines but not in P lines of the same model were identified. Mutation-specific Q-PCR was designed for sensitive quantification. Resistant cell and xenograft tumor growth were measured in response to drugs. Whole exome sequencing (>100X) and Ampliseq of 17 baseline tumor/normal pairs from TBCRC006 were performed.
Results: We found and validated the HER2 L755S mutation in the BT474/ATCC-LTR line and BT474/AZ-LR line (in ~30% of DNA/RNA), in which the HER pathway was reactivated for resistance. Overexpression of this mutation was previously shown to induce LR in HER2-negative BC cell lines, and resistant growth of BT474/AZ-LR line is significantly inhibited by HER2-L755S-specific siRNA knock-down, suggesting its role as an acquired L/LT resistance driver in HER2+ BC. Sequencing of BT474/AZ-LR single cell clones found the mutation in ~30% of HER2 copies in every cell. Using mutation-specific Q-PCR, we found statistically higher HER2 L755S levels in two BT474 parentals compared to P lines of SKBR3, AU565, and UACC812. These data suggest that HER2 L755S resistant subclones preexist in the BT474 parentals and were selected by L treatment to become the major clone in the two R lines. The HER1/2 irreversible tyrosine kinase inhibitor (TKI) afatinib (Afa) robustly inhibited growth of BT474/AZ-LR and BT474/ATCC-LTR cells (IC50: Afa 0.02µM vs. L 3 µM) and BT474/AZ-LR xenografts. Whole exome sequencing/Ampliseq of TBCRC006 found the HER2 L755S mutation in 1/17 primaries. This patient did not achieve pCR. The variant was present in 2% of DNA on both platforms, indicating a subclonal event of the resistance mutation.
Conclusion: Acquired L/LT resistance in the two BT474 R lines is due to selection of HER2 L755S subclones present in parental cells. The higher HER2 L755S
levels in BT474 parentals compared with other parentals, and detection of its subclonal presence in a pre-treatment HER2+ BC patient, suggest that sensitive mutation detection methods will be needed to identify patients with potentially actionable HER family mutations in primary tumor. Treating this patient group
with an irreversible TKI like Afa may prevent resistance and improve clinical outcome of this subset of HER2+ BC.
Presentation Number: SY07-04
Presentation Title: The evolutionary landscape of CLL: Therapeutic implications
Presentation Time: Sunday, Apr 19, 2015, 2:25 PM – 2:45 PM
Location: Grand Ballroom (300 Level), Pennsylvania Convention Center
Author Block: Catherine J. Wu. Dana-Farber Cancer Institute, Boston, MA
Abstract Body: Clonal evolution is a key feature of cancer progression and relapse. Recent studies across cancers have demonstrated the extensive degree of intratumoral heterogeneity present within individual cancers. We hypothesized that evolutionary dynamics contribute to the variations in disease tempo and response to therapy that are highly characteristic of chronic lymphocytic leukemia (CLL). We have recently investigated this phenomenon by developing a pipeline that estimates the fraction of cancer cells harboring each somatic mutation within a tumor through integration of whole-exome sequence (WES) and local copy number data (Landau et al., Cell 2013). By applying this analysis approach to 149 CLL cases, we discovered earlier and later cancer drivers, uncovered patterns of clonal evolution in CLL and linked the presence of subclones harboring driver mutations with adverse clinical outcome. Thus, our study, generated from a heterogeneous sample cohort, strongly supports the concept that CLL clonal evolution arises from mass extinction and therapeutic bottlenecks which lead to the emergence of highly fit (and treatment resistant) subclones. We further hypothesized that epigenetic heterogeneity also shapes CLL clonal evolution through interrelation with genetic heterogeneity. Indeed, in recent work, we have uncovered stochastic methylation disorder as the primary cause of methylation changes in CLL and cancer in general, and that this phenomena impacts gene transcription, genetic evolution and clinical outcome. Thus, integrated studies of genetic and epigenetic heterogeneity in CLL have revealed the complex and diverse evolutionary trajectories of these cancer cells.
Immunotherapy is exquisitely suited for specifically and simultaneously targeting multiple lesions. We have developed an approach that leverages whole-exome sequencing to systematically identify personal tumor mutations with immunogenic potential, which can be incorporated as antigen targets in multi-epitope personalized therapeutic vaccines. We are pioneering this approach in an ongoing trial in melanoma and will now expand this concept to address diverse malignancies. Our expectation is that the choice of tumor neoantigens for a vaccine bypasses thymic tolerance and thus generates highly specific and potent high-affinity T cell responses to eliminate tumors in any cancer, including both ‘trunk’ and ‘branch’ lesions.

 

Abstract Number: LB-056
Presentation Title: TP53 and RB1 alterations promote reprogramming and antiandrogen resistance in advanced prostate cancer
Presentation Time: Sunday, Apr 19, 2015, 4:50 PM – 5:05 PM
Location: Room 122, Pennsylvania Convention Center
Author Block: Ping Mu, Zhen Cao, Elizabeth Hoover, John Wongvipat, Chun-Hao Huang, Wouter Karthaus, Wassim Abida, Elisa De Stanchina, Charles Sawyers. Memorial Sloan Kettering Cancer Center, New York, NY
Abstract Body: Castration-resistant prostate cancer (CRPC) is one of the most difficult cancers to treat with conventional methods and is responsible for nearly all prostate cancer deaths in the US. The Sawyers laboratory first showed that the primary mechanism of resistance to antiandrogen therapy is elevated androgen receptor (AR) expression. Research based on this finding has led to the development of next-generation antiandrogen: enzalutamide. Despite the exciting clinical success of enzalutamide, about 60% of patients exhibit various degrees of resistance to this agent. Highly variable responses to enzalutamide limit the clinical benefit of this novel antiandrogen, underscoring the importance of understanding the mechanisms of enzalutamide resistance. Most recently, an unbiased SU2C-Prostate Cancer Dream Team metastatic CRPC sequencing project led by Dr. Sawyers and Dr. Chinnaiyan revealed that mutations in the TP53 locus are the most significantly enriched alteration in CRPC tumors when compared to primary prostate cancers. Moreover, deletions and decreased expressions of the TP53 and RB1 loci (co-occurrence and individual occurrence) are more commonly associated with CRPC than with primary tumors. These results established that alteration of the TP53 and RB1 pathways are associated with the development of antiandrogen resistance.
By knockdowning TP53 or/and RB1 in the castration resistant LNCaP/AR model, we demonstrate that the disruption of either TP53 or RB1 alone confers significant resistance to enzalutamide both in vitro and in vivo. Strikingly, the co-inactivation of these pathways confers the most dramatic resistance. Since up-regulation of either AR or AR target genes is not observed in the resistant tumors, loss of TP53 and RB1 function confers enzalutamide resistance likely through an AR independent mechanism. In the clinic, resistance to enzalutamide is increasingly being associated with a transition to a poorly differentiated or neuroendocrine-like histology. Interestingly, we observed significant up-regulations of the basal cell marker Ck5 and the neuroendocrine-like cell marker Synaptophysin in the TP53 and RB1 inactivated cells, as well as down-regulation of the luminal cell marker Ck8. The differences between these markers became even greater after enzalutamide treatment. By using the p53-stabilizing drug Nutlin, level of p53 is rescued and consequently the the decrease of AR protein caused by RB1 and TP53 knockdown is reversed. These results strongly suggest that interference of TP53 and RB1 pathways confers antiandrogen resistance by “priming” prostate cancer cells to reprogramming or transdifferentiation, likely neuroendocrine-like differentiation, in response to treatment. Futher experiments will be performed to assess the molecular mechanism of TP53/RB1 alterations in mediating cell programming and conferring antiandrogen resistance.

 

