Epigenetic Therapies — New Approaches
Coriell Institute for Medical Research
Principal Investigator(s):
Jean-Pierre Issa, MD
Stephen Baylin, MD
Peter Jones, PhD
- Principal Investigator(s) Contact Information
- Overview
- Project 1: Cyclin Dependent Kinases as Epigenetic Therapy Targets
- Project 2: Epigenetic Synergy Between DNMT and EZH1/2 Inhibitors for Therapy in Solid Tumors
- Project 3: Linking Epigenetic-Therapy Induction of Inflammasome Signaling to Generation of a BRCAness Phenotype
- Administrative Core
- Pathology Core
- Genomics Core
- Developmental Research Program
- Career Enhancement Program
- Institutional SPORE Website
Principal Investigator(s) Contact Information
Jean-Pierre Issa, MD
President & CEO
Coriell Institute for Medical Research
403 Haddon Avenue
Camden, NJ 08103-1505
(856) 966-7377
Stephen Baylin, MD
Professor
Van Andel Research Institute
333 Bostwick Avenue
Grand Rapids, MI 49503-2518
(616) 234-5000
Peter Jones, PhD
Chief Scientific Officer
Van Andel Research Institute
333 Bostwick Avenue
Grand Rapids, MI 49503-2518
(616) 234-5000
Overview
Epigenetics refers to stable gene expression patterns mediated by DNA methylation and/or chromatin remodeling and is involved in cellular identity and repression of spurious transcription, including from repetitive elements. Over the past 20 years, in work led in part by investigators in this project, epigenetic changes were recognized as important drivers of cancer formation, progression and resistance to therapy. This recognition, along with the reversible nature of the biochemical modifications required for epigenetics led to the field of Epigenetic Therapy, which aims to reprogram gene expression to achieve a therapeutic effect. This field, which started with DNA methyltransferase (DNMT) inhibitors, has grown to a dozen epigenetic targets and over 30 drugs in clinical trials. Four targets have made it to US-FDA approval (DNMTs, Histone Deacetylases (HDACs), EZH2 and Isocitrate Dehydrogenases) and tens of thousands of cancer patients benefit from this every year. With the identification of new targets and the recognition that epigenetics is involved in sensitivity and resistance to chemotherapy and immunotherapy, the clinical potential of epigenetic therapy has begun to be explored in earnest. There remain fundamental challenges, from the lack of robust biomarkers of activity, to the emergence of resistance, and to the unexplained divide in responses between hematologic malignancies and solid tumors.
This Epigenetic Therapy SPORE encompasses four major themes: (i) Develop and test drugs against new epigenetic targets, (ii) Mechanistic and translational studies of immunosensitization by epigenetic therapy, (iii) Studies of drug combinations that enhance the efficacy of known epigenetic drugs; and (iv) Biomarker studies to define sensitivity and resistance to epigenetic therapy in the clinic. These themes will be addressed through 3 projects: (i) Cyclin Dependent Kinases as Epigenetic Therapy Targets; (ii) Epigenetic synergy between DNMT and EZH1/2 inhibitors; (iii) Linking epigenetic-therapy induction of inflammasome signaling to generation of a BRCAness phenotype.
Project 1: Cyclin Dependent Kinases as Epigenetic Therapy Targets
Project Co-Leaders:
Jean-Pierre Issa, MD (Clinical Co-Leader)
Yi Zhang, PhD (Applied Co-Leader)
Epigenetic therapy aims to reprogram gene expression in cancer cells to achieve a therapeutic effect. To date, DNA methyltransferase (DNMT) inhibition (DNMTi) is the most effective form of epigenetic therapy, being particularly active in myeloid leukemias. Using a live cell assay to screen for drugs that achieve the same degree of epigenetic reprogramming as DNMTi, we discovered a new class of epigenetic drugs that activate silenced expression through inhibition of CDK9. Cyclin Dependent Kinases (CDKs) are of considerable clinical interest in cancer therapy and fall into two classes — cell cycle regulatory (e.g. CDK1,2,4,6 etc.) and transcriptional regulators (e.g. CDK7,9,12 etc.). Our new data place CDK9 at the heart of a node that regulates both gene silencing and activation. Targeting CDK9 has pleotropic effects on gene expression that appear ideal from an anti-tumor perspective: One observes simultaneous gene activation (of tumor suppressors), repression (of oncogenes), and induction of an interferon immune signature, which may be immunosensitizing for cancer therapy.
