Targeting Epigenetic Regulators for Cancer Therapy

Targeting Epigenetic Regulators for Cancer Therapy

Friday, May 24, 2013

The New York Academy of Sciences

Presented By

 

The highly coordinated activities of epigenetic regulators, such as histone acetyltransferases (HATs)*, methyltransferases, and chromatin-remodeling enzymes, are essential for controlling and maintaining normal gene expression patterns in humans. Deregulation of these epigenetic regulators, however, results in aberrant gene expression consequently leading to cancer and other diseases. Thus, in the past decade it has become increasingly clear that the heritable alterations in cancer cells occur not only at the level of the primary DNA sequence but also at the level of the cancer epigenome. As we advance our understanding of how alterations in specific epigenetic regulators lead to malignant cellular transformation, increasing efforts have been put forth to identify drugs that may inhibit the aberrant activities of these epigenetic regulators with the hopes of reversing the disease state. Indeed, anticancer drugs targeting DNA methyltransferases and histone deacetylases (HDACs)* have successfully demonstrated antitumor activity in the clinic, as exemplified by the HDAC inhibitor Vorinostat approved by the FDA in 2006. More recently reports on the roles of the bromodomain-containing BET family members and methyltransferase EZH2 in driving cell growth and survival have provided further validation of epigenetic regulators as critical drivers of the transformed cancer cell phenotype. In this symposium, we will review the advances made in understanding the roles of epigenetic regulators in cancer development and the progresses towards designing effective treatments targeting the epigenome.

*Reception to follow.

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Agenda

* Presentation titles and times are subject to change.


Friday, May 24, 2013

8:30 AM

Registration and Continental Breakfast

9:00 AM

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
Dash Dhanak, PhD, Janssen Pharmaceuticals R&D

9:10 AM

Signaling Function of Polycomb
Alexander Tarakhovsky, MD, PhD, Rockefeller University

9:50 AM

Molecular Decoding of Histone PTM Signatures in Cancer and Development
Haitao Li, PhD, Tsinghua University, China

10:30 AM

Coffee Break

11:00 AM

Targeting EZH2 in Prostate Cancers
X. Shirley Liu, PhD, Dana-Farber Cancer Institute

11:40 AM

Targeting Histone Methylation in Leukemia
Scott A. Armstrong, MD, PhD, Memorial Sloan-Kettering Cancer Center

12:20 PM

Lunch Break

1:20 PM

Drugging the Human Methylome: Discovery and Characterization of Inhibitors of Protein Methyltransferases for the Treatment of Genetically Defined Cancers
Robert A. Copeland, PhD, Epizyme, Inc.

2:00 PM

Global Re-organization of BET Chromatin Binding upon Bromodomain Inhibition and its Impact on Gene Expression
Robert Sims, PhD, Constellation

2:40 PM

Coffee Break

3:10 PM

BET Inhibitors and Cancer — Realizing Emerging Clinical Opportunities
Vicki L. Goodman, MD, GlaxoSmithKline

3:50 PM

DNA Methylation and the Cancer Epigenome — Biological and Translational implications
Stephen Baylin, MD, The Johns Hopkins University School of Medicine

4:30 PM

Concluding Remarks
Susan Wee, PhD, Bristol-Myers Squibb

4:35 PM

Networking Reception

5:30 PM

Close

Speakers

Organizers

Dash Dhanak, PhD

Janssen Pharmaceuticals R&D

Dash Dhanak recently joined Janssen R&D as VP and Global Head of the CREATe organization, overseeing all aspects of the company's drug discovery platform capabilities. Prior to this, he led the Cancer Epigenetics Discovery Performance Unit in GlaxoSmithKline's Oncology R&D Center in Collegeville, USA. In this role, he was responsible for setting the strategic direction of the group and directing cancer drug discovery activities targeting various chromatin modifications. Previously, Dash was VP and Head of GSK' s Oncology Medicinal Chemistry group, led multiple discovery teams and was instrumental in advancing numerous compounds to the clinical development pipeline at GSK. Before joining GSK, Dash received his PhD from the University of London and subsequently moved to Northwestern University to carry out postdoctoral research in natural product synthesis. He is a current member of the AACR Epigenome Task Force, has participated in the American Chemical Society Pharma Leaders Forum, as well as the American Cancer Society Peer Review Committee on Cancer Drug Development and the Multiple Myeloma Research Foundation Peer Review Committee. In addition, he has published extensively on a variety of drug discovery topics and has been an invited speaker at major scientific conferences.