Abstract Number: LB-146
Presentation Title: TGF-β-induced tumor heterogeneity and drug resistance of cancer stem cells
Presentation Time: Monday, Apr 20, 2015, 1:00 PM – 5:00 PM
Location: Section 41
Author Block: Naoki Oshimori1, Daniel Oristian1, Elaine Fuchs2. 1Rockefeller University, New York, NY; 2HHMI/Rockefeller University, New York, NY
Abstract Body: Among the most common and life-threatening cancers world-wide, squamous cell carcinoma (SCC) exhibit high rates of tumor recurrence following anti-cancer therapy. Subsets of cancer stem cells (CSCs) often escape anti-cancer therapeutics and promote recurrence. However, its sources and mechanisms that generate tumor heterogeneity and therapy-resistant cell population are largely unknown. Tumor microenvironment may drive intratumor heterogeneity by transmitting signaling factors, oxygen and metabolites to tumor cells depending on their proximity to the local sources. While the hypothesis is attractive, experimental evidence is lacking, and non-genetic mechanisms that drive functional heterogeneity remain largely unknown. As a potential non-genetic factor, we focused on TGF-β because of its multiple roles in tumor progression.
Here we devise a functional reporter system to monitor, track and modify TGF-β signaling in mouse skin SCC in vivo. Using this approach, we found that perivascular TGF-β in the tumor microenvironment generates heterogeneity in TGF-β signaling in neighboring CSCs. This heterogeneity is functionally important: small subsets of TGF-β-responding CSCs proliferate more slowly than their non-responding counterparts. They also exhibit invasive morphology and a malignant differentiation program compared to their non-responding neighbors. By lineage tracing, we show that although TGF-β-responding CSCs clonally expand more slowly they gain a growth advantage in a remarkable ability to escape cisplatin-induced apoptosis. We show that indeed it is their progenies that make a substantial contribution in tumor recurrence. Surprisingly, the slower proliferating state of this subset of CSCs within the cancer correlated with but did not confer the survival advantage to anti-cancer drugs. Using transcriptomic, biochemical and genetic analyses, we unravel a novel mechanism by which heterogeneity in the tumor microenvironment allows a subset of CSCs to respond to TGF-β, and evade anti-cancer drugs.
Our findings also show that TGF-β established ability to suppress proliferation and promote invasion and metastasis do not happen sequentially, but rather simultaneously. This new work build upon the roles of this factor in tumor progression, and sets an important paradigm for a non-genetic factor that produces tumor heterogeneity.
Abstract Number: LB-129
Presentation Title: Identifying tumor subpopulations and the functional consequences of intratumor heterogeneity using single-cell profiling of breast cancer patient-derived xenografts
Presentation Time: Monday, Apr 20, 2015, 1:00 PM – 5:00 PM
Location: Section 41
Author Block: Paul Savage1, Sadiq M. Saleh1, Ernesto Iacucci1, Timothe Revil1, Yu-Chang Wang1, Nicholas Bertos1, Anie Monast1, Hong Zhao1, Margarita Souleimanova1, Keith Szulwach2, Chandana Batchu2, Atilla Omeroglu1, Morag Park1, Ioannis Ragoussis1. 1McGill University, Montreal, QC, Canada; 2Fluidigm Corporation, South San Francisco, CA
Abstract Body: Human breast tumors have been shown to exhibit extensive inter- and intra-tumor heterogeneity. While recent advances in genomic technologies have allowed us to deconvolute this heterogeneity, few studies have addressed the functional consequences of diversity within tumor populations. Here, we identified an index case for which we have derived a patient-derived xenograft (PDX) as a renewable tissue source to identify subpopulations and perform functional assays. On pathology, the tumor was an invasive ductal carcinoma which was hormone receptor-negative, HER2-positive (IHC 2+, FISH average HER2/CEP17 2.4), though the FISH signal was noted to be heterogeneous. On gene expression profiling of bulk samples, the primary tumor and PDX were classified as basal-like. We performed single cell RNA and exome sequencing of the PDX to identify population structure. Using a single sample predictor of breast cancer subtype, we have identified single basal-like, HER2-enriched and normal-like cells co-existing within the PDX tumor. Genes differentially expressed between these subpopulations are involved in proliferation and differentiation. Functional studies distinguishing these subpopulations are ongoing. Microfluidic whole genome amplification followed by whole exome capture of 81 single cells showed high and homogeneous target enrichment with >75% of reads mapping uniquely on target. Variant calling using GATK and Samtools revealed founder mutations in key genes as BRCA1 and TP53, as well as subclonal mutations that are being investigated further. Loss of heterozygocity was observed in 16 TCGA cancer driver genes and novel mutations in 7 cancer driver genes. These findings may be important in understanding the functional consequences of intra-tumor heterogeneity with respect to clinically important phenotypes such as invasion, metastasis and drug-resistance.
Abstract Number: 2847
Presentation Title: High complexity barcoding to study clonal dynamics in response to cancer therapy
Presentation Time: Monday, Apr 20, 2015, 4:35 PM – 4:50 PM
Location: Room 118, Pennsylvania Convention Center
Author Block: Hyo-eun C. Bhang1, David A. Ruddy1, Viveksagar Krishnamurthy Radhakrishna1, Rui Zhao2, Iris Kao1, Daniel Rakiec1, Pamela Shaw1, Marissa Balak1, Justina X. Caushi1, Elizabeth Ackley1, Nicholas Keen1, Michael R. Schlabach1, Michael Palmer1, William R. Sellers1, Franziska Michor2, Vesselina G. Cooke1, Joshua M. Korn1, Frank Stegmeier1. 1Novartis Institutes for BioMedical Research, Cambridge, MA; 2Dana-Farber Cancer Institute, Boston, MA
Abstract Body: Targeted therapies, such as erlotinib and imatinib, lead to dramatic clinical responses, but the emergence of resistance presents a significant challenge. Recent studies have revealed intratumoral heterogeneity as a potential source for the emergence of therapeutic resistance. However, it is still unclear if relapse/resistance is driven predominantly by pre-existing or de novo acquired alterations. To address this question, we developed a high-complexity barcode library, ClonTracer, which contains over 27 million unique DNA barcodes and thus enables the high resolution tracking of cancer cells under drug treatment. Using this library in two clinically relevant resistance models, we demonstrate that the majority of resistant clones pre-exist as rare subpopulations that become selected in response to therapeutic challenge. Furthermore, our data provide direct evidence that both genetic and non-genetic resistance mechanisms pre-exist in cancer cell populations. The ClonTracer barcoding strategy, together with mathematical modeling, enabled us to quantitatively dissect the frequency of drug-resistant subpopulations and evaluate the impact of combination treatments on the clonal complexity of these cancer models. Hence, monitoring of clonal diversity in drug-resistant cell populations by the ClonTracer barcoding strategy described here may provide a valuable tool to optimize therapeutic regimens towards the goal of curative cancer therapies.
Abstract Number: 3590
Presentation Title: Resistance mechanisms to ALK inhibitors
Presentation Time: Tuesday, Apr 21, 2015, 8:00 AM -12:00 PM
Location: Section 31
Poster Board Number: 13
Author Block: Ryohei Katayama1, Noriko Yanagitani1, Sumie Koike1, Takuya Sakashita1, Satoru Kitazono1, Makoto Nishio1, Yasushi Okuno2, Jeffrey A. Engelman3, Alice T. Shaw3, Naoya Fujita1. 1Japanese Foundation for Cancer Research, Tokyo, Japan; 2Graduate School of Medicine, Kyoto University, Kyoto, Japan; 3Massachusetts General Hospital Cancer Center, Boston, MA
Abstract Body: Purpose: ALK-rearranged non-small cell lung cancer (NSCLC) was first reported in 2007. Approximately 3-5% of NSCLCs harbor an ALK gene rearrangement. The first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib is a standard therapy for patients with advanced ALK-rearranged NSCLC. Several next-generation ALK-TKIs have entered the clinic and have shown promising antitumor activity in crizotinib-resistant patients. As patients still relapse even on these next-generation ALK-TKIs, we examined mechanisms of resistance to one next-generation ALK-TKI – alectinib – and potential strategies to overcome this resistance.
Experimental Procedure: We established a cell line model of alectinib resistance, and analyzed resistant tumor specimens from patients who had relapsed on alectinib. Cell lines were also established under an IRB-approved protocol when there was sufficient fresh tumor tissue. We established Ba/F3 cells expressing EML4-ALK and performed ENU mutagenesis to compare potential crizotinib or alectinib-resistance mutations. In addition, we developed Ba/F3 models harboring ALK resistance mutations and evaluated the potency of multiple next-generation ALK-TKIs including 3rd generation ALK inhibitor in these models and in vivo. To elucidate structure-activity-relationships of ALK resistance mutations, we performed computational thermodynamic simulation with MP-CAFEE.
Results: We identified multiple resistance mutations, including ALK I1171N, I1171S, and V1180L, from the ENU mutagenesis screen and the cell line model. In addition we found secondary mutations at the I1171 residue from the Japanese patients who developed resistance to alectinib or crizotinib. Both ALK mutations (V1180L and I1171 mutations) conferred resistance to alectinib as well as to crizotinib, but were sensitive to ceritinib and other next-generation ALK-TKIs. Based on thermodynamics simulation, each resistance mutation is predicted to lead to distinct structural alterations that decrease the binding affinity of ALK-TKIs for ALK.
Conclusions: We have identified multiple alectinib-resistance mutations from the cell line model, patient derived cell lines, and tumor tissues, and ENU mutagenesis. ALK secondary mutations arising after alectinib exposure are sensitive to other next generation ALK-TKIs. These findings suggest a potential role for sequential therapy with multiple next-generation ALK-TKIs in patients with advanced, ALK-rearranged cancers.
Session Title: Mechanisms of Resistance: From Signaling Pathways to Stem Cells
Session Type: Major Symposium
Session Start/End Time: Tuesday, Apr 21, 2015, 10:30 AM -12:30 PM
Location: Terrace Ballroom II-III (400 Level), Pennsylvania Convention Center
CME: CME-Designated
CME/CE Hours: 2
Session Description: Even the most effective cancer therapies are limited due to the development of one or more resistance mechanisms. Acquired resistance to targeted therapies can, in some cases, be attributed to the selective propagation of a small population of intrinsically resistant cells. However, there is also evidence that cancer drugs themselves can drive resistance by triggering the biochemical- or genetic-reprogramming of cells within the tumor or its microenvironment. Therefore, understanding drug resistance at the molecular and biological levels may enable the selection of specific drug combinations to counteract these adaptive responses. This symposium will explore some of the recent advances addressing the molecular basis of cancer cell drug resistance. We will address how tumor cell signaling pathways become rewired to facilitate tumor cell survival in the face of some of our most promising cancer drugs. Another topic to be discussed involves how drugs select for or induce the reprogramming of tumor cells toward a stem-like, drug resistant fate. By targeting the molecular driver(s) of rewired signaling pathways and/or cancer stemness it may be possible to select drug combinations that prevent the reprogramming of tumors and thereby delay or eliminate the onset of drug resistance.
Presentations:
Chairperson
Tuesday, Apr 21, 2015, 10:30 AM -12:30 PM
David A. Cheresh. UCSD Moores Cancer Center, La Jolla, CA
Introduction
Tuesday, Apr 21, 2015, 10:30 AM -10:40 AM
Resistance to tyrosine kinase inhibitors: Heterogeneity and therapeutic strategies.
Tuesday, Apr 21, 2015, 10:40 AM -10:55 AM
Jeffrey A. Engelman. Massachusetts General Hospital, Boston, MA
Discussion
Tuesday, Apr 21, 2015, 10:55 AM -11:00 AM
NG04: Clinical acquired resistance to RAF inhibitor combinations in BRAF mutant colorectal cancer through MAPK pathway alterations
Tuesday, Apr 21, 2015, 11:00 AM -11:15 AM
Ryan B. Corcoran, Leanne G. Ahronian, Eliezer Van Allen, Erin M. Coffee, Nikhil Wagle, Eunice L. Kwak, Jason E. Faris, A. John Iafrate, Levi A. Garraway, Jeffrey A. Engelman. Massachusetts General Hospital Cancer Center, Boston, MA, Dana-Farber Cancer Institute, Boston, MA
Discussion
Tuesday, Apr 21, 2015, 11:15 AM -11:20 AM
SY27-02: Tumour heterogeneity and therapy resistance in melanoma
Tuesday, Apr 21, 2015, 11:20 AM -11:35 AM
Claudia Wellbrock. Univ. of Manchester, Manchester, United Kingdom