This project therefore aims to test the hypothesis that targeting CDKs leads to immunosensitizing epigenetic effects. We will confirm this hypothesis and test mechanisms and clinical/translational implications for cancer therapy in three aims: (i) Immunosensitization by CDK9 inhibition, in which we will study mechanisms and potential ways to enhance the effects; (ii) Epigenetic effects of CDKs, in which we will ask whether targeting CDK4,5,6 and 7 has similar epigenetic and immunosensitizing effects as targeting CDK9; and (iii) Preclinical studies and a clinical trial of combined CDK9 inhibition, DNMT inhibition and Immune checkpoint inhibition in AML and MDS, in which we will complete the necessary studies to bring CDK targeting as epigenetic therapy into the clinic, in combination with DNMT
targeting and immune checkpoint inhibition. Successful achievement of these aims will introduce a new form of epigenetic therapy for cancer and leukemias.
Project 2: Epigenetic Synergy Between DNMT and EZH1/2 Inhibitors for Therapy in Solid Tumors
Project Co-Leaders:
Scott Rothbart, PhD (Basic Co-Leader)
Stephen Baylin, MD (Applied Co-Leader)
DNA methyltransferase inhibitors (DNMTi), such as the FDA-approved nucleoside analog 5-aza-2'-deoxycytidine (DAC), are currently the only available clinical drugs that can reverse abnormal DNA methylation in cancer cells and have emerged as a potential means to increase the efficacy of immunotherapy in cancer. However, the DNA de-methylation utility of these agents, particularly in solid tumors, does not attain the desired downstream transcriptional consequences seen in preclinical models. As such, novel therapeutic strategies to regulate DNMT activity are urgently needed and are directly addressed in this SPORE project. Our preliminary data shows that several clinically applied EZH1/2 inhibitors block compensatory repressive activity of PRC2 at select tumor suppressor genes and repeat elements consequent to DNA methylation removal by DAC. Blocking this repressive “epigenetic switch,” which we propose is a key contributor to DNMTi resistance seen in patients treated with these drugs, may underlie an observed synergy of DNMTi+EZH1/2i to de-repress cancer-associated genic and intergenic transcriptional silencing. Our overall goal is to define mechanisms of transcriptional synergy and immune crosstalk consequent to DNMTi+EZH1/2i and evaluate the clinical potential of this epigenetic therapeutic combination, alone, and as a primer to immunotherapy. To this end, we will (Aim 1) define cancer cell-intrinsic chromatin regulatory mechanisms and cellular pathways involved in the molecular and therapeutic effects of combined EZH1/2 and DNMT inhibition. Concurrently, we will (Aim 2) determine in mouse models of checkpoint therapy resistant disease, the antitumor effects of combined EZH1/2 and DNMT inhibition on cancer vs. immune cells and those dependent on interactions between the two. In addition, a proposed Phase 1 clinical trial, inclusive of extensive correlative science endpoints, will (Aim 3) validate the impact of combination EZH1/2 and DNMT inhibitor therapy on immune-response gene signaling circuits and the tumor microenvironment across multiple solid tumor types. Impacts of our studies include: 1) defining exploitable mechanisms of molecular crosstalk associated with DNMTi therapy; 2) enabling effective clinical application of DNMTi+EZH1/2i therapy; 3) revealing correlative biomarkers to assess drug action in patient tumors; and 4) expanding opportunities for checkpoint and targeted immunotherapy combinations.
