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Histone deacetylases (HDACs) have proven to be a promising target for drug intervention and there are a number of HDAC inhibitors (HDACi) currently being tested at various pre-clinical and clinical stages. HDACi were primarily developed as anti-tumor agents for cancer, but many are now being explored for treating neurodegenerative, immunologic, metabolic, inflammatory and cardiovascular disorders. More recently, they are being developed as combination treatments along with small molecule cancer immunotherapy agents. However, much remains to be elucidated about the functional implications of modulating HDACs and understanding the signaling pathways that are triggered downstream.

Final Agenda


RECOMMENDED ALL ACCESS PACKAGE:

• September 19 Symposium: Next-Generation Histone Deacetylase Inhibitors

• September 19 Short Course: Convergence of Immunotherapy and Epigenetics for Cancer Treatment

• September 20-21 Conference: Targeting Histone Methyltransferases and Demethylases

• September 21-22 Conference: Targeting Epigenetic Readers and Chromatin Remodelers

• September 21 Short Course: DNA Methyl Transferase (DNMT) Inhibitors as Therapeutics


Monday, September 19

7:00 am Registration Open and Morning Coffee


HDACi IN CANCER IMMUNOTHERAPY

8:00 Chairperson’s Opening Remarks

Edward Holson, Ph.D., CSO, KDAc Therapeutics

8:10 KEYNOTE PRESENTATION: Targeting HDACs and HATs for Cancer Therapy

Edward Seto, Ph.D., Professor, Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, George Washington University

Histone deacetylases (HDACs) are potentially good targets for anti-cancer therapy because early studies indicate that HDAC inhibitors cause cell cycle arrest, revert cell transformation, and restrain tumor growth in animals. Recent data uncovered novel mechanistic insights of HDACs, which confirm and extend the tremendous value of further developing HDAC inhibitors for cancer treatment. These new findings also help to begin addressing challenges in exploiting HDAC inhibitors to ultimately benefit cancer patients.

8:40 Genetic and Pharmacologic Evidence of the Importance of HDAC8 Targeting in Tumor Immunotherapy

Wayne W. Hancock, M.D., Ph.D., Professor of Pathology and Chief of Transplant Immunology, Children’s Hospital of Philadelphia and University of Pennsylvania

Our conditional targeting of HDAC8 in T-cells, as well as our use of isoform-selective HDAC8 inhibitors in WT mice, show that HDAC8 targeting can impair Foxp3+ Treg cell function while preserving conventional T-cell responses, and promote anti-tumor immunity in immunocompetent hosts. These data indicate new options in immuno-oncology beyond the PD-1 and CTLA4 pathways, and provide insights into the biology of HDAC8 in adaptive immunity.

9:10 Epigenetic Modulation of Immunotherapy: Advances in Clinical Translation

Pamela Munster, M.D., Professor, Department of Medicine; Director, Early Phase Clinical Trials Unit, and Leader, Developmental Therapeutics Program, University of California San Francisco

An increasing body of literature suggests a role of HDAC inhibitors in reversing therapy resistance in solid tumor malignancies. In addition to their modulation on cell signaling pathways, our preclinical and clinical data suggests a significant contribution of HDAC inhibitors on immune modulators to reverse therapy resistance. Here we present data from studies in breast cancer and renal cell carcinoma.

9:40 Entinostat Development: Targeting Immune Suppressor Cells to Expand Utility of Immune Checkpoint Inhibitors

Peter Ordentlich, Ph.D., CTO and Founder, Syndax Pharmaceuticals

Entinostat is a class 1 HDAC selective inhibitor with direct effects on cancer cells and immune regulatory cells. Entinostat is being evaluated in a Phase 3 clinical trial for advanced hormone receptor positive breast cancer, and in Ph 1b/2 trials in combination with immune checkpoint inhibitors in melanoma, lung, ovarian, and triple-negative breast cancers. A review of the data and rationale for the combination of entinostat with immune checkpoint inhibitors will be provided.

10:10 Coffee Break


ROLE OF HDACi IN MODULATING CANCER PATHWAYS

10:40 HDACi Activate Innate Immune Cells and Regulatory Molecules

Ricky Johnstone, Ph.D., Assistant Director of Research Division; Co-Head, Cancer Therapeutics Program and Head - Gene Regulation Laboratory, Peter MacCallum Cancer Centre, Australia

The effects of HDACi on tumor cell growth and survival have been well documented. However, HDACi also have immunomodulatory properties that could be important for anti-tumor responses and could be harnessed to enhance the activities of other anti-cancer agents. I will present data showing that HDACi can activate different components of the innate immune response and these properties are important for the anti-tumor effects of HDACi.

