Epigenetics in Cancer: Translational Medicine Approaches

Epigenetics in Cancer: Translational Medicine Approaches

Thursday, November 10, 2016

The New York Academy of Sciences

Presented By

Roche

The New York Academy of Sciences

 

Epigenetics continues to be a burgeoning area for therapeutic intervention in oncology. This conference will bring together experts from both academia and industry to further explore epigenetic susceptibilities in cancer through the identification of novel targets and translational medicine approaches to define biomarkers, resistance mechanisms and clinical combination strategies.

Registration Pricing

Member$60
Member (Student / Postdoc / Resident / Fellow)$25
Nonmember (Academia)$105
Nonmember (Corporate)$160
Nonmember (Non-profit)$105
Nonmember (Student / Postdoc / Resident / Fellow)$70

Agenda

* Presentation titles and times are subject to change.


November 10, 2016

8:30 AM

Registration and Continental Breakfast

9:00 AM

Welcome and Opening Remarks
Sonya Dougal, PhD, The New York Academy of Sciences
Fiona Mack, PhD, Roche

Keynote Address

9:15 AM

Single-Molecule and Single-Cell Epigenetics on Earth and in Space
Chris Mason, PhD, Weill Cornell Medical College

Session 1: Insights from Mechanism Based Studies of Cancer Epigenetics

10:00 AM

LSD1 as a Candidate Therapeutic Target in Acute Myeloid Leukaemia
Tim Somervaille, PhD, FRCP, FRCPath, Cancer Research UK Manchester Institute

10:30 AM

Networking Coffee Break

11:00 AM

3D Chromasomal Topology, Stem Cell Differentiation and Initiation of Blood Cancer
Iannis Aifantis, PhD, New York University School of Medicine

11:30 AM

Epigenetic Regulations of Melanoma Drug Resistance
Emily Bernstein, PhD, Icahn School of Medicine at Mount Sinai

Data Blitz Presentations

12:00 PM

Somatic Cancer Mutation Y4884C in Mixed Lineage Leukemia 3 (MLL3) Histone Methyltransferase Changes Substrate Specificity
Ashley J. Canning, BS, SUNY Upstate Medical University

12:05 PM

HoxA7 is Essential for Glioma Stem Cell Survival and Tumorigenicity
Sheila R. Alcantara Llaguno, Memorial Sloan Kettering Cancer Center

12:10 PM

Epigenome Remodeling by Cancer-associated Oncohistone Mutations
Chao Lu, PhD, The Rockefeller University

12:15 PM

Networking Lunch Break

Session II: Translating Epigenetics to the Clinic: Biomarker and Therapeutic Insights

1:45 PM

Epigenetic Targets in Triple Negative Breast Cancer
Kornelia Polyak, MD, PhD, Dana-Farber Cancer Institute & Harvard Medical School

2:15 PM

Deciphering the Heterogeneous Epigenome of Acute Myeloid Leukemia
Sheng Li, PhD, The Jackson Laboratory for Genomic Medicine

2:45 PM

Role of Mutations in Epigenetic Regulators in Pathogenesis of Myeloid Malignancies
Ross Levine, MD, Memorial Sloan Kettering Cancer Center

3:15 PM

Networking Coffee Break

3:45 PM

Targeting Epigenetic Machinery in Cancer
Ryan Kruger, PhD, GlaxoSmithKline

4:15 PM

Considerations for Rational Combination Regimens with Epigenetic Agents
Jorge F. DiMartino, Celgene

4:45 PM

F100 Poster Prize Presentation and Closing Remarks
Gwen Nichols, MD, Roche Translational Clinical Research Center

5:00 PM

Networking Reception

6:00 PM

Adjourn

Organizers

Ross L. Levine, MD

Memorial Sloan Kettering Cancer Center

Fiona Mack, PhD

Roche

Dr. Fiona Mack is a Director of External Innovation located at Roche Innovation Center NY. In her current role she supports the assessment of external opportunities that complement Roche's oncology portfolio. In addition to these efforts, Fiona is also the Pre-Clinical Development Lead for RO7501790, the Roche-Oryzon LSD1 inhibitor currently in clinical development. Prior to joining Roche, Fiona was a Principal Research Scientist at Pfizer Oncology. There she was responsible for the evaluation and early development of novel platform technologies, including anti-sense therapeutics, T-cell engaging bi-specific antibodies and antibody drug conjugates. Fiona received her PhD in cell and molecular biology from the University of Pennsylvania where she investigated the role of hypoxic signaling in embryonic and cancer development.

