Epigenetics: Cancer and Beyond

Epigenetics: Cancer and Beyond

Thursday, April 28, 2016

The New York Academy of Sciences

Transcription of genetic information encoded in DNA is regulated by epigenetic processes that work in concert to affect chromatin structure. The process by which this occurs involves modification of chromatin by 'writers' that add post-translational modifications (such as acetylation) to amino acids present on histones. These modifications affect histone-DNA interactions, resulting in relaxation of chromatin and recruitment of proteins required for transcription. A key example of these epigenetic 'readers' are the bromodomain extra-terminal (BET) family which bind acetylated lysines found on histones in DNA coding sequences, mobilizing transcriptional machinery to these sites, and thus activating gene expression.

Importantly, epigenetic processes are widely accepted to play an important role in cancer, and BET proteins in particular have been heavily implicated in tumorigenesis by upregulating expression of oncogenic genes. BET proteins also have important roles in immune biology, cell growth, and differentiation. These roles underscore the therapeutic potential of targeting epigenetics for the treatment of complex disorders and bromodomain inhibitors, most notably those targeting BET families, have emerged as strong candidates. The objective of this symposium is to explore the therapeutic potential of pharmacologic modulation of the epigenome.

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Agenda

* Presentation times are subject to change.


Thursday, April 28, 2016

8:30 AM

Registration and Continental Breakfast

9:00 AM

Welcome and Opening Remarks
Sonya Dougal, PhD, The New York Academy of Sciences
Norman Wong, MD, FRCPC, Resverlogix Corp

Plenary Session I: Epigenetics in Health and Disease

9:10 AM

Coupling Oxygen Availability to Global Changes in Chromatin Accessibility
Craig B. Thompson, MD, Memorial Sloan-Kettering Cancer Center

9:55 AM

Exploiting Epigenetic Therapies for Drug Resistance and Immunomodulation
Roberto Pili, MD, Indiana University School of Medicine

10:30 AM

Networking Coffee Break

11:00 AM

Role of BRD4 in Immune Cells: A Study with Conditional Knockout Mice
Keiko Ozato, PhD, National Institute of Child Health and Human Development

11:35 AM

Chromatin Regulators as Cancer Dependencies
Christopher Vakoc, PhD, Cold Spring Harbor Laboratory

12:10 PM

Networking Lunch and Poster Session

Plenary Session II: Epigenetic Therapies

1:30 PM

Introduction
Dominique Verhelle, PhD, Third Rock Ventures

1:35 PM

Epigenetic Regulators as Dynamic Memory Devices
Michael Elowitz, PhD, California Institute of Technology

2:10 PM

EpiScience — Translating the Epigenetic Concept into Clinical Benefits
Daniel Vitt, PhD, 4SC

2:45 PM

New Horizons for BET Inhibition: Apabetalone for the Treatment of High-Risk Cardiovascular Disease
Ewelina Kulikowski, PhD, Resverlogix Corp

3:20 PM

Networking Coffee Break

3:50 PM

Preclinical Characterization of ZEN-3694, a Novel BET Bromodomain Inhibitor Entering Phase I Studies for Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Eric Campeau, PhD, Zenith Epigenetics

4:25 PM

Targeting Chromatin Regulatory Pathways in Cancer
Patrick Trojer, PhD, Constellation

5:00 PM

Poster Prize Presentation and Closing Remarks
George Zavoico, PhD, JonesTrading Institutional Services

5:10 PM

Networking Reception

6:00 PM

Adjourn

Organizers

Donald McCaffery

Resverlogix Corp

Norman Wong, MD, FRCPC

Resverlogix Corp

Sarah Zapotichny

Resverlogix Corp.