Presentation Number: SY27-02
Presentation Title: Tumour heterogeneity and therapy resistance in melanoma
Presentation Time: Tuesday, Apr 21, 2015, 11:20 AM -11:35 AM
Location: Terrace Ballroom II-III (400 Level), Pennsylvania Convention Center
Author Block: Claudia Wellbrock. Univ. of Manchester, Manchester, United Kingdom
Abstract Body: Solid tumors are structurally very complex; they consist of heterogeneous cancer cell populations, other non-cancerous cell types and a distinct extracellular matrix. Interactions of cancer cells with non-cancerous cells is well investigated, and our recent work in melanoma has demonstrated that the cellular environment that surrounds cancer cells has a major impact on the way a patient responds to MAP-kinase pathway targeting therapy.
We have shown that intra-tumor signaling within a heterogeneous tumor can have a major impact on the efficacy of BRAF and MEK inhibitors. With the increasing evidence of genetic and phenotypic heterogeneity within tumors, intra-tumor signaling between individual cancer-cell subpopulations is therefore a crucial factor that needs to be considered in future therapy approaches. Our work has identified the ‘melanocyte-lineage survival oncogene’ MITF as an important player in phenotypic heterogeneity (MITFhigh and MITFlow cells) in melanoma, and MITF expression levels are crucial for the response to MAP-kinase pathway targeted therapy. We found that ‘MITF heterogeneity’ can be caused by cell-autonomous mechanisms or by the microenvironment, including the immune-microenvironment.
We have identified various mechanisms underlying MITF action in resistance to BRAF and MEK inhibitors in melanoma. In MITFhigh expressing cells, MITF confers cell-autonomous resistance to MAP-kinase pathway targeted therapy. Moreover, it appears that in melanomas heterogeneous for MITF expression (MITFhigh and MITFlow cells), individual subpopulations of resistant and sensitive cells communicate and MITF can contribute to overall tumor-resistance through intra-tumor signaling. Finally, we have identified a novel approach of interfering with MITF action, which profoundly sensitizes melanoma to MAP-kinase pathway targeted therapy.
Discussion
Tuesday, Apr 21, 2015, 11:35 AM -11:40 AM
SY27-03: Breast cancer stem cell state transitions mediate therapeutic resistance
Tuesday, Apr 21, 2015, 11:40 AM -11:55 AM
Max S. Wicha. University of Michigan, Comprehensive Cancer Center, Ann Arbor, MI
Discussion
Tuesday, Apr 21, 2015, 11:55 AM -12:00 PM
SY27-04: Induction of cancer stemness and drug resistance by EGFR blockade
Tuesday, Apr 21, 2015, 12:00 PM -12:15 PM
David A. Cheresh. UCSD Moores Cancer Center, La Jolla, CA

 

Cellular Reprogramming in Carcinogenesis: Implications for Tumor Heterogeneity, Prognosis, and Therapy
Session Type: Major Symposium
Session Start/End Time: Tuesday, Apr 21, 2015, 10:30 AM -12:30 PM
Location: Room 103, Pennsylvania Convention Center
CME: CME-Designated
CME/CE Hours: 2
Session Description: Cancers, both solid and liquid, consist of phenotypically heterogeneous cell types that make up the full cellular complement of disease. Deep sequencing of bulk cancers also frequently reveals a genetic intratumoral heterogeneity that reflects clonal evolution in space and in time and under the influence of treatment. How the distinct phenotypic and genotypic cells contribute to individual cancer growth and progression is incompletely understood. In this symposium, we will discuss issues of cancer heterogeneity and effects on growth and treatment resistance, with emphasis on cancer cell functional properties and influences of the microenvironment, interclonal genomic heterogeneity, and lineage relationships between cancer cells with stem cell and differentiated properties. Understanding these complex cellular relationships within cancers will have critical implications for devising more effective treatments.
Presentations:
Chairperson
Tuesday, Apr 21, 2015, 10:30 AM -12:30 PM
Peter B. Dirks. Univ. of Toronto Hospital for Sick Children, Toronto, ON, Canada
Introduction

Tuesday, Apr 21, 2015, 10:30 AM -10:40 AM

Origins, evolution and selection in childhood leukaemia
Tuesday, Apr 21, 2015, 10:40 AM -11:00 AM
Tariq Enver. Cancer Research UK, London, United Kingdom
Discussion

Tuesday, Apr 21, 2015, 11:00 AM -11:05 AM

Cytokine-controlled stem cell plasticity inintestinal tumorigenesis
Tuesday, Apr 21, 2015, 11:05 AM -11:25 AM
Florian Greten. Georg-Speyer-Haus, Frankfurt, Germany
Discussion

Tuesday, Apr 21, 2015, 11:25 AM -11:30 AM

SY23-03: Intratumoural heterogeneity in human serous ovarian carcinoma
Tuesday, Apr 21, 2015, 11:30 AM -11:50 AM
John P. Stingl. Cancer Research UK Cambridge Research Inst., Cambridge, United Kingdom
Discussion

Tuesday, Apr 21, 2015, 11:50 AM -11:55 AM

Functional and genomic heterogeneity in brain tumors
Tuesday, Apr 21, 2015, 11:55 AM -12:15 PM

 

Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):851-6. doi: 10.1073/pnas.1320611111. Epub 2015 Jan 5.

Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity.

Meyer M1, Reimand J2, Lan X3, Head R1, Zhu X1, Kushida M1, Bayani J4, Pressey JC5, Lionel AC6, Clarke ID7, Cusimano M8, Squire JA9, Scherer SW6, Bernstein M10, Woodin MA5, Bader GD11, Dirks PB12.

Author information

Abstract

Glioblastoma (GBM) is a cancer comprised of morphologically, genetically, and phenotypically diverse cells. However, an understanding of the functional significance of intratumoral heterogeneity is lacking. We devised a method to isolate and functionally profile tumorigenic clones from patient glioblastoma samples. Individual clones demonstrated unique proliferation and differentiation abilities. Importantly, naïve patient tumors included clones that were temozolomide resistant, indicating that resistance to conventional GBM therapy can preexist in untreated tumors at a clonal level. Further, candidate therapies for resistant clones were detected with clone-specific drug screening. Genomic analyses revealed genes and pathways that associate with specific functional behavior of single clones. Our results suggest that functional clonal profiling used to identify tumorigenic and drug-resistant tumor clones will lead to the discovery of new GBM clone-specific treatment strategies.

—————————————————————————————————

 

739: Tumor cell plasticity with transition to a mesenchymal phenotype is a mechanism of chemoresistance that is reversed by Notch pathway inhibition in lung adenocarcinoma
Sunday, Apr 19, 2015, 1:00 PM – 5:00 PM
Khaled A. Hassan. University Of Michigan, Ann Arbor, MI

745: Oncostatin M receptor activation leads to molecular targeted therapy resistance in non-small cell lung cancer
Sunday, Apr 19, 2015, 1:00 PM – 5:00 PM
Kazuhiko Shien1, Vassiliki A. Papadimitrakopoulou1, Dennis Ruder1, Nana E. Hanson1, Neda Kalhor1, J. Jack Lee1, Waun Ki Hong1, Ximing Tang1, Roy S. Herbst2, Luc Girard3, John D. Minna3, Jonathan M. Kurie1, Ignacio I. Wistuba1, Julie G. Izzo1. 1University of Texas MD Anderson Cancer Center, Houston, TX; 2Yale Cancer Center, Yale School of Medicine, New Haven, CT; 3Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX

746: Activation of EGFR bypass signaling through TGFα overexpression induces acquired resistance to alectinib in ALK-translocated lung cancer cells
Sunday, Apr 19, 2015, 1:00 PM – 5:00 PM
Tetsuo Tani, Hiroyuki Yasuda, Junko Hamamoto, Aoi Kuroda, Daisuke Arai, Kota Ishioka, Keiko Ohgino, Ichiro Kawada, Katsuhiko Naoki, Hayashi Yuichiro, Tomoko Betsuyaku, Kenzo Soejima. Keio University, Tokyo, Japan

752: Elucidating the mechanisms of acquired resistance in lung adenocarcinomas
Sunday, Apr 19, 2015, 1:00 PM – 5:00 PM
Sandra Ortiz-Cuarán1, Lynnette Fernandez-Cuesta1, Christine M. Lovly2, Marc Bos1, Matthias Scheffler3, Sebastian Michels3, Kerstin Albus4, Lydia Meyer4, Katharina König4, Ilona Dahmen1, Christian Mueller1, Luca Ozretić4, Lars Tharun4, Philipp Schaub1, Alexandra Florin4, Berit Pinther1, Nike Bahlmann1, Sascha Ansén3, Martin Peifer1, Lukas C. Heukamp4, Reinhard Buettner4, Martin L. Sos1, Jürgen Wolf3, William Pao2, Roman K. Thomas1. 1University of Cologne, Cologne, Germany; 2Department of Medicine, Vanderbilt University, Nashville, TN; 3Department of Internal Medicine, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany; 4Institute of Pathology, University Hospital Cologne, Cologne, Germany