Christopher E. Mason, PhD

Weill Cornell Medical College

Christopher Mason completed his dual BS in Genetics and Biochemistry (2001) from University of Wisconsin-Madison, his PhD in Genetics (2006) from Yale University, and then completed his dual post-doctoral training as a post-doc (2009) at Yale Medical School in genetics and a post-doctoral Fellow of Genomics, Ethics, and Law at Yale Law School. He is currently an Associate Professor at Weill Cornell Medicine, with appointments at the Tri-Institutional Program on Computational Biology and Medicine between Cornell, Memorial Sloan-Kettering Cancer Center and Rockefeller University, the Sandra and Edward Meyer Cancer Center, and the Feil Family Brain and Mind Research Institute.

The Mason laboratory develops and deploys new biochemical and computational methods in functional genomics to elucidate the genetic basis of human disease and human physiology. We create and explore novel techniques in next-generation sequencing and algorithms for: tumor evolution, genome evolution, DNA and RNA modifications, and genome/epigenome engineering. We also work closely with NIST/FDA to build international standards for these methods, to ensure clinical-quality genome measurements/editing. We also work with NASA to build integrated molecular portraits of genomes, epigenomes, transcriptomes, and metagenomes for astronauts, which help establish the molecular foundations and genetic defenses for enabling long-term human space travel.

He has won the NIH's Transformative R01 Award, the Pershing Square Sohn Cancer Research Alliance Young Investigator award, the Hirschl-Weill-Caulier Career Scientist Award, the Vallee Foundation Young Investigator Award, the CDC Honor Award for Standardization of Clinical Testing, and the WorldQuant Foundation Research Scholar Award. He was named as one of the "Brilliant Ten" Scientists by Popular Science, featured as a TEDMED speaker, and called "The Genius of Genetics" by 92Y. He has more than 125 peer-reviewed papers that have been featured on the covers of Nature, Science, Nature Biotechnology, Nature Microbiology, Neuron, and Genome Biology and Evolution, as well as cited by the U.S. District Court and U.S. Supreme Court. His work has also appeared on the covers of the Wall Street Journal, TIME, LA Times, New York Times, and across many media (ABC, NBC, CBC, CBS, Fox, CNN, PBS, NASA, NatGeo). He has co-founded three biotechnology start-up companies (Genome Liberty, Biotia, and Molecular Logic) and serves as an advisor to many others. He lives with his daughter and wife in Brooklyn, New York.

Gwen Nichols, MD

Roche

Dr. Nichols is the Group Head for Molecularly Targeted Therapeutics and the Site Head for Oncology Translational Medicine at the Roche Innovation Center in New York. She received her MD with Honors from the State University of New York. She trained in internal medicine at the University of Chicago, and did her hematology–oncology fellowship at Memorial Sloan Kettering Cancer Center where she was chosen as Chief Fellow. She did post-doctoral research at MSKCC in Molecular Oncology and was an attending physician on the Leukemia Service before being recruited to Columbia University as Director of the Hematologic Malignancies Program. At Columbia she was a PI on numerous clinical trials, had an active laboratory doing translational research in hematologic malignancies, and was an Advisory Dean of Students. She served on the SWOG Leukemia Committee, on the Education Committee of ASCO, and continues to be on the Scientific Advisory Committee for the International Waldenstrom's Macroglobulinemia Foundation. Dr. Nichols was chosen "Physician of the Year" at Columbia, and received the Humanism in Medicine Award. Since joining the Roche early development team in 2007, she has been the clinical lead and Translational Medicine Leader for the MDM2 franchise. In her current role she supports several Roche programs for epigenetic modifiers.

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.

Sonya Dougal, PhD

The New York Academy of Sciences

Caitlin McOmish, PhD

The New York Academy of Sciences

Speakers

Iannis Aifantis, PhD

NYU School of Medicine

Widely known for his expertise in the fields of hematopoiesis and acute leukemia, Dr. Aifantis is a Professor and the Chair of the Department of Pathology at NYU School of Medicine. Dr. Aifantis attended the University of Crete in Greece, earned his PhD from the University of Paris V, Rene Descartes and completed his postdoctoral training at Harvard University, Dana Farber Cancer Institute. He started his independent career at University of Chicago in 2013 and joined NYU in 2006. Throughout his career, he earned many prestigious honors including the 2010 Vilcek Award for Creative Promise and the 2011 McCulloch & Till Award from the International Society for Hematology and Stem Cell Biology. Moreover, in 2009, he was selected as an Early Career Scientist by the Howard Hughes Medical Institute (HHMI). He is one of the leaders of the fields of hematopoiesis and leukemia, with diverse focus areas that include the study of protein stability, epigenetic regulation and tumor microenvironment. His lab was instrumental in the understanding of the molecular mechanisms of initiation and progression of both acute lymphoid and myeloid leukemia.