George Zavoico, PhD

Jones Trading Institutional Services

Sonya Dougal, PhD

The New York Academy of Sciences

Caitlin McOmish, PhD

The New York Academy of Sciences

Session Chairs

Dominique Verhelle, PhD, MBA

Third Rock Ventures

Dominique Verhelle is a strategic advisor at Third Rock Ventures. She is currently working on developing the strategy plan for a new company focusing on developing epigenetic therapies for Rare Diseases. Dominique has 21 years of experience in research focusing mainly on oncology and epigenetics. Her passion for epigenetic research started in 1999 in the laboratory of Christopher Glass at UCSD where she was Post-Doctoral fellow. She investigated the molecular mechanisms by which genes were activated or repressed during the differentiation and activation of hematopoietic cells. In 2003, she joined Celgene and applied in an industry setting her newly skill set to study the mechanism of action of Revlimid and Thalidomid and led the epigenetic effort in oncology. In 2012, she decided to pursue her passion for discovering epigenetic therapies in accepting the position of director of epigenetic in the Oncology Research Unit at Pfizer. For 3 years and a half, she led a pipeline of projects related to writers, erasers and readers for oncology purpose. Dominique relocated to Boston in October 2015 to take a new challenge: Apply epigenetic knowledge acquired from cancer research to develop new therapies for unmet medical needs in the rare diseases arena.

Dominique holds a PhD in Life Sciences from the University of Nice Sophia Antipolis, France and earned an MBA from the Rady School of Management, San Diego.

Norman CW Wong, MD, FRCPC

Resverlogix Corp

Norman Wong graduated from the University of Calgary, Faculty of Medicine in 1980. He completed his internal medicine residency training at the Calgary Foothills Hospital in 1983 before going to the University of Minnesota to undertake his endocrinology fellowship. His tenure in endocrinology training was supported by fellowship awards from the CIHR and the AHFMR. Norman's research interest deals with the molecular actions of hormones and specifically that related to the regulation of lipoprotein expression and pathogenesis of diabetes mellitus. His clinical interest encompasses patients with thyroid disease or diabetes mellitus. In 1987 he completed his fellowship and returned to the University of Calgary. He is currently a professor in both the department of Medicine and the department of Biochemistry & Molecular Biology. His past administrative roles include(s/d); associate VP research and international (2005), assistant dean (research) 2002–2005 and he is currently the director of the Libin Gene Therapy Unit. During his tenure as the associate vice-president of research and international, he continued his teaching activities in the Far East to facilitate the treatment of endocrine diseases with specific emphasis on diabetes mellitus and lipid disorders. His main research interest is to understand the regulation of the apolipoprotein AI gene the enhanced expression of which will hopefully be beneficial in lowering the risk cardiovascular disease, the number one cause of premature death in our society.

Keynote Speaker

Craig B. Thompson, MD

Memorial Sloan Kettering Cancer Center

Craig B. Thompson, MD is the President and Chief Executive Officer of Memorial Sloan Kettering Cancer Center (MSKCC). Dr. Thompson received his BS from Dartmouth and MD from the University of Pennsylvania, followed by clinical training in internal medicine at Harvard Medical School and in medical oncology at the Fred Hutchinson Cancer Research Institute. Dr. Thompson has extensive research experience in cancer, immunology, and translational medicine. His current research focuses on the regulation of cellular metabolism during cell growth/differentiation and on the role that metabolic changes play in the origin and progression of cancer. Dr. Thompson is a member of the Institute of Medicine, the National Academy of Sciences, the American Academy of Arts and Sciences, and the Medical Advisory Board of the Howard Hughes Medical Institute.

Speakers

Eric Campeau, PhD

Zenith Epigenetics

Eric Campeau is Director of Biology at Zenith Epigenetics in Calgary, Alberta. He is also a member of the advisory board of Addgene, a non-profit global plasmid repository. He obtained his PhD from McGill University, was a postdoctoral fellow and a scientist at the Lawrence Berkeley National Laboratory, and an instructor at the University of Massachusetts Medical School. His research interests cover multiple scientific areas, from developing new tools and technologies to elucidate biological mechanisms, to determine the mechanisms of action of small molecule inhibitors of epigenetic targets. He is also interested in identifying and developing molecular markers of response to epigenetic inhibitors, as well as translating these findings into patient stratification strategies for single agent and combination therapies for various cancers.