760: On the evolution of erlotinib-resistant NSCLC subpopulations
Sunday, Apr 19, 2015, 1:00 PM – 5:00 PM
Michael E. Ramirez1, Robert J. Steininger, III1, Lani F. Wu2, Steven J. Altschuler2. 1UT Southwestern, Dallas, TX; 2UCSF, San Francisco, CA
763: Implications of resistance patterns with NSCLC targeted agents
Sunday, Apr 19, 2015, 1:00 PM – 5:00 PM
David J. Stewart, Paul Wheatley-Price, Rob MacRae, Jason Pantarotto. University of Ottawa, Ottawa, ON, Canada

 

768: A kinome-wide siRNA screen identifies modifiers of sensitivity to the EGFR T790M-targeted tyrosine kinase inhibitor (TKI), AZD9291, in EGFR mutant lung adenocarcinoma
Sunday, Apr 19, 2015, 1:00 PM – 5:00 PM
Eiki Ichihara1, Joshua A. Bauer2, Pengcheng Lu3, Fei Ye3, Darren Cross4, William Pao1, Christine M. Lovly1. 1Vanderbilt University School of Medicine, Nashville, TN; 2Vanderbilt Institute of Chemical Biology High-Throughput Screening Facility, Nashville, TN; 3Vanderbilt University Medical Center, Nashville, TN; 4AstraZeneca Oncology Innovative Medicines, United Kingdom

LB-055: Clinical acquired resistance to RAF inhibitor combinations in BRAF-mutant colorectal cancer through MAPK pathway alterations
Sunday, Apr 19, 2015, 4:35 PM – 4:50 PM
Leanne G. Ahronian1, Erin M. Sennott1, Eliezer M. Van Allen2, Nikhil Wagle2, Eunice L. Kwak1, Jason E. Faris1, Jason T. Godfrey1, Koki Nishimura1, Kerry D. Lynch3, Craig H. Mermel1, Elizabeth L. Lockerman1, Anuj Kalsy1, Joseph M. Gurski, Jr.1, Samira Bahl4, Kristin Anderka4, Lisa M. Green4, Niall J. Lennon4, Tiffany G. Huynh3, Mari Mino-Kenudson3, Gad Getz1, Dora Dias-Santagata3, A. John Iafrate3, Jeffrey A. Engelman1, Levi A. Garraway2, Ryan B. Corcoran1. 1Massachusetts General Hospital Cancer Center, Boston, MA; 2Dana Farber Cancer Institute, Boston, MA; 3Massachusetts General Hospital Department of Pathology, Boston, MA; 4Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA

 

Other Articles on this Site Related to Tumor Heterogeneity Include

Notes On Tumor Heterogeneity: Targets and Mechanisms, from the 2015 AACR Meeting in Philadelphia PA

Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn

Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

CANCER COMPLEXITY: Heterogeneity in Tumor Progression and Drug Response – 2015 Annual Symposium @Koch Institute for Integrative Cancer Research at MIT – W34, 6/12/2015 9:00 AM EDT – 4:30 PM EDT

In vitro Models of Tumor Microenvironment for New Cancer Target and Drug Discovery, 11/17 – 11/19/2014, Hyatt Boston Harbor

What can we expect of tumor therapeutic response?

 

Read Full Post »


Twitter, Google, LinkedIn Enter in the Curation Foray: What’s Up With That?

 

Reporter: Stephen J. Williams, Ph.D.

Recently Twitter has announced a new feature which they hope to use to increase engagement on their platform. Originally dubbed Project Lightning and now called Moments, this feature involves many human curators which aggregate and curate tweets surrounding individual live events(which used to be under #Live).

As Madhu Muthukumar (@justmadhu), Twitter’s Product Manager, published a blog post describing Moments said:

“Every day, people share hundreds of millions of tweets. Among them are things you can’t experience anywhere but on Twitter: conversations between world leaders and celebrities, citizens reporting events as they happen, cultural memes, live commentary on the night’s big game, and many more,” the blog post noted. “We know finding these only-on-Twitter moments can be a challenge, especially if you haven’t followed certain accounts. But it doesn’t have to be.”

Please see more about Moments on his blog here.

Moments is a new tab on Twitter’s mobile and desktop home screens where the company will curate trending topics as they’re unfolding in real-time — from citizen-reported news to cultural memes to sports events and more. Moments will fall into five total categories, including “Today,” “News,” “Sports,” “Entertainment” and “Fun.” (Source: Fox)

Now It’s Google’s Turn

 

As Dana Blankenhorn wrote in his article Twitter, Google Try It Buzzfeed’s Way With Curation

in SeekingAlpha

What’s a challenge for Google is a direct threat to Twitter’s existence.

For all the talk about what doesn’t work in journalism, curation works. Following the news, collecting it and commenting, and encouraging discussion, is the “secret sauce” for companies like Buzzfeed, Vox, Vice and The Huffington Post, which often wind up getting more traffic from a story at, say The New York Times (NYSE:NYT), than the Times does as a result.

Curation is, in some ways, a throwback to the pre-Internet era. It’s done by people. (At least I think I’m a people.) So as odd as it is for Twitter (NYSE:TWTR) to announce it will curate live events it’s even odder to see Google (NASDAQ:GOOG) (NASDAQ:GOOGL) doing it in a project called YouTube Newswire.

Buzzfeed, Google’s content curation platform, made for desktop as well as a mobile app, allows sharing of curated news, viral videos.

The feel for both Twitter and Google’s content curation will be like a newspaper, with an army of human content curators determining what is the trendiest news to read or videos to watch.

BuzzFeed articles, or at least, the headlines can easily be mined from any social network but reading the whole article still requires that you open the link within the app or outside using a mobile web browser. Loading takes some time–a few seconds longer. Try browsing the BuzzFeed feed on the app and you’ll notice the obvious difference.

However it was earlier this summer in a Forbes article Why Apple, Snapchat and Twitter are betting on human editors, but Facebook and Google aren’t that Apple, Snapchat and Twitter as well as LinkedIn Pulse and Instragram were going to use human editors and curators while Facebook and Google were going to rely on their powerful algorithms. Google (now Alphabet) CEO Eric Schmidt has even called Apple’s human curated playlists “elitist” although Google Play has human curated playlists.

Maybe Google is responding to views on its Google News like this review in VentureBeat:

Google News: Less focused on social signals than textual ones, Google News uses its analytic tools to group together related stories and highlight the biggest ones. Unlike Techmeme, it’s entirely driven by algorithms, and that means it often makes weird choices. I’ve heard that Google uses social sharing signals from Google+ to help determine which stories appear on Google News, but have never heard definitive confirmation of that — and now that Google+ is all but dead, it’s mostly moot. I find Google News an unsatisfying home page, but it is a good place to search for news once you’ve found it.

Now WordPress Too!

 

WordPress also has announced its curation plugin called Curation Traffic.

According to WordPress

You Own the Platform, You Benefit from the Traffic

“The Curation Traffic™ System is a complete WordPress based content curation solution. Giving you all the tools and strategies you need to put content curation into action.

It is push-button simple and seamlessly integrates with any WordPress site or blog.

With Curation Traffic™, curating your first post is as easy as clicking “Curate” and the same post that may originally only been sent to Facebook or Twitter is now sent to your own site that you control, you benefit from, and still goes across all of your social sites.”

The theory the more you share on your platform the more engagement the better marketing experience. And with all the WordPress users out there they have already an army of human curators.

So That’s Great For News But What About Science and Medicine?

 

The news and trendy topics such as fashion and music are common in most people’s experiences. However more technical areas of science, medicine, engineering are not in most people’s domain so aggregation of content needs a process of peer review to sort basically “the fact from fiction”. On social media this is extremely important as sensational stories of breakthroughs can spread virally without proper vetting and even influence patient decisions about their own personal care.

Expertise Depends on Experience

In steps the human experience. On this site (www.pharmaceuticalintelligence.com) we attempt to do just this. A consortium of M.D.s, Ph.D. and other medical professionals spend their own time to aggregate not only topics of interest but curate on specific topics to add some more insight from acceptable sources over the web.

In Power of Analogy: Curation in Music, Music Critique as a Curation and Curation of Medical Research Findings – A Comparison; Dr. Larry Berstein compares a museum or music curator to curation of scientific findings and literature and draws similar conclusions from each: that a curation can be a tool to gain new insights previously unseen an observer. A way of stepping back to see a different picture, hear a different song.

 

For instance, using a Twitter platform, we curate #live meeting notes and tweets from meeting attendees (please see links below and links within) to give a live conference coverage

https://pharmaceuticalintelligence.com/press-coverage/

and curation and analysis give rise not only to meeting engagement butunique insights into presentations.

 

In addition, the use of a WordPress platform allows easy sharing among many different social platforms including Twitter, Google+, LinkedIn, Pinterest etc.

Hopefully, this will catch on to the big powers of Twitter, Google and Facebook to realize there exists armies of niche curation communities which they can draw on for expert curation in the biosciences.

Other posts on this site on Curation and include

 

Inevitability of Curation: Scientific Publishing moves to embrace Open Data, Libraries and Researchers are trying to keep up

The Methodology of Curation for Scientific Research Findings

Scientific Curation Fostering Expert Networks and Open Innovation: Lessons from Clive Thompson and others

The growing importance of content curation

Data Curation is for Big Data what Data Integration is for Small Data

Stem Cells and Cardiac Repair: Content Curation & Scientific Reporting

Cardiovascular Diseases and Pharmacological Therapy: Curations

Power of Analogy: Curation in Music, Music Critique as a Curation and Curation of Medical Research Findings – A Comparison

 

 

 

 

 

 

 

Read Full Post »


Curation of Recently Halted Oncology Trials Due to Serious Adverse Events – 2015

Curator: Stephen J. Williams, Ph.D.