Emily Bernstein, PhD

Icahn School of Medicine at Mount Sinai

Dr. Bernstein is an Associate Professor of Oncological Sciences and Dermatology at Mount Sinai School of Medicine in New York City. She performed her thesis research in the laboratory of Dr. Gregory Hannon at Cold Spring Harbor Laboratory with a PhD from Stony Brook University. Dr. Bernstein completed her postdoctoral studies with Dr. David Allis at The Rockefeller University. She has made important scientific contributions to various areas of biology during her career, including understanding the mechanisms underlying RNA interference and chromatin regulation, and more recently, how the latter can impact on disease. Her laboratory studies epigenetic mechanisms underlying stem cell biology and reprogramming, and cancer initiation and progression with a focus on malignant melanoma.

Jorge F. DiMartino, MD, PhD

Celgene

Jorge DiMartino MD, PhD is Vice President, Translational Development Oncology at Celgene in San Francisco. He joined Celgene in 2011 and has been leading a number of early stage oncology clinical programs as well as directing the Translational Research Laboratories at the Celgene San Francisco site. Jorge is the Head of the Epigenetics Thematic Center of Excellence, a fully integrated unit driving Drug Discovery through Clinical Proof of Concept efforts around epigenetic targets in cancer and inflammation. He also plays a key role in a number of external collaborations including Oncomed, Epizyme, Agios and Forma.

Prior to joining Celgene, Jorge was a Group Medical Director at Genentech in the Oncology Exploratory Clinical Development group. At Genentech, he led the early clinical development of the Hedgehog Pathway inhibitor, vismodegib, and managed a group of Medical Directors working on a diverse array of targeted small molecules as well as naked and armed antibodies from Late Stage Discovery through Phase II.

Jorge received his PhD in Immunology from Cornell University Graduate School of Medical Sciences, and his MD from University of California San Diego. He completed a residency in Pediatrics and a fellowship in Pediatric Hematology/Oncology, both at Stanford University School of Medicine where continues to see patients in the pediatric oncology as a member of the Adjunct Clinical Faculty.

Ryan Kruger, PhD

GlaxoSmithKline

Ryan Kruger graduated with his PhD in Pharmacology from the University of Pennsylvania in 2003 where he studied the enzymes responsible for attaching virulence factors to cell walls of bacteria. From there he went on to a postdoctoral fellowship with Chris Walsh at Harvard Medical School studying the enzymes involved in non-ribosomal peptide synthesis of natural product bacterial cell wall inhibitors. In 2005, Ryan joined GlaxoSmithKline Pharmaceuticals where he started in an enzymology group supporting the Oncology therapeutic area. In 2008 Ryan moved to the Biology Department within the Cancer Epigenetics Discovery Performance Unit, where he became Head of Biology in 2014 leading a group of 45 scientists tasked with bringing forward therapeutics targeting epigenetic machinery for the treatment of cancer. In addition, Ryan is the Early Development Leader for GSK2879552, GSK's LSD1 inhibitor currently in clinical development.

Ross L. Levine, MD

Memorial Sloan Kettering Cancer Center

Sheng Li, PhD

Jackson Laboratory for Genome Medicine

Dr. Sheng Li is an Assistant Professor of Computational Biology at Jackson Laboratory for Genome Medicine. She received her PhD in computational biology from Cornell University, Weill Graduate School of Biomedical Sciences and Institute of Computational Biomedicine. She has published a suite of comparisons of all current RNA-sequencing methods and technologies. She also developed a series of open source, computational methods and software for DNA methylation sequencing data analysis. Applying these next generation sequencing standards and software to cancer studies, she discovered novel oncogenic driver fusion genes and also developed quantitative matrices to define tumor epigenetic evolution.

Christopher E. Mason, PhD

Weill Cornell Medical College

Kornelia Polyak, MD, PhD

Dana Farber Cancer Institute, Harvard Medical School

Kornelia Polyak, MD, PhD, is a Professor of Medicine at Dana-Farber Cancer Institute, Harvard Medical School and is an internationally recognized leader of the breast cancer field. Research in Dr. Polyak's laboratory is dedicated to the molecular analysis of human breast cancer with the goal improving the clinical management of breast cancer patients. Her lab has devoted much effort to develop new ways to study tumors as a whole and to apply interdisciplinary approaches. Using these methods Dr. Polyak's lab has been at the forefront of studies analyzing purified cell populations from normal and neoplastic human breast tissue at genomic scale and in situ at single cell level and to apply mathematical and ecological models for the better understanding of breast tumor evolution. She has also been successful with the clinical translation of her findings including the testing of efficacy of JAK and BET bromodomain inhibitors for the treatment of triple negative breast cancer in clinical trials. Dr. Polyak have received numerous awards including the Paul Marks Prize for Cancer Research in 2011 and the 2012 AACR Outstanding Investigator Award for Breast Cancer Research. She is also a 2015 recipient of the NCI Outstanding Investigator award.

