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Day 1
Day 1 - Tuesday, November 8, 2016
Opening Remarks
Keynote Presentation
Tazemetostat, A First-in-Class Inhibitor of EZH2: From Bench to Bedside to Bench
Robert Copeland
Chief Scientific Officer
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, point mutations and synthetic lethal relationships. The enzyme EZH2 provides a representative example of altered PMTs that act as genetic drivers of specific human cancers. Point mutations 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. Also, deletion of the INI1 or SMARCA4 subunit of the SWI/SNF chromatin- remodeling complex occur in a number of cancer types. For example, INI1 is deleted in nearly all malignant rhabdoid tumors (MRTs), a cancer found mainly in children that carries a particularly poor prognosis. Similarly, the SMARCA4 subunit of SWI/SNF is deleted, for example, in malignant rhabdoid tumor of the ovary (MRTO, also referred to as small cell carcinoma of the ovary hypercalcemic type), an aggressive cancer affecting young women. An antagonistic relationship has been demonstrated between the biochemical action on chromatin of the SWI/SNF complex and EZH2 (in the context of the polycomb repressive complex 2), that is relieved in MRTs due to the INI1 deletion. MRTs and other INI1- or SMARCA4-negative cancers therefore demonstrate increased reliance on the enzymatic activity of EZH2 for proliferation, and we have shown that MRT cells deficient in INI1 are selectively killed by inhibition of EZH2 in cell culture and in mouse xenograft models. Drug discovery efforts have yielded a potent, selective inhibitor of EZH2, tazemetostat (EPZ-6438), that has now transitioned into phase 2 clinical trials. This inhibitor affects the appropriate histone methyl marks in cells, leads to selective cell killing that is dependent on genetic lesions associated with EZH2 activity and effects tumor growth inhibition in xenograft models. Combining tazemetostat with other treatment modalities for non-Hodgkins lymphoma results in dramatic synergy of anti-proliferative activity in preclinical models. Results of preclinical and phase 1 clinical studies of tazemetostat will be presented.
I. Novel Epigenetic Targets in Cancer
Thomas Deraedt
Harvard Medical School - Brigham Women's Hospital
Identification of Functional Lung Adenocarcinoma Susceptibility Loci through Positional Integration with Human Alveolar Cell Epigenomes
Ite A. Laird-Offringa
Associate Professor, Surgery, Biochemistry and Molecular Medicine
Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
Lung adenocarcinoma (LUAD) is the predominant lung cancer subtype. Although 15 single nucleotide polymorphisms (SNPs) have been reproducibly associated with LUAD susceptibility, mechanistic links to disease outcomes remain largely unexplored. This is in part because most SNPs identified in genome-wide association studies (GWAS) are not located in the coding regions of genes and are co-inherited with hundreds of SNPs in linkage disequilibrium (LD). Here we examined whether SNPs might increase LUAD risk by affecting gene enhancer function in alveolar epithelial cells (AECs), the purported cells of origin for LUAD. We performed ChIP-seq for enhancer histone marks using purified primary human AECs, and carried out formaldehyde- assisted identification of regulatory elements (FAIRE) to identify transcription factor accessible DNA. We integrated this data with LUAD index SNPs and SNPs in high LD (r2>0.5), predicted transcription factor binding sites, used luciferase reporter assays to test whether selected SNPs confer allele-specific enhancer activity in LUAD cell lines, and performed expression quantitative trait locus (eQTL) analysis to identify potential target genes affected by selected SNPs. 47 LUAD risk-associated SNPs mapped to putative AEC enhancers, and 11 of these were located in FAIRE peaks. Of those, seven were predicted to form transcription factor binding motifs. For four of these, ChIPseq data confirmed the binding of the predicted transcription factors. Our analyses provide possible mechanisms for the genetic susceptibility to LUAD, with the identification of strong functional SNP candidates that appear to affect AEC enhancers. Further investigation of these enhancers and their target genes may ultimately yield more effective and personalized strategies for LUAD risk assessment, prevention and treatment. Benefits of attending the presentation:
  • Understanding the importance of studying purified cell epigenomes
  • Envisioning how single nucleotide polymorphisms (SNPs) can affect epigenetic regulation
  • Learning about useful resources for epigenomic data mining