11:10 Design and Development of Novel, Orally-Active, Selective HDAC6 Inhibitors for the Treatment of Cancer

Stephen Shuttleworth, Ph.D., CSO, Karus Therapeutics Ltd.

11:40 Enhancing the Anti-Cancer Activity of Oncolytic Viruses by Using Histone Deacetylase Inhibitors

Antonio Marchini, Ph.D., Principal Investigator, Tumor Virology Division, German Cancer Research Center (DKFZ)

Oncolytic viruses (OVs) are promising anti-cancer agents due to their capacity to selectively kill cancer cells and to elicit robust anti-cancer immune responses. However, OVs alone are only rarely able to fully eradicate tumors in humans, calling for the rational design of combinatorial approaches. The possibility to enhance the anti-cancer potential of OVs by using histone deacetylase inhibitors will be discussed with a look into the future.

12:10 pm Enjoy Lunch on Your Own


EMERGING HDAC CHEMISTRY & BIOLOGY

1:40 Chairperson’s Opening Remarks

Timothy A. McKinsey, Ph.D., Associate Professor and Associate Division Head for Translational Research, and Director, Consortium for Fibrosis Research and Translation, Department of Medicine, Division of Cardiology, University of Colorado Denver

1:50 Light-Controlled Modulation of Gene Expression by Chemical Optoepigenetic Probes

Ralph Mazitschek, Ph.D., Assistant Professor, Harvard Medical School and Co-Director of the Chemical Biology Platform, Center for Systems Biology, Massachusetts General Hospital

We present a novel and generalizable approach, referred to as ‘Chemo-Optical Modulation of Epigenetically-regulated Transcription’ (COMET), that enables high-resolution, optical control of histone deacetylases based on photochromic inhibitors using visible light. The presented compounds have high isoform selectivity and exhibit a differential activity of three orders of magnitude in the presence of light.

2:20 Therapeutic Potential of Small-Molecule Agents Targeting Lysine Deacetylases: A Matter of Selectivity?

Seng-Lai “Thomas” Tan, Ph.D., Senior Director and Head of Immunology, Forma Therapeutics

Histone and non-histone lysine deacetylases are expressed in many different cell types, where they are known to regulate a wide variety of cellular processes. Genetic knockout mice devoid of specific lysine deacetylases have highlighted distinct functions of individual lysine deacetylases in different aspects of immune cell functions. We elucidate the molecular mechanisms by utilizing highly selective small-molecule inhibitors to specific lysine deacetylases.

2:50 Dual Inhibitor of HDAC and PDE5 Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

Julen Oyarzabal, Ph.D., Director, Translational Sciences, Center for Applied Medical Research (CIMA), University of Navarra

First-in-class molecule (CM-414), inhibitor of PDE5 and HDACs, rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and pTau levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission.

3:20 Refreshment Break

4:00 HDAC Inhibitors in Neurodegeneration: Challenges and Progress

Berkley A. Lynch, Ph.D., Senior Director, CNS Research, Rodin Therapeutics

Numerous studies in recent years have supported the role of histone deacetylase 2 (HDAC2) in synaptic plasticity, learning and memory, and in neurodegenerative diseases, including Alzheimer’s disease. HDAC inhibitors have been shown to reverse decreased synaptic gene expression and improve cognitive function in animal models of neurodegenerative diseases. Critical challenges include managing peripheral toxicity by synthesizing HDAC2 isoform selective compounds, and related strategies.

4:30 Epigenetics in the Brain: Happier and Smarter Mice through Inhibition of HDACs

Matthew Jarpe, Ph.D., Associate Vice President of Biology, Acetylon Pharmaceuticals

Histone deacetylases play a number of important roles in the nervous system. The extranuclear deacetylase HDAC6 regulates microtubule function and activity of the glucocorticoid receptor. The primarily nuclear Class I deacetylases regulate expression of synapse formation through control of positive and negative regulators of synapse formation. Newly discovered brain penetrant HDAC inhibitors affect cognition and mood in rodent models of neurodegenerative and psychiatric disorders.

