2016 Archived Content
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
Monday, September 19
7:00 am Registration Open and Morning Coffee
8:30 Chairperson’s Opening Remarks
Edward Holson, Ph.D., CSO, KDAc Therapeutics
8:40 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.
9:10 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.
9:40 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
10:40 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.
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 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.
12:10 pm Enjoy Lunch on Your Own
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 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.
2:50 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.
3:20 Refreshment Break
4:00 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.
4:30 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.
5:00 Exploring
the Role of HDAC6 in Myeloproliferative Neoplasms
Lanzhu Yue, Ph.D. Post-doctoral Fellow, Department of
Immunology, H. Lee Moffitt Cancer Center
The
JAK-STAT pathway is constitutively activated in myeloproliferative neoplasms
(MPNs) and JAK2 is a clinically validated drug target. HDAC6 may modulate
JAK activity at least in part through HSP90 deacetylation in certain
transformed cell lines. We thus utilized highly selective HDAC6 inhibitors and
HDAC6-deficient mice to investigate the role of HDAC6 in JAK-STAT activation
and its therapeutic potential in MPN.
5:30 Close of Symposium
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