  • Obtaining an overview of the steps towards identifying functional SNPs
Pancancer identification of DNA methylation driven genes for target discovery and subtyping
Olivier Gevaert
Assistant Professor, Medicine, and Biomedical Data Science
Stanford University
In this work we present MethylMix a novel algorithm to identify DNA methylation driven genes and apply MethylMix in a pancancer analysis of The Cancer Genome Atlas. Our pancancer application of MethylMix is the first unbiased pancancer analysis of differentially methylated and transcriptionally predictive genes. Previous methods have not taken this integrated approach and mostly focused on differential hypermethylation, while hypomethylation has been historically understudied. Moreover, MethylMix, has been designed with the highest possible statistical stringency. We have developed this algorithm over the course of several years and MethylMix has evolved into a robust method implemented in R and available in bioconductor. We compared MethylMix with three other algorithms (IMA, COHCAP and minfi) and show higher enrichment of cancer driver genes. Next, MethylMix identified 42 pancancer hypomethylated genes and 266 pancancer hypermethylated genes. We also introduce a novel statistic called the Differential Methylation value (DM-value) and use this statistic to define molecular subgroups for twelve cancer sites. Using DM-values, we identified novel methylation subgroups for renal cell carcinoma and head and neck squamous carcinoma with survival implications. Finally, we demonstrate for the first time a pancancer differential methylation analysis by combining over 4000 cases across twelve cancer sites in a pancancer map. This map shows novel methylation patterns across twelve cancer sites and we identified four mixed pancancer clusters. We also show that our methylation based clustering identified unique pancancer clusters not identified by gene expression, copy number or mutation data.
Afternoon Networking Break
Multidimensional effects of resminostat, an HDAC inhibitor in phase II clinical development -gene regulation, differentiation induction, immune sensitization
Daniel Vitt
Chief Scientific Officer and Chief Development Officer
Over the last years the paradigm, that the pharmacological effect of histone deacetylase inhibitors (HDACi) is mainly based on up regulation of gene transcription due to histone hyperacetylation, was complemented by a better understanding of the regulating impact of HDACi on gene transcription and non-histone proteins. Today, changes in cell differentiation, DNA-damage repair, cell cycle, angiogenesis and apoptosis are well-accepted consequence of the pleiotropic effect of HDACi. Resminostat is a potent, orally available inhibitor of class I, IIb and IV HDAC enzymes, with a pronounced activity against HDAC6. Resminostat dose- dependently and reversibly inhibits HDACs, modifies histone acetylation and induces changes in gene expression in tumor cells resulting in cell growth inhibition, modified cell differentiation and enhanced tumor immunogenicity. Whole genome mRNA and miRNA expression analysis as well as cellular assays demonstrated that resminostat is able to mediate inhibition of EMT processes and induction of differentiation in mesenchymal HCC cells by modulation of the WNT signaling pathway. Additionally, expression analysis on tumor cells of various origins revealed that resminostat enhances immunogenicity of tumor cells and in particular expression of NKG2D ligands. Consequently, resminostat treatment resulted in a strongly increased sensitivity of K562 tumor cells to NK cell mediated lysis. In a different cellular model, where resminostat and the opsonizing anti-CD20 antibody rituximab alone only slightly enhanced NK cell mediated cytotoxicity of ABC-DLBC lymphoma cell line U2932, combination of both resulted in strong increase of U2932 cell lysis and synergistic combination index. In contrast to previously implied negative effect of HDAC inhibitors on NK cell function, we could demonstrate that resminostat does not negatively affect NK cell viability. The effects of resminostat on gene transcription reflect the pleiotropic action of HDACi. However, pathway analysis allowed to narrow down these multidimensional effects of resminostat on immune response and cell differentiation supporting the current clinical development of the compound in HCC and CTCL. Additionally, resminostat qualifies for combinatorial approaches with NK cell based cancer immunotherapies like opsonizing antibodies, NK cell engaging bispecific antibodies, NKG2D-CAR T cells, or adoptive NK cell transfer.