Project 3: Linking Epigenetic-Therapy Induction of Inflammasome Signaling to Generation of a BRCAness Phenotype
Project Co-Leaders:
Kenneth Nephew, PhD (Basic Co-Leader)
Feyruz Rassool, PhD (Basic Co-Leader)
Kathy Miller, MD (Clinical Co-Leader)
PARP inhibitor (PARPi) resistance remains a clinical hurdle, with therapy limited to breast and ovarian cancer (OC) patients with BRCA mutations, and some activity seen in OC patients with intact BRCA. Our preclinical studies demonstrate that combining a hypomethylating agent (DNMT inhibitor) and the novel PARPi talazoparib inhibited tumor growth regardless of BRCA mutation status in both breast and OC by inducing STING-dependent inflammasome signaling that generates a BRCAness phenotype, synergistically causing cancer cell death. This led to a dose finding phase I clinical trial in TNBC funded by Pfizer and Astex. The overall goal of this proposal is to expand the benefit of PARPi therapy to a larger group of patients and further dissect mechanisms of PARPi cytotoxicity and resistance. Our central hypothesis is epigenetic therapy-inducing inflammasome signaling generates BRCAness that enhances the efficacy of PARPi in BRCA-proficient TNBC and OC. We propose three aims. Aim 1: To test the hypothesis that combining DNMTi + PARPi generates STING-dependent IFN and inflammasome signaling leading to a BRCAness phenotype that increases anti-tumor immunity in the tumor microenvironment. We will conduct mechanistic studies of factors linking immune signaling to BRCAness phenotype, functional analysis of immune subsets in immune-competent mice treated with PARPi-DNMTi combination. Aim 2: To test the hypothesis that DNMTi in combination with PARPi activate reactive oxygen species (ROS)-mediated DNA damage leading to cell death in BRCA-proficient TNBC and OC. We will investigate how ROS generated by DNMTi-PARPi combination enhances DNA damage response (DDR) signaling, induces STING activation and enhances immune responses against TNBC and OC tumors using immune-competent mice. Aim 3: To assess the clinical activity of DNMTi-PARPi combination in TNBC and OC patients in phase I/II clinical trials. After completing the ongoing phase 1, we propose a phase II study in two patient cohorts (one TNBC, one OC), serial tumor biopsies and circulating correlatives to test mechanistic hypotheses derived from our preclinical studies. Impact: Combining DNMTi-PARPi to induce STING-mediated immune signaling linked to induction of a BRCAness-HRD phenotype represents a potentially important therapeutic option for women diagnosed with TNBC and OC who lack BRCA mutations.
Administrative Core
Core Directors:
Jean-Pierre Issa, MD
Stephen Baylin, MD
Peter Jones, PhD
The Administrative Core will provide essential support to the Coriell Institute for Medical Research (Coriell) and Van Andel Institute (VAI) Epigenetic Therapy SPORE PIs and investigators to maximize success. It will be codirected by Drs. Jean-Pierre Issa, Stephen Baylin, and Peter Jones, who co-chair the Executive Committee and provide overall supervision of three Projects, two additional Cores, Developmental Research (DRP) and Career Enhancement (CEP) Programs, and scientific direction of the SPORE. The Core Co-Directors will rely on the extensive broad-based scientific, research, and SPORE experience of the Internal and External Advisory Boards in critical decision making. An oversight committee consisting of the SPORE PIs and three clinical experts from the VAI-SU2C team will ensure prioritization of SPORE trials within the VAI-SU2C team and at clinical sites. The SPORE will be founded on planning, integration, and translational research efforts supported by this Core. Its leadership and staff will be responsible for monitoring/planning scientific activities; providing scientific direction; ensuring emphasis on translational research; ensuring interdisciplinary and inter-SPORE integration with major epigenetic therapy programs within/outside Coriell and VAI and other broad translational research activities; and providing optimal administrative and fiscal management.
Pathology Core
Core Director:
Scott Jewell, PhD
The Pathology and Biospecimen Core (PBC) will manage the collection of patient-derived biospecimens as determined by the trial parameters with collections occurring at pre-post treatment time points to meet the research aims of the proposed SPORE projects.
The PBC Core will provide collection materials, specimen labels and manage shipments of biospecimens to VAI. The PBC Core will assess and maintain excellent quality in the collection of biospecimens for use in the correlative science research. The PBC Core will provide histology assessment, and process pre-post therapy biospecimens to isolate DNA and RNA derivatives for the Genomic Core assessment of BRCAness gene expression, DNA methylation and global gene expression including ERVs. The PBC Core’s for Flow Cytometry Core and Genomics will provide immune monitoring and Methylation EPIC BeadChip array data, respectively.