The following is reports of oncology clinical trials in 2015 which have been halted for Serious Adverse Events (SAE), in most instances of an idiopathic nature. For comparison I have listed (as of this writing) the oncology drug approvals (8) for 2015. (from CenterWatch.com)

Oncology Drugs Approved in 2015

Farydak (panobinostat); Novartis; For the treatment of multiple myeloma, Approved February 2015

Ibrance (palbociclib); Pfizer; For the treatment of ER-positive, HER2-negative breast cancer, Approved February 2015

Lenvima (lenvatinib); Eisai; For the treatment of thyroid cancer, Approved February 2015

Lonsurf (trifluridine and tipiracil); Taiho Oncology; For the treatment of metastatic colorectal cancer , Approved September 2015

Odomzo (sonidegib); Novartis; For the treatment of locally advanced basal cell carcinoma, July 2015

Opdivo (nivolumab); Bristol-Myers Squibb; For the treatment of metastatic squamous non-small cell lung cancer, Approved March 2015

Unituxin (dinutuximab); United Therapeutics; For the treatment of pediatrics with high-risk neuroblastoma, Approved March 2015

Varubi (rolapitant); Tesaro; For the prevention of delayed nausea and vomiting associated with chemotherapy, Approved September 2015


Death Forces FDA to Place Clinical Hold on Advaxis (ADXS) Cancer Drug

from Biospace News

October 7, 2015
By Alex Keown, BioSpace.com Breaking News Staff

PRINCETON, N.J. – Following the death of a patient, the U.S. Food and Drug Administration (FDA) placed a hold on Advaxis (ADXS)’s experimental cancer treatment axalimogene filolisbac, which is currently in mid-stage trials.

In a statement issued this morning, Advaxis maintains the patient’s death was a result of the severity of her cancer and not due to the company’s experimental cancer treatment. It is seeking proof from the FDA that the drug was not a factor in the death. Still, the hold on the experimental cancer drug will cause the company to halt four clinical trials, Advaxis said. Other clinical trials, including those with the experimental ADXS-PSA and ADXS-HER2, are not affected by this hold. The company said it will continue to actively enroll and dose patients.

The FDA placed a hold on the drug on Oct. 2 after the company submitted a safety report to the regulatory agency that week. The drug is being developed to treat patients with persistent or recurrent metastatic (squamous or non-squamous cell) carcinoma of the cervix (PRmCC) who have progressed on at least one prior line of systemic therapy. Phase I trials released at the end of September showed treatment with axalimogene filolisbac resulted in a 38.5 percent 12-month overall survival rate in 26 patients. Patients typically fighting PRmCC who have failed at least one line of therapy have a typical survival rate of four to seven months.

Read full story here


FDA Halts Trial of Halozyme’s PEGPH20 for Pancreatic Cancer

Apr 9, 2014 Alex Philippidis

Halozyme Therapeutics acknowledged today that the FDA placed a formal clinical hold on its troubled Study 202 assessing its experimental drug PEGPH20 in patients with pancreatic cancer—less than a week after the company temporarily halted enrolling and dosing patients in the ongoing Phase II trial.

The agency told Halozyme it placed the clinical hold following the company’s pause in study activity. The trial’s independent data monitoring committee is evaluating data from the trial to learn why patients treated with PEGPH20 as well as nab-paclitaxel and gemcitabine saw a higher rate of blood clots and other thromboembolic events compared with patients treated with nab-paclitaxel and gemcitabine alone.

“We will be providing this information to the data monitoring committee and the FDA in parallel so they can complete their respective assessments,” Helen Torley, M.B. Ch.B., M.R.C.P., Halozyme’s president and CEO, said in a statement.

“Pancreatic cancer has one of the lowest survival rates of any cancer. We remain committed to evaluating PEGPH20 as a possible therapy to address this devastating disease,” Dr. Torley added.

As with Halozyme’s statement last week, the company’s latest remarks did not indicate when Halozyme expects to resume enrolling and dosing patients in Study 202, or how many patients had been enrolled and dosed when the temporary halt occurred.

The trial was envisioned as having 124 subjects, divided evenly between a treatment arm of PEGPH20 and nab-paclitaxel, and a gemcitabine arm, preceded by eight subject “run-in” phase assessing safety and tolerability, according to Study 202’s page on ClinicalTrials.gov (NCT01839487), last updated on January 27.

The study is one of two Phase II trials for PEGPH20; the other, SWOG, also aims to assess the drug for pancreatic cancer.

PEGPH20 is an investigational PEGylated form of Halozyme’s FDA-approved recombinant human hyaluronidase rHuPH20 (marketed as Hylenex®), designed to dramatically increases the half-life of the compound in the blood and allow for intravenous administration.

The temporary halt for Study 202 came two months after Halozyme publicly cited “potential acceleration of the PEGPH20 program” among several R&D programs for which it raised funds through a public offering of common stock that closed in February and generated approximately $107.8 million in net proceeds.

Read more at GenNEWS


FDA orders CytRx to halt patient enrollment after death of a cancer patient

CytRx ($CYTR) has run into an unexpected roadblock with its cancer drug conjugate aldoxorubicin, slamming the brakes on new patient recruitment in all their clinical trials after the FDA dropped a partial clinical hold on the program. According to the biotech the hold was forced by the death of a patient who was given the drug through a compassionate use program.

LA-based CytRx execs say that patients already enrolled in the studies will continue to receive the therapy as investigators added new safety measures, retooling trial protocols to include an “appropriate inclusion/exclusion criteria, an additional patient screening assessment and an evaluation of serum electrolytes prior to aldoxorubicin administration.” The patient who died, they added, had not qualified for any of its studies.

As it stands now, the biotech doesn’t know exactly how long the partial hold will last, but their announcement sought to calm jumpy investors, saying they expected to resolve the FDA’s demands “expeditiously” and can stick to their current timelines. CytRx says it expects to report preliminary results from their mid-stage study of Kaposi’s sarcoma in the second quarter of 2015 and preliminary results from the ongoing Phase II clinical trial of aldoxorubicin in glioblastoma multiforme in the first half of 2015. The company added that it is committed to completing enrollment in their Phase III trial by the end of next year.

hat reassurance appears to have helped with investors, who seemed to count this as more of a temporary setback than a catastrophe. Shares for CytRx were down about 9% in mid-morning trading.

Aldoxorubicin uses a linker molecule to attach to albumin in the blood and concentrate in tumors, where the acidic environment releases the chemotherapy doxorubicin in doses up to four times higher than what’s used now. Late last year their stock soared after their drug scored promising results for progression-free survival in a Phase IIb trial.

This case illustrates one reason why biotechs often quietly squirm under the pressure of compassionate use programs. They can be expensive to operate, time-consuming and raise fresh concerns when a patient dies or experiences a setback. On the other hand, if regulators take action like this following the death of an advanced stage cancer patient, there may have been something about the case that triggered broader concerns for the entire patient population


Clot risk in Lilly lung-cancer drug raises FDA concerns

July 7, 2015

Eli Lilly and Co.’s experimental lung cancer drug has raised concerns with U.S. regulators that it may increase patients’ risk of suffering potentially deadly blood clots.

The drug, known as necitumumab, improved patients’ overall chances of survival, yet people taking the medicine also experienced more risk, Food and Drug Administration staff said in a report Tuesday. Indianapolis-based Lilly is seeking to sell the medicine to treat a subset of the most common type of lung cancer.

FDA advisers will meet Thursday to discuss the risks and benefits of necitumumab for patients with advanced squamous non-small cell lung cancer, in combination with chemotherapy. The FDA is expected to decide if Lilly can sell the drug by the end of the year.

While the safety of necitumumab reflects that of similar drugs, the increased danger of clotting “in this already high risk population is of concern,” FDA staff wrote.

One study showed that out of 538 patients taking necitumumab and chemotherapy, 9 percent experienced a serious clot, compared with 5 percent of 541 patients given only chemotherapy, according to the staff report.

Squamous lung cancer accounts for 25 percent to 30 percent of all lung cancer, according to the American Cancer Society.

Patients in a clinical trial who took necitumumab lived a median of 11.5 months, 1.6 months longer than those who got only chemotherapy, the FDA staff report said.

Opdivo Side Effects Center (as seen on Rxlist.com) (NOTE:TRIAL NOT HALTED)

Last reviewed on RxList 10/05/2015

Opdivo (nivolumab) is a human monoclonal antibody used to treat patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor; and to treat metastatic squamous non-small cell lung cancer with progression on or after platinum-based chemotherapy. Common side effects of Opdivo include fatigue, rash, itching, cough, upper respiratory tract infection, swelling of the extremities, shortness of breath, muscle pain, decreased appetite, nausea, vomiting, constipation, diarrhea, weakness, swelling, fever, abdominal pain, chest pain, joint pain, and weight loss.


Opdivo FDA Prescribing Information: Side Effects
(Adverse Reactions)

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data described in the WARNINGS AND PRECAUTIONS section and below reflect exposure to OPDIVO in Trial 1, a randomized trial in patients with unresectable or metastatic melanoma and in Trial 3, a single-arm trial in patients with metastatic squamous non-small cell lung cancer (NSCLC).

Clinically significant adverse reactions were evaluated in a total of 691 patients enrolled in Trials 1, 3, or an additional dose finding study (n=306) administering OPDIVO at doses of 0.1 to 10 mg/kg every 2 weeks [see WARNINGS AND PRECAUTIONS].

