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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.
Novel Epigenetic Targets in Cancer
Moderator: Jun Qi
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
Targeting Epigenetic Proteins for Cancer Therapy
Jun Qi
Lead Scientist
Dana-Farber Cancer Institute
Over the past decade, epigenetic proteins have become intensely studied targets for drug discovery in cancer owing to the general view that epigenetic misregulation, in combination with gene mutation, plays a major role in tumorigenesis. Bromodomains are epigenetic readers that recognize the acetylated lysine side chain on histones. We designed and synthesized a thienodiazepine based small molecule, JQ1, which potently inhibits the BET (bromodomain and extraterminal domain) subfamily of bromodomains, with exquisite efficacy for BRD4. JQ1 exhibits excellent efficacy without obvious toxicity in both cell line and patient-derived murine xenograft models. Using this chemical tool in multiple biological systems has furthered our understanding of bromodomain inhibition in variety of diseases including hematologic malignancies, brain tumors and heart failure. We engaged in a medicinal chemistry focusing on optimization of the JQ1 scaffold with structure guidance, and have taken forward several optimized compounds for further evaluation, including our leading molecule, which exhibited high binding affinity toward BRD4 with improved pharmacokinetic properties, including longer in vivo half-life in mice. The molecule has entered human clinical investigation, and generated promising clinical data for the patients with NUT-midline carcinoma, and leukemia with significantly decreased tumor burden and increased overall survival. Taken together, we have successfully developed our probe molecule, JQ1, a chemical probe that effectively displaces BRD4 from chromatin to a clinical candidate that has entered clinic trials for BRD4-dependent cancers and hematologic malignancies.
Dissecting the Context-dependent Contribution of the Chromatin Associated Sin3B to Cancer Progression in vivo
Gregory David
Associate Professor, Biochemistry and Molecular Pharmacology
New York University School of Medicine
Sin3B is an essential component of the Sin3-HDAC co-repressor complex that is recruited by sequence specific transcription factors in order to repress the expresso of their target genes. We had previously demonstrated that the chromatin-associated Sin3B protein is required for oncogenic KRas-driven senescence. Cellular senescence has been defined as a stable cell cycle exit triggered by different stress, including oncogene activation and telomere attrition. In addition to cell cycle exit, hallmarks of senescence include the secretion of a specific set of proteins collectively referred to as SASP (for Senescence-Associated Secretory Phenotype). As it limits the proliferation of damaged cells, senescence was first hypothesized to serve as a barrier against cancer progression. To directly investigate the contribution of senescence in cancer progression, we have generated a mouse model of pancreatic cancer, where Sin3B can be specifically inactivated in the pancreas. In stark contrast with the expected role of senescence as a barrier against cancer progression, our results indicate that Sin3B inactivation led to delayed pancreatic cancer progression, correlating with an impaired oncogene-associated inflammation. Conversely, in a mouse model of prostate cancer, Sin3B inactivation promotes cancer progression. Together, these observations suggest that senescence can modulate cancer progression in a context dependent manner, and its effects on tumorigenesis likely extend beyond the control of cellular proliferation. Finally, we will present our approach to uncouple cell cycle exit from SASP production, in order to decipher the specific contribution of the SASP on cancer progression.
Thomas Deraedt
Harvard Medical School - Brigham Women's Hospital
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
Short Oral Presentation from Exemplary Submitted Abstracts
Networking Reception & Poster Session
Day 2
Day 2 - Wednesday, November 9, 2016
Continental Breakfast & Registration
Genetic & Epigenetic Changes: Cancer Stem Cells
Moderator: Hansen He
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.
Cancer Cell Heterogeneity, Chromatin, Retrotransposable Elements, H3K9 And K27-Methylation
Marie Classon
Scientist, Molecular Oncology
Establishing and maintaining phenotypic heterogeneity within cell populations is an evolutionarily conserved mechanism that can ensure survival upon stress exposure. We previously identified a cancer cell subpopulation that survives treatment with otherwise lethal drugs. Here we show that the genomes of these transiently and reversibly drug-tolerant persisters (DTPs) assume a highly heterochromatic state that requires factors that modify or bind trimethylated lysine 9 in the histone H3 protein (H3K9me3). The increase in H3K9me3 in DTPs, relative to that in the bulk population of drug sensitive cells, is most prominent in chromatin at sites of evolutionarily young Long Interspersed Repeat Element?1 (LINE-1) sequences. Disruption of the H3K9me3-mediated heterochromatin state in DTPs results in increased LINE-1 expression and apoptosis. This response is partially rescued by reducing LINE-1 RNA expression or their encoded reverse transcriptase activity. These findings establish a role for epigenetic silencing of LINE-1 transposable elements as a survival strategy for DTPs during otherwise lethal drug exposures.