Liang Schweizer, PhD

Bristol-Myers Squibb

Liang Schweizer, PhD, a Senior Principal Scientist in Lead Evaluation and Mechanistic BioChemistry at Bristol-Myers Squibb Co., heads a group of scientists and oversees 40+ in vitro pharmacology projects across different disease areas (mainly in oncology, immunology, cardiovascular and metabolic diseases). Before that, she was a senior research investigator in oncology drug discovery at BMS, directing cancer drug discovery programs, as well as contributing to multiple exploratory programs and full-phase programs. Liang graduated from the Biology department of the University of Science and Technology of China (USTC), then went on to earn a Master's degree in Microbial Engineering from the University of Minnesota, minor in Chemical Engineering. In 1999, Liang received her PhD from the University of Zurich, working on Wnt and Hh signaling in Drosophila development under the guidance of Dr. Konrad Basler. Her postdoctoral training was in the laboratory of Dr. Harold Varmus at Memorial Sloan Kettering Cancer Center (MSKCC), specializing in Wnt signaling and cancer.

Susan Wee, PhD

Bristol-Myers Squibb

Susan Wee, PhD, is a Senior Research Investigator in the Oncology drug discovery department at Bristol-Myers Squibb located in Princeton, NJ. She leads a team of scientists on both exploratory and full-phase cancer drug discovery programs. Her research interests span the role of epigenetic regulators in cancer to identifying druggable targets in the WNT-signaling pathway. Prior to joining BMS, Susan was a Presidential Postdoctoral Fellow at the Novartis Institute for Biomedical Research where she conducted research on the role of the PI3K and MEK signaling pathways in cancer. Susan graduated from Harvard University in 2005 from the department of Cancer Cell Biology.

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Scott A. Armstrong, MD, PhD

Memorial Sloan-Kettering Cancer Center

Dr. Armstrong is a physician-scientist and leading cancer researcher in the fields of cancer epigenetics and stem cell biology with a focus on leukemia. He is director of the Center for Leukemia Research, and Vice Chair of Pediatrics at Memorial Sloan Kettering Cancer Center. His landmark findings have pointed to potential new therapies for leukemia. Dr. Armstrong obtained his MD and PhD degrees from the University of Texas Southwestern Medical School. He completed an internship and residency at Children’s Hospital Boston and clinical and research fellowships at the Dana-Farber Cancer Institute under the direction of Dr. Stanley Korsmeyer. Dr. Armstrong has been awarded the Till and McCulloch Award from the International Society of Experimental Hematology and the Paul Marks Prize for Cancer Research from Memorial Sloan Kettering Cancer Center.

Stephen Baylin, MD

The Johns Hopkins University School of Medicine

Dr. Stephen Baylin, Deputy Director at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, studies epigenetic gene silencing in cancer. He and his colleagues have fostered the concept that DNA hypermethylation of gene promoters, and associated transcriptional silencing, can serve as alternatives to mutations for producing loss of tumor suppressor gene function. His group studies the function of genes involved, devises approaches to screen the cancer genome for such genes, and to unravel the molecular mechanisms responsible for the initiation and maintenance of the gene silencing. They also aim to utilize all of the above findings for translational purposes.

Robert A. Copeland, PhD

Epizyme, Inc.