Tim Somervaille PhD, FRCP, FRCPath

Cancer Research UK Manchester Institute

Tim Somervaille is Senior Group Leader at the Cancer Research UK Manchester Institute where he leads the Leukaemia Biology Laboratory. He is also Honorary Consultant in Haematology at The Christie NHS Foundation Trust. His scientific and clinical research interest is in myeloid cancer, including acute myeloid leukaemia and the myeloproliferative disorders. Tim's medical training was at Imperial College London and University College London. His scientific training was at University College London and Stanford University.

Abstracts

Single-Molecule and Single-Cell Epigenetics on Earth and in Space
Christopher Mason, PhD, Weill Cornell Medicine

Several new technologies enable high-resolution characterization of single cells and populations of cells, such as patients' response to chemotherapy and leukemia patients as they evolve at epigenetic and genetic layers. Here, we describe new methods to characterize modified bases of DNA (epigenomes) and RNA (epitranscriptomes) with single-molecule and enrichment-based methods, and their impact on tracing clinical dynamics during care. We also show how portable DNA sequencing on nanopore-based, single-molecule sensors can enable rapid diagnostics for epigenetics and we also present data from the first-ever DNA sequencing and epigenetics experiments in microgravity and in space. These results show the promise of novel technologies in epigenetics, unique measures of clinical responses for cancer patients, and emerging applications for long-term monitoring of human health and cellular states in remote areas.

LSD1 as a Candidate Therapeutic Target in Acute Myeloid Leukaemia
Tim Somervaille, PhD, FRCP, FRCPath, Cancer Research UK Manchester Institute

The assumption has been that pharmacological inhibitors of LSD1 target the enzyme's histone demethylase activity to induce differentiation in acute myeloid leukemia (AML). However, we observed that drug-induced changes in transcription preceded changes in histone methylation modifications targeted by LSD1 and that AML cell proliferation did not require the catalytic activity of LSD1. Instead, concomitant with up-regulation of a myeloid differentiation program, a tranylcypromine-derivative inhibitor induced physical separation of LSD1 from the transcription factor GFI1, and more generally from chromatin. Physical separation of GFI1 from LSD1 was required for drug-induced differentiation. Evaluation of genome wide histone acetylation reveals that enhancers bound and repressed by GFI1 are activated following treatment of cells with LSD1 inhibitors. Thus, pharmacological inhibition of LSD1 promotes differentiation by disabling the activity of a key myeloid transcription factors, through abrogation of protein:protein interactions rather than blockade of histone demethylase activity and leading to activation of GFI1-bound enhancers.

3D Chromasomal Topology, Stem Cell Differentiation and Initiation of Blood Cancer
Iannis Aifantis, PhD, Department of Pathology and Perlmutter Cancer Center, NYU School of Medicine

Acute myeloid leukemia (AML) is the most common adult leukemia characterized by excessive proliferation of abnormal hematopoietic stem cells (HSC) and myeloid progenitors. AML continues to have a dismal survival rate amongst all subtypes of leukemia (<50% five-year overall survival rate), which can largely be attributed to limited advances in treatment regimens that, for the last decades, have relied on the use of two non-targeted cytotoxic drugs: cytarabine and anthracycline. Large-scale sequencing efforts have shed new light on genetic and epigenetic determinants of AML. Interestingly, these studies identified a frequent co-occurrence of somatic mutation between genes encoding cohesin complex subunits (such as STAG2, SMC1A, RAD21 and SMC3) and well-characterized AML oncogenic triggers, such as FLT3-ITD, TET2, and NPM1. Our recent work has demonstrated an important role for the cohesin complex in normal stem/progenitor self-renewal and differentiation, gene regulation, and suppression of myeloproliferative neoplasms and AML, despite the precise mechanisms underlying these functions remaining poorly understood. It is believed that cohesin may suppress tumor formation by regulating chromatin looping at loci critical for self-renewal and myeloid progenitor differentiation. Utilizing established models of murine and human AML, this presentation focuses on the molecular mechanisms of cohesin-dependent myeloid tumor-suppression, with an emphasis on proposing novel treatment approaches that can exploit these functions. Overall, we focus on the idea that DNA looping and thus alteration of the 3D chromosomal topology can influence hematopoietic stem cell homeostasis, differentiation and transformation leading to the initiation of hematopoietic malignancy. Cohesin mutations is one mechanism to achieve that but is not the only one as mutations on other proteins/genes involved in 3D topological organization (CTCF, MEDIATOR etc) have also been reported in a number of blood tumors.