Michael Elowitz, PhD

California Institute of Technology

Michael Elowitz is a Howard Hughes Medical Institute Investigator and Professor of Biology and Biological Engineering, and Applied Physics at Caltech. Dr. Elowitz's laboratory uses synthetic biology approaches, together with dynamic, quantitative single-cell imaging, to identify fundamental design principles that enable gene circuits to function in living cells and tissues. Elowitz developed the Repressilator, an artificial genetic clock that generates gene expression oscillations in individual E.coli cells, and since then has continued to design and build other synthetic genetic circuits for programming or rewiring functions in living cells. His lab showed that gene expression in intrinsically stochastic, or 'noisy,' and revealed how this noise functions to enable a variety of cellular functions that would be difficult or impossible without it, from probabilistic differentiation to time-based regulation.

Currently, Elowitz's lab is bringing synthetic biology approaches to the multicellular level, designing synthetic circuits that can help us both understand the principles underlying natural signaling and regulatory processes, and also program novel developmental behaviors. Elowitz received his PhD in Physics from Princeton University, and did postdoctoral research at Rockefeller University. Honors include the HFSP Nakasone Aware, MacArthur Fellowship, and Allen Distinguished Investigator Award. In 2015 Elowitz was inducted as a member of the American Academy of Arts and Sciences.

Ewelina Kulikowski, PhD

Resverlogix Corp

Ewelina Kulikowski, PhD is the Senior Vice President of Research & Development at Resverlogix Corp., a leading epigenetics company, creating first-in-class small molecule therapeutics for BET inhibition. Dr. Kulikowski is head of the research and development program at Resverlogix and contributes to various aspects of the clinical and business development of novel drugs for the treatment of cardiovascular, inflammatory, orphan and neurodegenerative diseases. She has been involved in the discovery, development, IND and clinical path of apabetalone (RVX-208) since its discovery in both a scientific and business capacity. Dr. Kulikowski has previously served as the Director of Research Development, leading the vascular inflammation and ophthalmology programs at Resverlogix, and as Director of Business Development & Scientific Affairs. She received her PhD in Oncology from The University of Calgary in 2004, and has been at Resverlogix since 2005.

Keiko Ozato, PhD

National Institute of Child Health and Human Development

Keiko Ozato received her PhD from Kyoto University in Japan, and trained in developmental biology and immunology at Carnegie Institution of Washington and in National Cancer Institute, National Institutes of Health (NIH), before starting an independent laboratory in the National Institute of Child Health and Human Development, NIH. She has been a tenured senior investigator in NICHD, NIH, since 1987. The focus of her laboratory has been chromatin and epigenetic regulation of innate immunity. To date, Keiko Ozato has published more than 350 research papers in the area of gene regulation and immunology. During this period, she has received a number of awards, including a Zuiho-shou from the Japanese Emperor in 2012. Her current studies center on three nuclear proteins; the chromatin binding factor BRD4, a DNA binding transcription factor IRF8 and the variant histone H3.3. Her laboratory isolated a murine Brd4 in 2000 and did pioneering research on BET bromodomain proteins. Briefly, her laboratory reported that (a) BRD4 binds to acetylated histones, (b) associates with mitotic chromosomes, and (c) facilitates transcription elongation by interacting with P-TEFb. Her laboratory also isolated IRF8, and showed that this factor is essential for establishing innate protection against various pathogens by regulating genes important for functional activation of macrophages and dendritic cells. As for the histone H3.3, her laboratory recently reported that interferon stimulation causes rapid deposition of this variant histone in activated genes.