The PBC Core will collect process and store approximately 2,800 specimens of peripheral blood, bone marrow, tumor pre-post biopsies for Project 1,2 and 3. The PBC Core will also provide access and distribution of specimens to approved correlative research investigators beyond the principal SPORE investigators.
Genomics Core
Core Director:
Jaroslav Jelinek, MD, PhD
The Genomics, Epigenomics, and Bioinformatics Core will cooperate with all SPORE Projects and the Pathology/Biospecimen Core. Project 1 studies immune-sensitization by inhibition of cyclin-dependent kinase CDK9. The Core will analyze (i) gene expression and chromatin accessibility in tumor and immune cells in preclinical models of tumors treated with CDK9 inhibitors, (ii) genome-wide effects of CDK4, 6 and 7 inhibition on DNA methylation and gene expression, and (iii) support preclinical studies and a clinical trial combining CDK9, DNA methyltransferase (DNMT) and immune checkpoints inhibitors. Project 2 is focused on epigenetic synergy between inhibitors of DNMT and Polycomb repressive complex subunits EZH1/2 for therapy in solid tumors. The Core will analyze DNA methylation, ChIP-seq, RNA-seq and exome sequencing data to assess the combinatory effects of DNMT and EZH1/2 inhibitors and perform single-cell RNA-seq analysis of the tumor tissue to delineate tumor-associated immune populations. Project 3 combines induction of inflammasome signaling by hypomethylating agents with inhibitors of polyADP-ribosylation to induce death of cancer cells. The Core will assess genome-wide and LINE-1 repeat methylation, expression of endogenous retroviruses and other repetitive elements in tumors and sorted immune cells.
Developmental Research Program
Program Directors:
Jean-Pierre Issa, MD
Peter Jones, PhD
The specific objectives of the Developmental Research Program are to:
- Publicize the availability of funds for pilot translational research studies in the field of Epigenetic Therapy for cancers.
- Identify through this mechanism innovative projects with significant potential for developing and improving Epigenetic Therapies for cancers.
- Encourage collaborations of projects with scientists within the SPORE and outside the SPORE, specifically the Van Andel Institute-Stand Up To Cancer Epigenetics Dream Team (VAI-SU2C).
- Enhance the communication between the SPORE leaders and VAI-SU2C Investigators to encourage the development of innovative epigenetics therapies for cancer.
- Ensure program flexibility so that developmental projects that show promise can be: 1) funded for a second year; 2) encouraged to apply for peer-reviewed funding (i.e. R01); or 3) expanded to become full SPORE projects.
To achieve our aims, we will establish 1) specific criteria for selection and funding through a peer review mechanism, and 2) mechanisms for close monitoring of, and collaboration between the SPORE leaders and program awardees to enhance the quality of the translational research goals.
Career Enhancement Program
Program Directors:
Jean-Pierre Issa, MD
Peter Jones, PhD
The goal of the Career Enhancement Program (CEP) is to provide training and guidance for academic physician scientists, clinician-investigators, and laboratory-based scientists who wish to dedicate their career and research efforts to translational cancer epigenetics research. To achieve this goal, the CEP will pursue the following specific aims:
- Recruit, train, and mentor physicians, scientists, and senior postdoctoral fellows to become excellent investigators focused on cancer epigenetics translational research.
- Educate awardees in all the basic principles of cancer epigenetics biology, including molecular, cellular and systems biology, drug development, pharmacokinetic and pharmacodynamics studies, and basic principles of biostatistics and bioinformatics.
- Provide a firm foundation for awardees in the specific area of cancer epigenetics translational and early clinical research.
These objectives will be achieved through strong mentorship in which awardees will be instructed in the principles of clinical, basic, and translational cancer epigenetics research. Specific areas of education may include scientific and clinical methods, biomedical ethics, statistical design and analysis, bioinformatics, biology, biochemistry, genetics, epidemiology, and other areas relevant to individual projects. Mentorship will include laboratory-based investigators, clinical-translational investigators, biostatisticians, bioinformaticians and epidemiologists.