Epigenetic Regulation of Melanoma Drug Resistance
Emily Bernstein, PhD, Icahn School of Medicine at Mount Sinai

Cutaneous melanoma is a highly aggressive skin cancer and one of the most challenging cancers in its therapeutic management. Emerging studies demonstrate that cancer is a result of a concerted action of genetic and epigenetic alterations. Surprisingly, our understanding of the 'epigenetic landscape' of melanoma remains poorly understood. We have shown a critical role for histone variants of the H2A family in regulating melanoma pathogenesis. For example, macroH2A acts as a barrier to melanoma growth and metastasis (Kapoor et al., Nature 2010), and H2A.Z.2 promotes melanoma growth by positively regulating transcription of E2F target genes (Vardabasso et al., Molecular Cell 2015). Studies will be presented of our ongoing efforts to identify key epigenetic players in melanoma progression and drug resistance to MAPK signaling inhibitors. In particular, we have recently identified novel chromatin modifiers that play a key role in promoting resistance to the standard of care combination of Dabrafenib+Trametinib targeted therapy for BRAFV600E-mutant melanoma.
 
Coauthors: Thomas Strub, Flavia Ghiraldini, Saul Carcamo, Aleksandra Wroblewska, Brian Brown, Man Li, Steven Chen, Bin Zheng, and Kaitlyn Fragogiannis, Icahn School of Medicine at Mount Sinai; Stuart Gallagher and Peter Hersey, Royal North Shore Hospital, University of Sydney.

Role of Mutations and Epigenetic Regulators in Pathogenesis of Myeloid Malignancies
Ross Levine, MD, Memorial Sloan Kettering Cancer Center

Clinical, cytogenetic, and gene-based studies have been used to inform biology and improve prognostication for patients with acute myeloid leukemia (AML), myelodysplasia (MDS), and myeloroliferative neoplasms (MPN). Most recently, a series of candidate gene and whole genome studies have identified recurrent somatic mutations in AML patients including TET2, ASXL1, DNMT3A, and cohesin complex mutations. Moreover, these mutations can be used to improve risk stratification in AML independent of established clinical parameters. Integrating mutational data with dose-intensity revealed that high-dose daunorubicin improved survival in patients with DNMT3A/NPM1 mutations or MLL translocations relative to treatment with standard dose daunorubicin, but not in patients wild-type for these alterations. These data provide important clinical implications of genetic alterations in AML by delineating mutation combination genotypes that predict outcome in AML and improve AML risk stratification. Of biologic importance, the TET family of proteins have been shown to place a hydroxyl mark on methylated DNA and lead to DNA demethylation. We and others have found that TET2/IDH mutations leads to loss of DNA hydroxymethylation and a hypermethylation phenotype in leukemia patients. In addition, in vitro and in vivo studies show that TET2 loss or neomorphic IDH1/2 mutations leads to impaired hematopoietic differentiation, increased stem cell self-renewal, and myeloid transformation in vivo. We have also investigated the role of mutant DNMT3A in AML pathogenesis, and shown that these mutations cooperate with other disease alleles to induce leukemic transformation and to confer chemoresistance due to impaired DNA damage sensing. We will present novel data showing how these mutations coopt the epigenetic state of hematopoietic stem/progenitor cells in order to contribute to transformation and that these mutations have biologic and prognostic relevance.

Targeting Epigenetic Machinery in Cancer
Ryan Kruger, PhD, Cancer Epigenetics DPU, GlaxoSmithKline

Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for new targeted therapies. The current presentation describes the biological activity of a potent, selective, orally bioavailable, reversible inhibitor of Protein Arginine Methyltransferase 5 (PRMT5). Inhibition of PRMT5 results in changes in levels of symmetrically dimethylated arginine residues on a variety of proteins including members of the spliceosome. This results in changes in RNA splicing of a large number of transcripts including MDM4. PRMT5 inhibition causes an isoform switch of MDM4 resulting in a shorter form of the protein that is no longer able to downregulate p53. This in turn leads to an upregulation of the p53 pathway and ultimately leads to an antiproliferative effect in cancer cell lines suggesting PRMT5 inhibition could be a novel strategy to treat a variety of cancers.

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