Robert A. Copeland, PhD is Executive Vice President and Chief Scientific Officer at Epizyme, Inc. He joined Epizyme in September 2008, from GlaxoSmithKline, where he was Vice President of Cancer Biology, Oncology Center of Excellence in Drug Discovery. Dr. Copeland has also served as Adjunct Professor of Biochemistry and Biophysics and a Fellow of the Eldridge Reeves Johnson Foundation at the University of Pennsylvania, School of Medicine, on the Scientific Advisory Board of Sigma-Aldrich, on the American Chemical Society Committee for Professional Training and on the Governance Council of the American Society for Biochemistry & Molecular Biology. He is currently on the Editorial Boards of the Journal of Biological Chemistry, Current Drug Discovery Technologies and Molecular Cancer Therapeutics and is a member of the Faculty of 1000.

Before joining GSK he held scientific staff positions at Merck Research Laboratories, DuPont-Merck and Bristol-Myers Squibb and a faculty position at the University of Chicago, Pritzker School of Medicine. Dr. Copeland received his B.S. in chemistry from Seton Hall University, his doctorate in chemistry from Princeton University and did postdoctoral studies as the Chaim Weizmann Fellow at the California Institute of Technology. His research interest is in elucidating the determinants of drug recognition by their biological targets, and the use of this information in the discovery and design of new medicines. A common theme throughout his research has been the role of protein dynamics in drug-target interactions. In 2005-2006 Dr. Copeland formulated the concept of drug-target residence time, a novel, alternative approach to drug optimization that has been widely adopted throughout the biotechnology and pharmaceutical industries. He has contributed to drug discovery and development efforts across a wide range of therapeutic areas leading to 17 drug candidates entering human clinical trials. These include the Phase III cancer drugs Dabrafenib, Foretinib and Trametinib and the marketed antibiotic Altabax (Retapamulin). Dr. Copeland has contributed more than 180 publications to the scientific literature, holds 8 issued U.S. patents and has authored 5 books in the areas of protein science and enzymology. His most recent book, Evaluation of Enzyme Inhibitors in Drug Discovery: A Guide for Medicinal Chemists and Pharmacologists, 2nd Edition (Wiley, Hoboken, NJ), published in March 2013.

Vicki L. Goodman, MD

GlaxoSmithKline

Dr. Goodman is a medical oncologist and hematologist and is currently the lead physician in the Cancer Epigenetics Discovery Performance Unit at GlaxoSmithKline. She leads the development programs for the GSK BET, EZH2 and LSD-1 inhibitors. Dr. Goodman has been at GSK for 6 years where she has been involved in the development of pazopanib and was then the clinical lead for dabrafenib. Prior to joining GSK, she was a medical officer in the Division of Drug Oncology Products at the U.S. FDA. Dr. Goodman trained in internal medicine and hematology/oncology at the University of Michigan.

Haitao Li, PhD

Tsinghua University, China

Haitao Li received his PhD degree in Molecular Biophysics at the Institute of Biophysics, Chinese Academy of Sciences in 2003. Then he did his postdoctoral training with Dr. Dinshaw Patel at the Memorial Sloan-Kettering Cancer Center, New York. He joined Tsinghua Medical School as a tenure-track associate professor in 2010. Dr. Li’s research is directed towards a molecular understanding of epigenetic regulations - the way the genetic information is organized and decoded at chromosomal level. His laboratory at Tsinghua applies macromolecular crystallography in combination with other biochemical, biophysical and cell biological approaches to study the structure and function of key epigenetic regulators impacting on human disease and stem cell biology. Epigenetic mechanisms include chemical modifications to histones or DNA, histone variants, chromatin remodeling, and non-coding RNAs. Dr. Li has made important contributions to the understanding of epigenetic mechanisms by elucidating the molecular basis for site- and state-specific histone modification readout by a series of histone “reader” modules including PHD finger, MBT, ADD, and bromodomain. Recently, Dr. Li has extended his research to histone modification pattern readout by integrated or paired “reader” modules. It’s anticipated that these efforts will provide novel examples and mechanistic details about epigenetic regulation and its role in gene expression and chromatin structural control.