Roberto Pili, MD

Indiana University School of Medicine

Roberto Pili, MD, is the medical director of genitourinary oncology and co-leader of the developing research program in genitourinary malignancies at the Indiana University Melvin and Bren Simon Cancer Center which supports the research for prostate, bladder, and kidney cancers. He is also the Robert Wallace Miller Professor of Oncology at the Indiana University School of Medicine, a translational researcher at the IU Simon Cancer Center, and is a nationally recognized expert in prostate, renal and bladder cancers. His program's scientists collaborate with researchers at the Purdue University Center for Cancer Research. Both centers are National Cancer Institute-designated cancer centers, and the two are among an elite group of 68 cancer centers across the country that focus on the rapid translation of research discoveries to directly benefit people with cancer. His research focuses on the development of novel therapeutic agents, including epigenetic agents such as histone deacetylase inhibitors and understanding their immunomodulatory effects. He also conducts phase I/II clinical trials of novel agents for the treatment of genitourinary malignancies. Dr. Pili is the recipient of research grants from the National Cancer Institute, and is a member of the American Society of Clinical Oncology and the American Association for Cancer Research. He serves as a reviewer for study sections of the NCI and the Department of Defense and he has authored or co-authored more than 150 journal publications and book chapters.

Patrick Trojer, PhD

Constellation

Patrick Trojer is currently Vice President at Constellation Pharmaceuticals, heading the Research organization of the company. He oversees Constellation's oncology target identification and validation, all drug discovery activities from hit identification to DC nomination and pre-clinical and clinical biomarker discovery efforts. He has strong expertise and an extensive track record in epigenetics, chromatin biology and cancer biology. Patrick was the project team lead on the EZH2 discovery program that successfully progressed all the way from hit identification to the clinic. He is a founding scientist of Constellation Pharmaceuticals. Patrick did his postdoctoral studies in Dr. Danny Reinberg's laboratory at NYU School of Medicine focused on understanding functional consequences of dynamic changes in histone lysine methylation states. He obtained his PhD in biology with a focus on Protein Biochemistry and Molecular Biology at the Leopold Franzens University in Innsbruck, Austria.

Christopher Vakoc, MD, PhD

Cold Spring Harbor Laboratory

After graduating with a degree in biochemistry from Penn State University, Chris earned PhD (2005) and MD (2007) degrees from the University of Pennsylvania. His dissertation research was performed in the laboratory of Gerd Blobel, where he studied basic mechanisms of long-range enhancer function, hematopoietic transcription factors, and histone lysine methylation. In 2008, Chris accepted a position as a Cold Spring Harbor Laboratory Fellow, which is a program that allows young scientists to pursue independent research before taking a faculty position. During this time, Chris initiated research into how chromatin modifications support the pathogenesis of leukemia. A key focus of this work has been to leverage functional genomics approaches to reveal unique chromatin regulator dependencies in cancer cells. This has led to the identification of several chromatin regulator pathways that are essential to maintain the leukemia cell state, which includes the discovery of BRD4 as a drug target in acute myeloid leukemia. This work has also revealed novel mechanisms of transcriptional regulation, such as identifying a role for MLL as a mitotic bookmark and a role for TRIM33 in enhancer decommissioning. Chris is currently an associate professor at CSHL.

Daniel Vitt, PhD

4SC AG

Dr. Daniel Vitt is the CSO of 4SC AG in Martinsried, Germany which he co-founded in 1997. As a member of the Executive Board he is responsible for all preclinical and clinical development activities at 4SC group. In this position, he contributed essentially to 4SC's maturing therapeutic pipeline and succeeded in bringing several projects in the area of oncology and immunology towards clinical development stage, among them 4SC-202, an epigenetic cancer drug and vidofludimus which has completed phase II studies in IBD and rheumatoid arthritis. Daniel Vitt completed his Doctorate in organic chemistry at the Institute of Organic Chemistry, University of Würzburg, Germany, in 1998. He is member of the supervisory board of quattro reserach GmbH in Munich and member of the scientific advisory board of CI3 Cluster for individualized immune intervention in Mainz, Germany.