Unresectable or Metastatic Melanoma

The safety of OPDIVO was evaluated in Trial 1, a randomized, open-label trial in which 370 patients with unresectable or metastatic melanoma received OPDIVO 3 mg/kg every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102), either dacarbazine 1000 mg/m² every 3 weeks or the combination of carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m² every 3 weeks [see Clinical Studies]. The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) with a median of eight doses (range: 1 to 31) in OPDIVO-treated patients and was 2 months (range: 1 day to 9.6+ months) in chemotherapy treated patients. In this ongoing trial, 24% of patients received OPDIVO for greater than 6 months and 3% of patients received OPDIVO for greater than 1 year.

In Trial 1, patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids ( > 10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV.

The study population characteristics in the OPDIVO group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% white, baseline ECOG performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the OPDIVO group with elevated LDH at baseline (51% vs. 38%).

OPDIVO was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving OPDIVO had a drug delay for an adverse reaction. Serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% to less than 5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.


FDA Approves Eisai’s LENVIMA™ (lenvatinib) for the Treatment of Patients with Locally Recurrent or Metastatic, Progressive, Radioactive Iodine-Refractory Differentiated Thyroid Cancer

– Press release from Eisai (NOTE: TRIAL NOT HALTED)

Feb 13, 2015

WOODCLIFF LAKE, N.J., Feb. 13, 2015 /PRNewswire/ — Eisai Inc. announced today that the U.S. Food and Drug Administration (FDA) approved the company’s receptor tyrosine kinase inhibitor LENVIMA™ (lenvatinib) for the treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC). LENVIMA was approved following a priority review by the FDA, which is designated for drugs the FDA believes have the potential to provide a significant improvement in the treatment of a serious condition. LENVIMA demonstrated a statistically significant progression-free survival (PFS) prolongation and response rate in patients with progressive, differentiated thyroid cancer who had become refractory to radioactive iodine (RAI) therapy.

In the clinical trial, adverse events led to dose reductions in 68% of patients who received LENVIMA and 5% of patients who received placebo. Some patients will need to discontinue treatment for serious adverse reactions. In the trial, 18% of patients treated with LENVIMA and 5% who received placebo discontinued treatment. The most common adverse reactions (at least 10%) that resulted in dose reductions of LENVIMA were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%).

AstraZeneca halts a pair of lung cancer trials over a safety scare

From October 9, 2015 | By of FierceBiotech

“AstraZeneca ($AZN) is pressing pause on trials combining two of its most important pipeline cancer treatments after tracking reports of lung disease, halting enrollment as it gathers more information.

The company is testing a combination of AZD9291 and durvalumab, formerly MEDI4736, in two studies involving patients with non-small cell lung cancer. Late last month, AstraZeneca hit the brakes on enrollment in both trials due to an increase in reports of interstitial lung disease, which can lead to dangerous scarring and impaired pulmonary function. The pauses are temporary, the company stressed in an emailed statement, and patients already enrolled in the study will be given new consent forms to ensure they understand the risks before choosing whether keep getting treatment.”

Other posts on this site on Cytotoxicity and Cancer include

Novel Approaches to Cancer Therapy [11.1]

Misfolded Proteins – from Little Villains to Little Helpers… Against Cancer

Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer

A Synthesis of the Beauty and Complexity of How We View Cancer

Good and Bad News Reported for Ovarian Cancer Therapy

Read Full Post »


Abraham Verghese, MD, Physician and Notable Author

Curators: Larry H. Bernstein, MD and Aviva Lev-Ari, PhD, RN

LPBI

Series E. 2; 12.3

There are few who combine a career as physician, teacher and author as well as Abraham Verghese, whose name is a frequent byline in newspapers and magazines across the world, and more recently, in demand as aTED speaker. He himself is also a regular focus of attention in media – both medical and general – that range from National Public Radio, the New England Journal of Medicine, and the New York Times to The Guardian, and The Times of India.

His work as a physician informs his writing and the reflection that comes through his writing helps him empathize with his patients, and to see them individually, as human beings who are suffering, fearful and in need not just of treatment, but of comfort and reassurance. Imagining his patients’ experience has driven his work throughout his medical career. His emphasis on empathy and healing is the focus of his talks, nationally and internationally, as he stresses the importance of the patient-physician relationship in an era of advances in medical technology that often tend to de-personalize medical care.

“I still find,” he says, “the best way to understand a hospitalized patient is not by staring at a computer screen, but going to see that patient. For it is at the bedside that I can figure out what’s important to the patient and how the data you have accumulated makes sense.”

Abraham Verghese talks about medicine and fiction to Kim O’Dell of the Heinz Foundation after receiving the 2014 Heinz Award for Arts and Humanities.

Abraham Verghese, MD, MACP, is Professor and Linda R. Meier and Joan F. Lane Provostial Professor, and Vice Chair for the Theory and Practice of Medicine at the School of Medicine at Stanford University. He is also a critically acclaimed, best-selling author and a physician with an international reputation for his focus on healing in an era where technology often overwhelms the human side of medicine. In February 2014, he received a Heinz Award from Teresa Heinz and the Heinz Family Foundation. The awards given annually in the areas of Arts and Humanities; Environment; Human Condition; Public Policy; and Technology, the Economy and Employment, celebrate the enduring spirit of hope and the power of innovation.

Early Years

Born in Addis Ababa in 1955,  the second of three sons of Indian parents recruited by Emperor Haile Selassie to teach in Ethiopia, he grew up near the capital and began his medical training there. When the emperor was deposed, Verghese briefly joined his parents who had moved to the United States because of the war, working as an orderly in a hospital before completing his medical education in India at Madras Medical College. Both the civil unrest and this time as a hospital orderly were to leave a significant mark on his life and work.

After graduation, he left India for a medical residency in the United States and, like many other foreign medical graduates, he found only the less popular hospitals and communities open to him, an experience he described in one of his early New Yorker articles, The Cowpath to America.

From Johnson City, Tennessee, where    he was an internal medicine resident from 1980 to 1983, he moved to the Northeast for a fellowship at Boston University School of Medicine, working at Boston City Hospital for two years. It was here that he first saw the early signs of the HIV epidemic and later, when he returned to Johnson City as an assistant professor of medicine, he saw the second epidemic, rural AIDS, and his life took the turn for which he is now so well known – caring for a seemingly unending line of young AIDS patients in an era when little could be done other than help them through their premature and painful deaths. Long before retrovirals, this was often the most a physician could do and it taught Abraham Verghese the subtle difference between healing and curing.

First Books

Abraham Verghese’s early years as an orderly, his caring for terminal AIDS patients, the insights he gained from the deep relationships he formed and the suffering he witnessed were intensely transformative. These were the cumulative experiences around which his first book, My Own Country: A Doctor’s Story, is centered.

Such was his growing interest in writing in the late 1980s that he decided to take some time away from medicine to study at the Iowa Writers Workshop at the University of Iowa, where he earned a Master of Fine Arts degree in 1991. Since then, his writing has appeared in The New Yorker, Texas Monthly, Atlantic, The New York Times, The New York Times Magazine, Granta, Forbes.com, and The Wall Street Journal, among others.

After leaving Iowa, he became professor of medicine and chief of the Division of Infectious Diseases at Texas Tech Health Sciences Center in El Paso, Texas, where he lived for the next 11 years. In addition to writing his first book, which was one of five chosen as Best Book of the Year by TIME magazine and later made into a Showtime movie directed by Mira Nair, he also wrote a second best-selling book, The Tennis Partner: A Story of Friendship and Loss, about his friend and frequent tennis partner’s losing struggle with addiction. This was named a New York Times’ Notable Book.

Emphasis on the Physician-Patient Relationship

He left El Paso in 2002 and, as founding director of the Center for Medical Humanities & Ethics at the University of Texas Health Science Center San Antonio, he brought the deep-seated empathy for patient suffering that had been honed by his previous experiences to his new role in the medical humanities.

He gave the new Center a guiding mission, “Imagining the Patient’s Experience,” to emphasize the importance of interactive patient care. He saw empathy as a way to preserve the innate caring and sensitivity that brings students to medical school, but which the rigors of their training frequently suppress. In San Antonio, also, he became more focused on bedside medicine, inviting small groups of medical students to accompany him on bedside rounds. Rounds gave him a way to share one-on-one the value he placed on the physical examination in diagnosing patients and demonstrating attentiveness to patients and their families, a vital key in the healing process.

Dr. Verghese’s deep interest in bedside medicine and his reputation as a clinician, teacher and writer led to his recruitment to Stanford University School of Medicine in 2007 as a tenured professor and senior associate chair for the Theory and Practice of Medicine. He has since been named the Linda R. Meier and Joan F. Lane Provostial Professor Vice Chair for the Theory and Practice of Medicine at the Stanford School of Medicine.

In his writing and his work, he continues to emphasize the importance of bedside medicine and physical examination in an era of advanced medical technology. He contends the patient in the bed often has less attention than the patient data in the computer. His December 2008 article in the New England Journal of Medicine, Culture Shock: Patient as Icon, Icon as Patient, clearly lays out his viewpoint.

In his novel, Cutting for Stone, he also addresses the issue.

“I wanted the reader to see how entering medicine was a passionate quest, a romantic pursuit, a spiritual calling, a privileged yet hazardous undertaking,” he said. “It’s a view of medicine I don’t think too many young people see in the West because, frankly, in the sterile hallways of modern medical-industrial complexes, where physicians and nurses are hunkered down behind computer monitors, and patients are whisked off here and there for all manner of tests, that side of medicine gets lost.”

Today, as a popular invited speaker, he has more forums than his writing to expound on his views on patient care. He talks nationally and internationally on the subject, in addition to talks and readings from his books. He has also led the effort at the Stanford School of Medicine to establish the Stanford 25, where residents and students are taught techniques and skills to recognize the basic phenotypic expressions of disease that manifest as abnormal physical signs.

More About Abraham Verghese

Physician Returns: Stanford Medical Center Report

Bedside Manners: Q/A with Abraham Verghese in Texas Monthly

Treat the Patient, Not the CT Scan: Op Ed in the New York Times

Click on a topic or read the entire series.