X. Shirley Liu, PhD

Dana-Farber Cancer Institute

Dr. X. Shirley Liu is Professor of Biostatistics and Computational Biology at Harvard School of Public Health, Director of the Center for Functional Cancer Epigenetics at the Dana-Farber Cancer Institute, and Associate Member at the Broad Institute of Harvard and MIT. Her research focuses on computational models of transcriptional and epigenetic regulation by algorithm development and data integration for high throughput data. She has developed a number of widely used transcription factor motif finding and ChIP-chip/Seq analysis algorithms, and has conducted pioneering research studies on gene regulation in development, metabolism, and cancers. Her work has been applied to identify novel functions and partners of transcription factors, chromatin regulators, and lncRNAs in cancer.

Robert Sims, PhD

Constellation Pharmaceuticals, Inc.

Robert Sims is the Senior Director of Biology at Constellation Pharmaceuticals, a company dedicated to the discovery and development of chromatin therapeutics. He obtained his BS and PhD degrees in microbiology and molecular biology from the University of Texas, Austin, USA. He did his postdoctoral studies with Danny Reinberg at UMDNJ-Robert Wood Johnson Medical School and NYU School of Medicine where he focused on deciphering the functionality of chromatin adaptors.

Alexander Tarakhovsky, MD, PhD

The Rockefeller University

Born in the former USSR, Dr. Tarakhovsky received his medical degree from the Kiev Medical Institute in Ukraine in 1978 and his PhD from the Institute for Oncology at the Academy of Science in Kiev in 1982. He has worked as a research associate at the Institute for Oncology, the Cancer Research Center in Moscow and the Institute for Molecular Genetics in Tallinn, Estonia. In 1992, he became a Humboldt Fellow and later a Research Associate at the Institute of Genetics at the University of Cologne, in Germany; he was promoted to group leader in 1994, and tenured Professor and Head of the Laboratory for Lymphocyte Signaling in 1996. He moved that lab to The Rockefeller University in 2000 when he was appointed Irene Diamond Associate Professor; he was named tenured full Professor in 2003. The laboratory's current interest is to identify the epigenetic mechanisms of adaptive and innate immune responses. The most significant achievements in this direction include the identification of the role of histone lysine methyltransferase Ezh2 in antibody repertoire formation, discovery of a novel nuclear PKCd signaling pathway that causes autoimmunity, identifying the novel signaling pathway that utilizes lysine methylation for signal-dependent lymphocyte activation and the discovery of functional histone-like sequences (histone mimics) in non-histone mammalian and viral proteins.

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Abstracts

Molecular Decoding of Histone PTM Signatures in Cancer and Development
Haitao Li, PhD, Tsinghua University, China

Chromatin modifications, such as histone post- translational modifications (PTMs) and DNA methylation, are considered to constitute a layer of "epigenetic codes", which help to organize the genetic information at chromatin level and play an important role in gene expression, cell differentiation and development. Recent progresses suggest that the “ON” or “OFF” states of chromatin are not simply determined by a single histone or epigenetic mark. In fact, chromatin modifications often exist in pair or as a pattern to mediate or disrupt certain downstream molecular recognition events, thereby contributing to the establishment and maintenance of particular cellular traits. Here I report on the molecular basis for histone PTM pattern decoding by paired reader modules involving tudor, PHD, bromo, and ADD domains. The work presented here highlights how chromatin regulators make use of paired or integrated reader modules to translate particular epigenetic signature into unique functional outcomes in health and disease.

Targeting Histone Methylation in Leukemia
Scott A. Armstrong, MD, PhD, Memorial Sloan-Kettering Cancer Center

Leukemias harboring rearrangements of the MLL gene carry a poor prognosis. Over the past 6 years, it has become increasingly clear that fusions of MLL induce widespread epigenetic deregulation that may mediate much of their transforming activity. The histone methyltransferase DOT1L, which methylates histone 3 on lysine 79 (H3K79), has received particular attention. Genome-wide H3K79 methylation profiles in MLL-rearranged leukemias are abnormal, and can serve to distinguish MLL-rearranged from other types of leukemias. Loss of H3K79 methylation affects expression of MLL-target loci and is detrimental to the leukemogenic activity of MLL-rearranged cells, suggesting that a DOT1L dependent, aberrant epigenetic program drives transformation in these leukemias. Small molecule DOT1L inhibitors have been developed and selectively inhibit proliferation of MLL-rearranged leukemia cells. These molecules are now in clinical trials for patients with relapsed refractory leukemia. Also, the Polycomb Repressive Complex 2 (PRC2) has been implicated in self-renewal and cancer progression, and its components are overexpressed in many cancers, but its role in cancer development and progression remains unclear. We have used conditional alleles for the PRC2 components Enhancer of Zeste 2 (Ezh2) and Embryonic Ectoderm Development (Eed) to characterize the role of PRC2 function in leukemia development and progression. Compared to wildtype leukemia, Ezh2-null MLL-AF9-mediated acute myeloid leukemia (AML) show decreased organ infiltration and failed to accelerate upon secondary transplantation. These data show that histone-modifying enzymes play critical roles in leukemia and may be relevant therapeutic targets in these diseases.