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Abstracts

Coupling Oxygen Availability to Global Changes in Chromatin Accessibility
Craig B. Thompson, MD, Memorial Sloan Kettering Cancer Center

Somatic mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) contribute to the pathogenesis of cancer via production of the 'oncometabolite' D-2-hydroxyglutarate (D-2HG). Elevated D-2HG can block differentiation of malignant cells by functioning as a competitive inhibitor of alpha-ketoglutarate (alpha-KG) dependent enzymes, including Jumonji family histone lysine demethylases. 2HG is a chiral molecule that can exist in either the D- or L- enantiomer. Although cancer-associated IDH1/2 mutations exclusively produce D-2HG, biochemical studies have demonstrated that L-2HG functions as a more potent inhibitor of alpha-KG-dependent enzymes. Here we report the discovery of a physiologic regulation of L-2HG production that can globally reduce chromatin accessibility. Under conditions of oxygen limitation, mammalian cells selectively produce L-2HG via enzymatic reduction of alpha-KG. Hypoxia-induced L-2HG is not mediated by IDH1 or IDH2, but instead results from promiscuous substrate usage by lactate dehydrogenase A (LDHA). During hypoxia, the resulting increase in L-2HG is necessary and sufficient for the induction of increased methylation of histone repressive marks, including histone 3 lysine 9 (H3K9me3). Thus, L-2HG appears to function as a metabolic signaling intermediate, translating information about oxygen availability into epigenetic modifications that can influence gene expression and cellular differentiation.
 
Coauthors: Andrew M. Intlekofer1, Raymond G. Dematteo1, Lydia W. Finley1, Sriram Venneti2, Arién Rustenburg1, Patrick B. Grinaway1, John D. Chodera1, Alexander Judkins3, and Justin R. Cross1.
 
1. Memorial Sloan Kettering Cancer Center, New York.
2. University of Michigan, Ann Arbor.
3. Children's Hospital, Los Angeles.

Exploiting Epigenetics to Overcome Tumor Adaptation to Targeted Therapies
Roberto Pili, MD, Indiana University School of Medicine

Several potential mechanisms have been identified to play a role in the adaptation of the tumor microenvironment to anticancer therapies. Epigenetic changes may be involved in both intrinsic and acquired drug resistance to treatments such as antiangiogenics and immunotherapies. The presentation will go over two examples of therapeutic strategies to induce epigenetic changes, including targeting the histone methyl transferase EZH2 to overcome resistance to tyrosine kinase receptor inhibitors, and the class I histone deacetylases (HDAC) to enhance immunotherapies. Results from a phase II study combining the HDAC inhibitor entinostat and high dose interleukin 2 in renal cell carcinoma patients will be presented. Future development of HDAC inhibitors as immunomodulators will be discussed.

Role of BRD4 in Immune Cells: A Study With Conditional Knockout Mice
Keiko Ozato1

BRD4 is a BET family of bromodomain protein that binds to acetylated histones. It interacts with the elongation factor P-TEFb and promotes transcriptional activity of many cellular and viral genes. BRD4 is expressed broadly throughout embryonic development and in adult. BRD4 is Thought to be essential for survival, since the gene disruption in mice blocks early embryogenesis. Development of small molecule inhibitors that interferes with the interaction of the BET bromodomain with acetyl histone tails has provided new knowledge on the function of BRD4. A large body of published studies show that inhibition of BRD4 by the small molecule inhibitors, such as JQ1 and I-BET, potently suppresses the growth and pathogenesis of various blood cell cancers and solid tumors. These inhibitors are also shown to reduce inflammation and athelogenesis, thus offering a potentially new avenue of therapy for various chronic diseases. However, there are many unsolved questions regarding BRD4’s function and its mechanism of action. It is important to gain understanding of the role of BRD4 in normal physiology, without inhibitors. To this end we have constructed Brd4 conditional knockout mice and are studying its role in the developing immune system using various Cre constructs. We present evidence suggesting that Brd4 disruption leads to marked dysregulation of self-renewal potential in the embryonic hematopoietic stem cells (HSCs) and loss of subsequent immune cell development, along with altered defective erythropoiesis. These observations will be discussed in the context of BRD4’s activity in cell cycle progression and global gene profiling.
 