HDAC inhibition, gene regulation, immune sensitization
Jun Qi
Lead Scientist
Dana-Farber Cancer Institute
II. Histone variants and Histone Modifications
Marie Classon
Scientist, Molecular Oncology
Felice Elefant
Associate Professor
Drexel University
Short Oral Presentation from Exemplary Submitted Abstracts
Networking Reception & Poster Session
Day 2
Day 2 - Wednesday, November 9, 2016
Continental Breakfast & Registration
III. Non-coding RNA
Linking genetic variations to noncoding RNAs in cancer
Hansen He
Assistant Professor, Medical Biophysics
Princess Margaret Cancer Centre, University Health Network
Trait-associated SNPs identified through Genome-Wide Association Studies are enriched in regulatory regions. However, the functional link between these SNPs and their target genes remains elusive. Due to their involvement in fundamental biological processes, long noncoding RNAs (lncRNAs) represent an attractive class of candidates to mediate cancer risk. Through integrative analysis of the lncRNA transcriptome with genomic and prostate cancer GWAS SNP data, we identified 45 candidate lncRNAs associated with risk to prostate cancer. The mechanism underlying the top hit, PCAT1, was evaluated further: a risk variant at rs7463708 increases binding of ONECUT2, a novel AR interacting transcription factor, at a distal enhancer that loops to PCAT1 promoter, resulting in upregulation of PCAT1 upon prolonged androgen treatment. In addition, PCAT1 interacts with AR and LSD1 and is required for their recruitment to the enhancers of GNMT and DHCR24, two androgen late response genes implicated in prostate cancer development and progression. PCAT1 promotes prostate cancer cell proliferation and tumour growth in vitro and in vivo. These findings suggest that modulating lncRNA expression is an important mechanism for risk SNPs in promoting prostate transformation.
Discovery and functional validation of candidate tumor suppressor lncRNAs in lung adenocarcinoma
Crystal Marconett
Assistant Professor, Surgery, Biochemistry and Molecular Medicine
Keck School of Medicine of USC
Lung cancer is the leading cause of cancer-related mortality, with a 5-year mortality rate approaching 85%. My lab focuses on the major histological subtype, lung adenocarcinoma (LUAD). Using a combination of bioinformatics and biological analyses, we have uncovered a role for novel regulatory RNAs in the etiology of LUAD development. Our current research focuses primarily on LINC00261, a long non-coding RNA with effects on proliferation and metastasis of cancer cells. It is our hope to identity key regulators of cancer development and progression, so that targeted therapeutics can be developed to help improve the overall survival rate for this deadly disease.
Morning Networking Break
IV. Genetic & Epigenetic Changes: Cancer Stem Cells
Daniel De Carvalho
Princess Margaret Cancer Centre
Gregory David
Associate Professor, Biochemistry and Molecular Pharmacology
New York University School of Medicine
MLL in development and disease
Yali Dou
Associate Professor
University of Michigan
Mixed lineage leukemia protein 1 (MLL1) is one of the histone H3 lysine 4 (K4) methyltransferases in mammals and plays important roles in Hox gene regulation. Rearrangements of MLL1 gene including translocation, amplification and tandem duplication are common in acute leukemia and associate with extremely poor prognosis. Based on biochemical characterization of the MLL1 complex, we have developed the first-in- class small molecule inhibitor that targets MLL1 methyltransferase activity. Using this probe, we have demonstrated that inhibiting MLL1 function is sufficient to block MLL1 fusion protein mediated leukemogenesis. We have also revealed a novel function of MLL1 in preventing reversion of committed cell fate of pluripotent stem cells. Our study shows the essential function of histone H3 K4 methylation in cell fate determination. We envision broad applications of MLL1 inhibitors in basic and translational research.