Daniel De Carvalho
Princess Margaret Cancer Centre
Morning Networking Break
Non-coding RNA
Moderator: Marie Classon
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.
[Short Oral Presentation from Exemplary Submitted Abstracts]
Epigenetic Regulation of Chemosensitivity in Triple Negative Breast Cancer Stem-Like Cells
Oana Tudoran
The Oncology Institute "I. Chiricuta"
Lunch provided by GTCbio
Epigenetic Tools and Technologies
Moderator: Thomas Kleen
Novel Recombinant Antibodies As Tools For Epigenetic And Drug Discovery Research
Terry Kelly
R&D Director
Active Motif
Antibodies are important tools for biomedical research enabling a variety of applications including labeling or targeting specific cell populations, localizing of specific epitopes, target-based enrichment and so on. Given that antibodies are key to advancing scientific research it is important that high quality, specific and renewable sources of antibodies are available. This is not always the case and as a result many projects have failed or data cannot be reproduced when a new batch of the same antibody is used. While monoclonal antibodies can overcome some of these limitations- they too are often not clonal and the “clones” can be lost or evolve over time. To overcome these challenges and further increase antibodies’ usefulness as tools Active Motif has developed Abflex antibodies- a line of recombinant antibodies that can be covalently tagged with almost any label in a directed and reproducible manner. Abflex antibodies contain an Avitag sequence for directed biotinylation, 6XHis tag as well as a sortase recognition motif, which can be used to add a variety of labels including fluorophores, enzymatic substrates (HRP, AP), FRET substrates, among others or to directly conjugate antibodies to solid substrates like beads or plates. Antibodies are specifically labeled at the end of the constant region of the heavy chain so as to not interfere with antigen recognition. Furthermore due to this unique tagging ability the same antibody can be labeled in an application specific manner removing the need for secondary antibodies and multiple antibodies to the same target, each of which would need to be validated for specificity. We have found that our Abflex recombinant antibodies perform better than the parental monoclonals from which they were derived and our directed labeling approach leads to increased sensitivity in a variety of assays. Recombinant Abflex antibodies overcome the current challenges associated with using antibodies for research namely the lack of clonality, reproducibility, and finite supply and in addition through our directed labeling expands the usefulness of antibodies as research tools.
Convergence of Immuno- and Epigenetic Therapies
Thomas De Raedt
Harvard Medical School - Brigham Women's Hospital
Immunotherapy is at the forefront of cancer research. Observed clinical responses, with for example PD1-antibody checkpoint blockade, can be spectacular and durable. Unfortunately however these responses are only observed in a small proportion of the patient population and are often dependent on a favorable immune microenvironment in the tumor. The research community is building on these early successes and many efforts being made to develop combination therapies that improve the response rates of immunotherapy. One approach is the identification of drugs that result in a more favorable immune microenvironment, enhancing the probability of immune checkpoint blockade to work.
The combination of MEK (PD-0325901) and BRD4 inhibitors (JQ1) potently kills MPNST cells by synergistically inhibiting the RAS transcriptional output. Surprisingly, upon combined inhibition of MEK and BRD4, we observe a rapid (3 days) influx of CTLs (CD8 positive T-cells) in the tumor. Our data suggests that for MPNSTs, non-cell autonomous mechanisms contribute to tumor shrinkage induced by MEK and BRD4 inhibition in vivo. The elevated number of CD8 positive T-cells present in the tumor dramatically increases the CD8/Treg ratio; a ratio used as a measure for success of immunotherapy in the clinic.
Importantly the majority of the CD8 T-cells present in the MPNSTs express markers of exhaustion (PD1). It was thus not surprising that addition of the anti-PD1 antibody to our PD-0325901/JQ1 therapy significantly enhanced tumor regression in our MPNST model.
Benefits: Enhancing immunotherapy, understanding role of epigenetic modulation in immune cells
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 M. 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.
Paul Giresi
Conference Concludes

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cancer-epigenetics Agenda