Bedside Medicine
Books – General
Cutting for Stone
Cutting for Stone, Origin of the Title
Ethiopia
Favorite Writers
Fiction Writing
Future
Home
Medicine
Medicine and Writing
Success
Suffering
Training as a Writer

Bedside Medicine

You talk a lot about the lost art of bedside diagnosis. Can you describe what that is and why losing it is a bad thing?

As we’ve gotten very fancy in technology and the incredible detail with which we can see the body, we sometimes lose sight of how much we can see about the body just from examining the patient. The physical exam really allows you to order tests more judiciously and to ask better questions of the test.

Tell us about your vision for teaching medical students and physicians.

Yes. I’ve learned by coming full circle that the most important way we have to influence medical students and residents is really at the bedside, one by one. There really is no shortcut; there is no classroom lecture that can substitute. Stanford has such a wonderful reputation for research, and we wanted to try and make sure that it also had an equivalent reputation for the clinical training of our students and our residents.

So the clinical encounter at the bedside is terribly important. In other words, you can have all the theoretical knowledge in the world, and if your interaction with the patient is somehow clumsy and not done well, the relationship won’t even begin.

The computerized medical record, along with burgeoning technology, has seriously threatened the patient/physician interaction in the hospital.

I would contend, and I will keep saying this till the day it stops being true, that the patient in the bed has now become an icon for the real patient, who is in the computer, the patient I call the iPatient. The patient in the bed simply exists to signify that there is a file in the computer.

Now, of course, I’m being facetious. We clearly pay attention to the person in the bed, but what I mean to say is that looking at the body, orienting oneself from the body has become almost passé. The body is viewed as incidental, in many cases for good reason, because a mammogram or CT scan can perhaps see much more clearly than the human hand. Nevertheless, there are things that only the human hand can find, like whether it’s painful in a particular spot. That’s not something that any machine can tell you. There isn’t any machine in the world that can do a knee reflex and convey the information of a tendon reflex. There are elements of this exam that are so important, and in this era of biomarkers and other sexy tests, we have forgotten the value of the good physical.

What is it about the practice of medicine today that prompts doctors to rush into ordering tests vs. taking their time to do the bedside diagnosis?

For one thing, the tests are very, very good. The kind of detail you can get from a CAT scan is far superior to what your hand can tell you. On the other hand, only your hand can tell you where it hurts by pushing on a certain place. … We’re all intrinsically prone to allowing technology to take the place of common sense and I think that’s a danger. … The tests have become an easy shortcut. They’re an efficient, quick way to get information. But the great danger I see is this: I think that people fail to really connect with patients when they don’t examine them. I think the carefully done physical is a wonderful way to convey your attentiveness to the patient.

How can professors and medical schools help address the primary care shortfall?

It’s a struggle … but if you’re going to do it, you’re going to do it only by showing them the charm and the magic of being at the bedside. There is no passion and romance that you can illustrate to them in front of a computer, which is where a lot of care takes place these days. The only way to excite students about medicine is to do it one by one, by them seeing you being the kind of physician that they’d like to be.

Your two non-fiction books are very autobiographical. What’s the difference between penning fiction and non-fiction? How was the process of writing Cutting for Stone different for you than penning the other books?

I must say that fiction was always my first love; indeed, one of my first published stories as a very dark AIDS story titled ‘Lilacs’ which appeared in the New Yorker. That led to my getting a contract to write My Own Country, a non-fiction book about my AIDS practice and experience in small town Tennessee, followed by another memoir, The Tennis Partner (the story of the loss of a physician friend to drug addiction and suicide). These were things I had witnessed that I had to tell, but when I was done with the second book, I was keen to get back to fiction.

What was so different about writing a novel for me was that sense of discovering the story (unlike non-fiction, where you sort of know what happened and what you will write about–the story has presented itself so to speak, and now it is about selection). My ambition for the novel was tell a great story, an old-fashioned, truth-telling story.

All I had at the outset was an image of a beautiful Indian nun giving birth in a mission hospital in Africa, a place redolent with Dettol and carbolic acid scents, a place so basic, so unadorned, that nothing separates doctor and patient, no layers of paperwork, cubicles and forms. That is all I had. I did not know the whole plot or how it ended. (and see answer to next question as to how I eventually did plot, and even then there were surprises).

did know that I wanted the whole novel to be of medicine, by which I mean I wanted every person, scene and place to be informed by medicine, kind of the way that Zola’s novels are of Paris. I wanted very much to celebrate an aspect of medicine that gets buried in the way television depicts the practice: I wanted the reader to see how entering medicine was a quest, a romantic pursuit, a spiritual calling, an undertaking that could put you at some personal risk (of losing your selfhood, your obligation to family) but which could also save you. It’s a view of medicine I don’t think too many of my students see – we live in a world of haste where physicians and nurses are hunkered down behind computer monitors, and patients are whisked off here and there for this and that test, that side of medicine gets lost.

What inspired you to write each of your books? Was there a moment of epiphany for each one, when you decided that you simply had to put that story down on paper?

Many moments of epiphany in all of my books. There was no real moment in time when any of them started, but very often for me, writing about something is a way to understand it better, or just understand it in the first place. I became a character in the stories with a sense of discovering the import as I wrote rather than writing because I understood it.

Living through the time of AIDS in Tennessee, and helplessly with David as he was spiraling down in El Paso – writing these first two books helped me more deeply understand those experiences. With Cutting for Stone, I arbitrarily chose twins, then twins became the motive for the story, and ultimately they were the focus for the characters’ redemption. I could not have anticipated any of that when I began writing, but it became clear as I progressed. A series of epiphanies, you could say.

Was there a single idea behind or genesis for Cutting for Stone?

My ambition as a writer was to tell a great story, an old-fashioned, truth-telling story. But beyond that, my single goal was to portray an aspect of medicine that gets buried in the way television depicts the practice: I wanted the reader to see how entering medicine was a passionate quest, a romantic pursuit, a spiritual calling, a privileged yet hazardous undertaking.

It’s a view of medicine I don’t think too many young people see in the West because, frankly, in the sterile hallways of modern medical-industrial complexes where physicians and nurses are hunkered down behind computer monitors, and patients are whisked off here and there for this and that test, that side of medicine gets lost.

So I began with the image of a mission hospital in Africa, redolent with Dettol, the antiseptic of choice of the tropics; I wanted to portray a place so basic, so unadorned, that nothing separates doctor and patient, no layers of paperwork, technology or specialists, no disguising of the nature of the patient’s experience or the raw physician experience. It’s a setting where the nature of the suffering, the fiduciary responsibility and moral obligation to the patient and society are no longer abstract terms. In that setting I wanted to put very human, fallible characters-people like Sister Mary Joseph Praise and Thomas Stone. I wanted the whole novel to be of medicine, populated by people in medicine, the way Zola’s novels are of Paris.

Where did the idea for the story of these twins germinate and how did it grow?

When I actually sat down to begin to write this book, what kept recurring was an image of a beautiful, south-Indian nun who suddenly and precipitously goes into labor in a mission hospital in Africa. That act of her going into labor throws everyone for a loop and causes utter confusion at the hospital. That’s all I had to begin with.

I saw her succumbing in that labor, and I saw one of the twins becoming the narrator of the story and looking back in somewhat of an antique voice. So I kept writing, developing the ideas, themes, and characters.

I found some reassurance in a quote by E.L. Doctorow who says about writing that, ‘It’s like driving a car at night. You never see further than your headlights, but you can make the whole trip that way.’ It was often nerve wracking not to know what lay ahead. I’d heard master storytellers like John Irving say that if you’re just making it up as you go along, if you have no plot, then you weren’t a writer, but an ordinary liar!

Halfway through the book, I felt my characters were so alive that their choices were infinite. I had to know what was going to happen, so I met with my editor and we hammered out a plot. My relief at that point was huge; I could concentrate on language and the telling. What surprised me is that even then there were so many discoveries, so many truths that emerged unexpectedly. It affirms for me what I most love about writing, and that is that it is not a rational, logical process

One of the most striking elements of Cutting for Stone is the intimacy with not just one character, but an entire cast. Though Marion tells the story, we become deeply involved in each person’s struggles, not just his own. Which characters did you feel closest to while writing the book? And why did others feel more distant?

Characters, by the way, do not start out rounded. They emerge. I think Ghosh is the character whose emergence and whose full blossoming I loved most. He is essentially fair, kind and eminently faithful, a family man, and above all patient – all the qualities I would like to have myself, but don’t always. He is the consummate internist too, which I also aspire to be. He gives me something to strive for.

Hema, too, is someone I deeply understood – or understand as well as a male writing a novel can understand a woman. Thomas Stone is both more alien and familiar – a doctor caught up in the illusion that work can redeem his character failings. Shiva – I let him be distant, impenetrable, because that is the nature of his character. My editor would sometimes be frustrated with me because she could not ‘see’ Shiva, and I would say to her, ‘Yes! That is the point. There is a quality to him, an Asperger’s-like patina, that makes him hard to know.’

In your earlier books, you touch on the breakup of your personal life due to the strain of practicing medicine. Do these experiences echo through Dr. Stone’s choosing work over life – and to what degree?

Yes, I felt a great empathy for Stone and his feeling that medical work is the most wonderful work you can ever do and yet how he hurt the people around him by losing himself in a love for his work that was so extreme.

An aim of the novel was to show just how medicine and the magic word, ‘work’ can both heal and cripple, how it is a trap and yet it is a balm and as Yeats would say, the challenge is to find that balance between the ‘perfection of the life or of the work’ and in the book there are characters who exemplify both ends of that spectrum. Dr. Stone was very skilled, he focused on the moment and had great knowledge and wisdom, but it was not enough to save him. Perhaps there is some of my own life in that thought, who knows?