Coauthors: Anup Dey1, Tiyun Wu1, Akira Nishiyama1, Karl Pfeifer1, Jingfang Zhu2, Ryoji Yagi2, Dinah Singer3 and Anne Gegonne3
1 Division of Developmental Biology, National Institute of Child Health and Human Development, NIH
2 Labortory of Immunology, National Institutes of Allergy and Infectious Diseases
3 Experimental Immunology Branch, National Cancer Institute, NIH

Chromatin Regulators as Cancer Dependencies
Christopher Vakoc, MD, PhD, Cold Spring Harbor Laboratory

Chromatin deregulation is a major pathogenic mechanism that drives the formation of human cancer. Consequently, targeting of chromatin regulatory machineries is an attractive therapeutic strategy to selectively eliminate cancer cells. Our research seeks to comprehensively identify essential chromatin regulators in various hematological and solid tumors and understand underlying basic mechanisms that underlie such dependencies. In my presentation, I will discuss our recent efforts at utilizing CRISPR-Cas9 screening as a means to reveal essential protein domains in cancer cells. This approach should have broad utility in cancer drug target discovery and as a tool for investigating basic gene regulatory mechanisms. I will also discuss our latest work investigating the mechanism of BRD4 function in leukemia. We and others previously identified BRD4, a member of the BET family of bromodomain-containing proteins, as a drug target in leukemia and our ongoing work seeks to reveal underlying mechanisms of BRD4 function in this disease context. I will present our recent findings regarding the downstream effectors of BRD4 function that allow transcriptional activation, specifically in leukemia.
 
Coauthors: Junwei Shi, Chen Shen, Anand Bhagwat, and Jae-Seok Roe, Cold Spring Harbor Laboratory.

Epigenetic Regulators as Dynamic Memory Devices
Michael B. Elowitz, PhD, California Institute of Technology and Howard Hughes Medical Institute (HHMI)

Chromatin regulators play a major role in establishing and maintaining gene expression states. Yet how they control gene expression in single cells, quantitatively and over time, remains unclear. We used time-lapse microscopy to analyze the dynamic effects of four silencers associated with diverse modifications: DNA methylation, histone deacetylation, and histone methylation. For all regulators, silencing and reactivation occurred in all-or-none events, enabling the regulators to modulate the fraction of cells silenced rather than the amount of gene expression. These dynamics could be described by a three-state model involving stochastic transitions between active, reversibly silent, and irreversibly silent states. Through their individual transition rates, these regulators operate over different time scales and generate distinct types of epigenetic memory. Our results provide a framework for understanding and engineering mammalian chromatin regulation and epigenetic memory.
 
Coauthors: Lacramioara Bintu1, John Yong1, Yaron E. Antebi1, Kayla McCue1, Yasuhiro Kazuki2, Narumi Uno2, and Mitsuo Oshimura2.
 
1. Division of Biology and Biological Engineering, California Institute of Technology.
2. Chromosome Engineering Research Center, Tottori University, Yonago, Japan.
3. Howard Hughes Medical Institute (HHMI) and Department of Applied Physics, California Institute of Technology.

Epigenetic Regulators of Tumor Microenvironment — New Ways for Enhancing Responses to Immunotherpies
Daniel Vitt, PhD, 4SC AG, Martinsried, Germany

Epigenetic therapeutics were shown to regulate multiple important components of the tumor microenvironment and to be able to increase immunogenicity of tumor cells by multiple mechanisms. The presentation will provide a rationale and conclusive evidence for different combination strategies for the two epigenetic response modifiers 4SC-202 and resminostat with different cancer immunotherapeutic approaches including immune checkpoint inhibitors, opsonizing antibodies and immune stimulating therapies.
 
Coauthors: Hella Kohlhof and Svetlana Hamm, 4SC AG, Martinsried, Germany.