5:00 HDAC Inhibitors for Cardiometabolic Disease

Timothy A. McKinsey, Ph.D., Associate Professor and Associate Division Head for Translational Research, and Director, Consortium for Fibrosis Research and Translation, Department of Medicine, Division of Cardiology, University of Colorado Denver

Heart failure (HF) afflicts ~6 million people in the U.S. alone, and is associated with a 5-year mortality rate that approaches 50%. Obesity is a major risk factor for the development of HF. I will discuss our recent findings that suggest novel roles for specific HDAC isoforms at the interface between obesity and HF, and the potential for isoform-selective HDAC inhibitors for the treatment of cardiometabolic disease.

5:30 HDAC in Fatty Acid Metabolism and Obesity

Tso Pang Yao, Ph.D., Professor of Pharmacology and Cancer Biology and Associate Professor of Radiation Oncology, Duke University School of Medicine

Reversible protein acetylation has emerged as a prevalent regulatory modification in metabolism. However, its specific impact on human metabolic disease and obesity remains to be established. I will discuss a novel regulatory role of HDAC in coordinating fatty acid acquisition and metabolism and its impact on adipose tissue remodeling linked to obesity.

6:00 Therapeutically Targeting HDAC9 in Inflammatory Bowel Diseases

Dimitrios Iliopoulos, Ph.D., MBA, Professor, David Geffen School of Medicine and Founding Director, Center for Systems Biomedicine, University of California at Los Angeles

A novel epigenomic profiling assay revealed the importance of HDAC9 in IBD pathogenesis. HDAC9 was found to be activated in colonic biopsies from 3 different cohorts of IBD patients. It was found to regulate a network of 21 IBD susceptibility loci. A novel HDACi, having specificity for HDAC9 was developed and it blocked the inflammatory response in IBD cellular and animal models. Furthermore, we have developed an HDAC9 companion diagnostic test for IBD patient stratification.

6:30 Close of Symposium


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SEPTEMBER 19 SYMPOSIA:

Next-Generation Histone Deacetylase Inhibitors

Strategies for Tackling Rare Genetic Diseases

Understanding CRISPR: Mechanisms and Applications

Autoimmunity – Small Molecule Approaches

NK Cell-Based Cancer Immunotherapy

Medical Dermatology Therapeutic R&D and Technical Innovation

CONFERENCES

SEPTEMBER 20-21

Targeting Histone Methyltransferases and Demethylases

Targeting the Ubiquitin Proteasome System

Targeting the Microbiome
– Part 1

GPCR-Based Drug Discovery - Part 1

Advances in Gene Editing and Gene Silencing – Part 1

Gene Therapy Breakthroughs

Antibodies Against Membrane Protein Targets – Part 1

Targeting Cardio-Metabolic Diseases

Targeting Ocular Disorders

SEPTEMBER 21-22

Targeting Epigenetic Readers and Chromatin Remodelers

Kinase Inhibitor Discovery

Targeting the Microbiome
– Part 2

GPCR-Based Drug Discovery - Part 2

Advances in Gene Editing and Gene Silencing – Part 2

Translating Cancer Genomics

Antibodies Against Membrane Protein Targets – Part 2

Metabolomics in Drug Discovery

TRAINING SEMINAR: Data Visualization

SHORT COURSES*

Monday, September 19
8:00 - 11:00 am

(SC1) Immunology Basics for Chemists

(SC4) Medical Dermatology Therapeutic R&D and Technical Innovation - Part 1

Monday, September 19
2:00 - 3:00 pm

(SC5) GPCR Structure-Based Drug Discovery

(SC6) RNA as a Small Molecule Drug Target

(SC7) Using IP Landscape Studies to Improve Your Confidence

(SC8) Medical Dermatology Therapeutic R&D and Technical Innovation - Part 2

Monday, September 19
3:30 - 6:30 pm

(SC9) Targeting of GPCRs with Monoclonal Antibodies

(SC12) Introduction to Gene Editing

Monday, September 19
7:00 - 9:30 pm

(SC13) Convergence of Immunotherapy and Epigenetics for Cancer Treatment

Wednesday, September 21
7:00 - 9:30 pm

(SC14) Cancer Metabolism: Pathways, Targets and Clinical Updates

(SC15) Introduction to Allosteric Modulators and Biased Ligands of GPCRs

(SC16) Functional Screening Strategies Using CRISPR and RNAi