At the heart of this novel there is a love story – that of Sister Mary Joseph Praise and Dr. Thomas Stone – which informs almost everything that happens to each character in the book, and yet one of these characters is dead and one has not been seen by anyone for decades. How did you conceive of their relationship, and how do they exert such force on the novel even though neither is present for the majority of it?

Love to me has a quality to it like a trip wire – hence we ‘fall’ in love, instead of simply ‘arriving’ to love. Love comes down to a set of wills trying to match and sometimes mismatching in spectacular fashion; I think all love is unrequited unless we have a clone of ourselves and even then the love is unrequited. In my day job I see all too often that people’s appreciation of the existence of love, of the meaning of love, or of the idea that the meaning of life turns out to be love – all these are arrived at too late, when the love is long lost, or arrived at just before the moment of death.

The medical passages were fascinating. Do you keep a medical journal?

I don’t keep a journal as much as I write notes when I observe something I want to remember later, so I can recall the situation – the feelings, the interaction – at a later time. I have always scribbled. For some of the intense medical situations in the book, some very fine, accomplished surgeons allowed me over the years to be present as they worked, understanding that I wanted to be able to convey the wonder of surgery, of curing, of healing. It was an honor and I am deeply grateful to have been able to do this.

Where does the title ‘Cutting for Stone’ come from?

There is a line in the Hippocratic Oath that says: … I will not cut for stone, even for patients in whom the disease is manifest … It stems from the days when bladder stones were epidemic, a cause of great suffering, probably from bad water and who knows what else. Adults and children suffered so much with these – and died prematurely of infection and kidney failure.

There were itinerant stone cutters – lithologists – who could cut either into the bladder or the perineum and get the stone out, but because they cleaned the knife by wiping it on their blood-stiffened surgical aprons, patients usually died of infection the next day.

Hence the proscription, ‘hou shall not cut for stone.’ It has always seemed to me a curious thing to say when we recite the oath in this day and age. But I love the Hippocratic Oath (or oaths, because its origins and authorship are far from clear), and always try to attend medical school commencement. When the new graduates stand and take the oath, all the physicians in the room are invited to rise and retake the oath.

You bring Ethiopia to life so vividly – its contradictions of beauty and poverty. Addis Ababa (and Missing Hospital) is so much a part of each character though some come to it from other places or leave it for other places. Why did you decide to set much of this novel there? And how do you think the atmosphere of the place affected your life?

Even in this era of the visual, I think a novel can bring out the feel of a place better than almost any vehicle. It’s another thing that Somerset Maugham did so well. The few images one sees of Ethiopia are uniformly negative, about war and poverty. I wanted to depict my love for that land and its people, for their incredible beauty and grace and their wonderful character.

I wanted also to convey the loss many felt when the old order gave way to the new. Ethiopia had the blight of being ruled by a man named Mengistu for too many years, a man propped up by Russia and Cuba. My medical school education was actually interrupted when Mengistu came to power and the emperor went to jail. As an expatriate, I had to leave. It was my moment of loss. Many of my medical schoolmates became guerilla fighters, trying to unseat the government. Some died in the struggle. One of them fought for over twenty years, and his forces finally toppled the dictator.

What books have made the most difference in your life?

Several books were seminal in my coming to medicine, allowing me to see medicine as a calling, a romantic and noble pursuit. Of Human Bondage by Somerset Maugham was one such book. Also A.J. Cronin’s The Citadel and Keys of the Kingdom. That used to be how people came to be drawn to medical school. Now, perhaps television and movies fulfill that role.

My favorite novel has little to do with medicine despite its name, and happens to be a great love story – it’s Love in the Time of Cholera by Gabriel Garcia Marquez. Some writers read George Eliot’s Middlemarch every year. I read Love in the Time of Cholera.

What’s the best way to get a child interested in reading?

I don’t know the best way, and I wish someone would show me! But I do know it’s important. What we often forget is that when we read and enjoy a good novel, we are engaging in a collaborative act with the writer. The writer gives us the words, we provide the imagination, and somewhere in middle space, we jointly create this fictional dream, this mental movie. It requires effort on our part – it is not a passive act, but a creative one to read a book. The writer has to give you just enough words, not too many; just enough so that you can imagine the rest. If you have ever been horribly disappointed when your favorite book was made into a movie, because the actor looked nothing like the person you had conjured up in my mind, then you know what I mean.

I believe that, as the writer John Fowles has said, that if you don’t practice this skill of taking words on a page and turning them into pictures, then a part of the brain atrophies. I try to make this point with our medical students: that reading stories, novels, keeps a part of the brain alive, and it relates to the clinical imagination. I don’t know a single clinician I have greatly admired over the years who has not also enjoyed good literature or some aspect of the arts. I think it is no coincidence. That is where the right brain comes in. Medicine is, and will always be – no matter how much technology we introduce – an art and a science. You need both.

Your first two books are non-fiction, but you’ve said that you have always thought of yourself as a fiction writer first. How so?

Fiction is truly my first love. To paraphrase Dorothy Allison, fiction is the great lie that tells the truth about how the world really lives. It is why in teaching medical students I use Tolstoy’s The Death of Ivan Ilych to teach about end-of-life, and Bastard out of Carolina to help students really understand child abuse. A textbook rarely gives them the kind of truth or understanding achieved in the best fiction.

One of my first published short stories was ‘Lilacs,’ in which the protagonist has HIV. Its appearance in The New Yorker in 1991 was a part of what led to my contract to write My Own Country, a memoir of my years of caring for persons with HIV in rural Tennessee. While writing that book I found myself living through an intense personal story of friendship and loss that led to a second non-fiction book, The Tennis Partner. But after that, I passed up on an offer to write a third non-fiction book. I was keen to get back to fiction, to explore that kind of truth.

My true call to medicine came in the form of a book. By the time I picked up Of Human Bondage by Somerset Maugham I had already read Lolita and Lady Chatterley’s Lover. I was twelve, I think. Maugham’s protagonist, Philip, sets out for Paris to become an artist. Money is tight, and he lives on the brink of starvation, and finally finds he does not have the talent. He is crushed and disappointed but also relieved to have discovered what is not to be his calling. He returns to London and enters medical school. When after years of slogging away he enters the outpatient clinic for the first time, he realizes he has made the right choice. The particular lines that stayed with me, that have haunted me, were: ‘there was humanity there in the rough, the materials the artist worked on; and Philip felt a curious thrill when it occurred to him that he was in the position of the artist…’

The phrase ‘humanity there in the rough’ spoke directly to my twelve-year-old mind. I took it to mean that if one had no God-given talent to be an artist (or mathematician), one could aspire to be a doctor, perhaps even a good one. The beauty of medicine is that it is proletarian, and its prime prerequisite is that you have an interest in humanity in the rough. Many of us also come to medicine because we are wounded in some way. Thomas Stone is a great example, but so is Marion Stone.

Medicine plays a big part in your novel, and it is also something that unites people of different races and religions in Cutting for Stone: Hindus, Christians, Indians, Africans and Westerners all work for a common goal: curing the patient. Is this the message of your book?

Indeed, I wanted the whole novel to be of medicine, populated by people in medicine, the way Zola’s novels are of Paris. If I begin with a mission hospital in Africa, a place redolent with Dettol and carbolic acid scents, it is because I think that in a place so basic, the nature of the suffering, the fiduciary responsibility and moral obligation to the patient and society are no longer abstract terms. Indeed, nothing separates doctor and patient, no layers of paperwork, technology or specialists and you can’t disguise the nature of the patient’s experience or the raw physician experience.

Then I put in very human, fallible characters — people like Sister Mary Joseph Praise, Thomas Stone. To take the story to America was to contrast this world with Western medicine, its power and beauty, but also its failings. Contrasting an inner city underfunded non-academic center with a ‘Mecca’ of a tertiary referral center was also I think a good way to point out the strengths and weaknesses of both and also to highlight the very different people who inhabit such places.

But ultimately, I think the intent was to point out that even though medicine changes, the fundamental role of the physician, the need for their presence, does not change, and the importance of that presence is greater than ever. Cure is laudable but not always something we achieve, but comforting and healing is something we can do. It is the healing or Samaritan or priestly function of being a physician that we seem loath to claim.

A few months ago, a 40 year-old woman came to an emergency room in a hospital close to where I live,and she was brought in confused. Her blood pressure was an alarming 230 over 170. Within a few minutes, she went into cardiac collapse. She was resuscitated, stabilized, whisked over to a CAT scan suite right next to the emergency room, because they were concerned about blood clots in the lung. And the CAT scan revealed no blood clots in the lung, but it showed bilateral, visible, palpable breast masses,breast tumors, that had metastasized widely all over the body. And the real tragedy was, if you look through her records, she had been seen in four or five other health care institutions in the preceding two years. Four or five opportunities to see the breast masses, touch the breast mass, intervene at a much earlier stage than when we saw her.

http://www.ted.com/talks/abraham_verghese_a_doctor_s_touch?language=en#

https://www.youtube.com/user/TEDtalksDirector

TEDED – A doctor’s touch

Welcome to the Stanford Medicine 25 website. Remember, this site is NOT the Stanford Medicine 25; it is only a map to a territory, one that must be explored in person! The Stanford Medicine 25 consists of hands-on sessions in small groups. You can’t substitute for that, and we don’t try to. However, this site provides a place to go to remind ourselves of what we have learned, or are about to learn in a hands-on session.

http://stanfordmedicine25.stanford.edu/the25/

American College of Cardiology 2015 Annual Meeting: Simon Dack Lecture: “I Carry Your Heart” by Abraham Verghese, MD

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/04/08/american-college-of-cardiology-2015-annual-meeting-simon-dack-lecture-i-carry-your-heart-by-abraham-verghese-md/

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