New Horizons for BET Inhibition: Apabetalone for the Treatment of High-Risk Cardiovascular Disease
Ewelina Kulikowski, PhD, Resverlogix Corp., Calgary

Epigenetic pathophysiology derived from either constitutional or environmental causes is important in many disease processes. Apabetalone, an inhibitor of the epigenetic regulators bromodomain and extraterminal (BET) proteins, is currently in a phase 3 secondary prevention outcomes trial (BETonMACE; NCT02586155) in patients with cardiovascular disease (CVD) and diabetes mellitus (DM). In phase 2b post-hoc analysis, Apabetalone treatment of patients with CVD resulted in a 55% relative risk reduction in major adverse cardiac events (MACE) following 6 months of treatment, almost exclusively accounted for by favorable effects in those with DM co-morbidity and/or those with heightened inflammation (elevated C-reactive protein). A hallmark of many diseases such as cancer, inflammation and more recently CVD, is aberrant transcription. BET proteins control recruitment of transcriptional machinery to coordinate this process. BET inhibition by apabetalone has been shown to modulate gene expression pathways that underlie CVD including reverse cholesterol transport, acute phase response, vascular inflammation, coagulation and complement. BET inhibition by apabetalone has been shown to reduce expression and secretion of components of the complement and coagulation cascades as well as mediators of the acute phase response and vascular inflammation, in vitro and in vivo. Moreover, apabetalone targets markers of inflammation, thrombosis, plaque instability and modulates innate immune pathways in CVD patients. Those effects may explain the lower incidence of MACE observed in clinical trials. Because of its multimodal action, BET inhibition is a novel target for therapeutic intervention in CVD, DM, neurodegenerative disease and a variety of orphan indications.
 
Coauthors: Sylwia Wasiak1, Dean Gilham1, Laura Tsujikawa1, Chris Halliday1, Mike Sweeney2, Jan Johansson2, and Norman C.W. Wong1.
 
1. Resverlogix Corp., Calgary.
2. Resverlogix Corp., San Francisco.

Preclinical Characterization of ZEN-3694, a Novel BET Bromodomain Inhibitor Entering Phase I Studies for Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Eric Campeau, PhD, Zenith Epigenetics Corporation, Calgary

Targeting of proteins involved in the epigenetic regulation of oncogenesis has been motivated by the elucidation of their pivotal roles in various cancer programs, as well as the recent discovery of small molecules that could potently inhibit these proteins. Of these, inhibition of the bromodomain and extra-terminal (BET) proteins has shown potent inhibition of several transcriptional programs known to promote tumorigenesis, and promising evidence of clinical activities in leukemia and lymphoma have been presented. ZEN-3694 is a novel pan-BET bromodomain inhibitor displaying anti-tumor activity in various preclinical models. In vitro and in vivo characterization of ZEN-3694 will be presented, as well as evidence of activities in various models of CRPC that are resistant to current therapies. An overview of the planned phase I clinical trial in mCRPC with ZEN-3694 will also be discussed.
 
Coauthors: Sarah Attwell, Ravi Jahagirdar, Karen Norek, Cyrus Calosing, Laura Tsujikawa, Olesya A. Kharenko, Reena G. Patel, Emily M. Gesner, Sanjay Lakhotia, and Henrik C. Hansen, Zenith Epigenetics Corporation, Calgary.

Targeting Chromatin Regulatory Pathways in Cancer
Patrick Trojer, PhD, Constellation Pharmaceuticals Inc., Cambridge

Chromatin regulatory pathways are widely recognized as part of the cell's repertoire to dynamically alter chromatin structure, and thus to regulate processes that require access to DNA, including the regulation of transcription, DNA damage response and replication. Several protein families, lysine methyltransferases (KMTs) and demethylases (KDMs), were identified as transcriptional co-regulators, controlling placement and removal of histone lysine methylation marks to allow for changes in gene expression in response to a variety of stimuli.
 
Genomic and transcriptomic sequencing campaigns have revealed that KMTs and KDMs are frequently dysregulated in cancer, suggesting that cancer cells utilize manipulation of histone lysine methylation patterns as a means to tweak gene expression programs to gain a growth advantage. Multiple KMTs and KDMs have been identified as candidate oncogenic drivers in recent years. The development of small molecule KMT and KDM inhibitors constitutes an attractive approach to selectively alter histone methylation patterns and transcriptional programs, ultimately allowing for the suppression of aberrant gene expression in cancer cells. The discovery of KMT and KDM inhibitors, their application in various oncology contexts, as well as mechanistic consequences of target inhibition will be discussed.

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