Humaira Gowher
Associate Professor
Purdue University
Lunch on Your Own
V. Epigenetic Tools and Technologies
Epigenetic Immune Cell Markers - Immune Monitoring for Immuno-Oncology trials and Novel Diagnostics
Thomas Kleen
Executive Vice President Immune Monitoring
Epiontis GmbH
The recent discovery of cell type specific epigenetic markers allows precise and robust quantification of immune cells in all human samples from only 75ul-250ul of blood or small amounts of tissue. The tests are based on quantitative PCR targeting genomic DNA. Therefore, readout is precise, stable and samples can be simply frozen and easily shipped. This allows the unprecedented capability to monitor patients in multicenter studies, retrospective studies, comparison of results between different studies, and routine monitoring. Logistics, sample requirements, stability of cells in blood samples and cost considerations have precluded the use of standard monitoring assays like Flow cytometry and ELISPOT in many studies. Epigenetic based, validated quantification assays for regulatory T cells (Tregs), Th17 cells, Tfh cells, CD4+ and CD8+ cells, overall T cells (CD3+), B cells, NK cells (CD56 dim), neutrophil granulocytes and monocytes are the first examples of a next generation of immune monitoring tools that can be used in these settings. The unparalleled efficacy of current immunotherapy agents (anti-CTLA-4 and PD1/PD-L1 targeted therapies) together with other novel Immunotherapeutics in the pipeline has made immune monitoring in clinical trials obligatory. Monitoring both systemic changes in the blood and even more crucially intratumoral changes of cell counts and ratios of relevant leukocyte subpopulations in affected tissues is necessary to gain insights into potential early surrogate markers of treatment success, ultimately paving the way to acceptable secondary en
Glioma Stratification with a single test to measure DNA methylation biomarkers (MGMT & CIMP) and the primary mutations for glioma subtyping (IDH1 R132H & H3.3 K27M) using Coupled Abscription PCR Signaling
Michelle Hanna
CEO and Scientific Director
RiboMed Biotechnologies, Inc.
In June 2016, the World Health Organization announced new guidelines for the stratification of brain tumors (gliomas) before treatment. In addition to MGMT methylation, molecular biomarkers for stratification now recommended are mutations in IDH1 and IDH2 (primarily IDH1 R132H) that cause CIMP (CpG Island Methylation Phenotype). Tumor samples received by clinical laboratories often contain insufficient amplifiable DNA to measure gene-specific DNA methylation for even a single target with bisulfite or MSRE based methods. In order to simultaneously detect both DNA methylation panels and associated mutations, even in challenging samples of low concentration or damaged DNA, a new detection method, Coupled Abscription PCR Signaling (CAPS), was developed. Samples from patients with recurrent high grade glioma were analyzed using CAPS to (1) measure methylation of the MGMT promoter, (2) measure methylation of a three gene panel to determine the G-CIMP, and (3) probe for the presence of the IDH1 R132H mutation. IDH1 R132H status was also determined by sequencing. In 26/26 samples, results obtained for IDH1 R132H with CAPS matched sequencing results. In 25/26, CIMP status obtained from the three gene methylation panel correlated with the IDH1 R132H status. In a single case, both CAPS and sequencing scored negatively for the IDH1 R132H mutation, but the tumor was clearly CIMP+ based on DNA methylation analysis. Additional sequencing is underway to determine if this tumor contains a different mutation in IDH1 or a mutation in IDH2. CAPS based detection and a simpler three gene CIMP panel make it possible to now analyze multiple biomarkers even when only limited FFPE tumor material is available for testing. Together, this MGMT/CIMP/IDH1 R132H diagnostic increases the applicability and reliability for prognostic assessment of patients diagnosed with brain cancer compared to currently available assays.
Johanna Samuelsson
Gene Regulation Product and Service Manager
Active Motif
Paul Giresi
Afternoon Networking Break
VI. Epigenetic Mechanism of Drug Resistance
Geno Shi
Associate Professor, Medicine
Brigham and Womens Hospital
Networking Reception & Poster Session

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cancer-epigenetics Agenda