Drugging the Human Methylome: Discovery and Characterization of Inhibitors of Protein Methyltransferases for the Treatment of Genetically Defined Cancers
Robert A. Copeland, PhD, Epizyme, Inc.

The protein methyltransferases (PMTs) constitute a class of enzymes that catalyze the methylation of lysine or arginine residues on histones and other proteins. A number of PMTs have been shown to be genetically altered in cancers through, for example, gene amplification, chromosomal translocations and point mutations. The enzymes DOT1L and EZH2 provide two representative examples of altered PMTs that act as genetic drivers of specific human cancers. The enzymatic activity of DOT1L is associated with a chromosomal translocation that is universally found in patients with mixed-lineage leukemia. Point mutations at Y641 of EZH2 are found in a subset of non-Hodgkins lymphoma patients; the enzymatic activity of both wild type and mutant EZH2 are required for pathogenesis in these patients. Drug discovery efforts have yielded potent, selective inhibitors of each of these targets. These inhibitors affect the appropriate histone methyl marks in cells, lead to selective cell killing that is dependent on genetic alteration of the target enzyme and effect tumor growth inhibition in xenograft models. These data portent the effective use of selective PMT inhibitors as a novel modality for future personalized cancer therapeutics.

Global Re-organization of BET Chromatin Binding upon Bromodomain Inhibition and Its Impact on Gene Expression
Robert Sims, PhD, Constellation Pharmaceuticals, Inc.

The BET family of chromatin adaptors selectively regulates the transcription of key cancer genes. Recently, we and others have described the rapid and potent abrogation of MYC gene transcription by small molecule inhibitors of the BET family bromodomains. Treatment of MYC-dependent cancer cells with BET inhibitors results in growth arrest and apoptosis in cell culture and anti-tumor activity in xenograft animal models of multiple myeloma, lymphoma, and acute leukemia. We have further characterized the molecular impact of BET bromodomain inhibition, specifically in the context of global chromatin re-organization and transcriptional control. Upon inhibitor treatment, we observe a global alteration in BET and MYC chromatin localization, histone modifications, and RNA polymerase II distribution. Despite this, a remarkably small subset of genes is observed to be direct BET transcriptional targets. Additionally, we have utilized biochemical screening, structural biology, medicinal chemistry, and in vivo pharmacology to develop a series of BET bromodomain inhibitors that are highly potent, selective, and optimized for clinical development.

BET Inhibitors and Cancer – Realizing Emerging Clinical Opportunities
Vicki L. Goodman, MD, GlaxoSmithKline Oncology R&D

Epigenetic abnormalities are frequent and recurring events in cancer. Bromodomains (BRDs) are small protein domains found in a variety of proteins that recognize and bind to acetylated histone tails. This binding affects chromatin structure and facilitates the localization of transcriptional complexes to specific genes, thereby regulating epigenetically controlled processes including gene transcription and mRNA elongation. The BRD and extra-terminal (BET) family of BRD proteins includes the BRD2, BRD3, BRD4 and BRDT [testes] proteins. The investigational agent GSK525762 is a potent inhibitor of the BET family of proteins and prevents the binding required for macromolecular complex assembly and the subsequent transcriptional response. The pre-clinical rationale for development of this agent and how this is being translated into an early clinical development strategy will be discussed.

* Additional abstracts to follow.

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