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 in 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. However, much remains to be elucidated about the functional implications of modulating HDACs and understanding the signaling pathways that can cause adverse cellular effects and unwanted toxicity. Next Generation Histone Deacetylase Inhibitors, tracks both the scientific and clinical progress being made to better understand the cellular function of this complex drug target family.
Monday, September 21
7:00 am Registration and Morning Coffee
8:30 Chairperson’s Opening Remarks
Wayne W. Hancock, M.D., Ph.D., Children’s Hospital of Philadelphia
8:40 KEYNOTE: Low Dosing of HDAC Inhibitors for Treating Inflammatory Diseases
Charles Dinarello, M.D., Professor of Medicine and Immunology, University of Colorado School of Medicine; Professor of Experimental Medicine at Radboud University, Netherlands
HDACi’s are studied in a broad spectrum of diseases, for the most part due to the anti-inflammatory and immunomodulatory properties of HDACi’s, often observed in vitro and also in animal models. The reduction in inflammation by HDACi’s is consistently observed at low concentrations compared with the higher concentrations required for killing tumor cells. This characteristic makes HDACi’s attractive and safe candidates for treating chronic diseases.
9:10 Similarities and Differences between the Effects of Isoform-Selective HDAC Inhibition and HDAC Gene Deletion
Wayne W. Hancock, M.D., Ph.D., Professor of Pathology, Chief, Transplant Immunology, Children’s Hospital of Philadelphia and University of Pennsylvania
The data generated when an HDAC gene is knocked down or out altogether is typically considered the gold standard for understanding the biologic importance of a given HDAC. We have examples of major differences arising between gene deletion during embryogenesis and gene deletion in the same cell type using conditional approaches in adult mice. Which data set to believe, and how does HDAC inhibition pharmacologically match or differ from gene targeting? The answers are relevant to all efforts to develop pharmacologic HDACi.
9:40 HDAC Inhibitors for Cardiovascular Disease
Timothy A. McKinsey, Ph.D., Associate Professor, Associate Division Head, Translational Research, Department of Medicine, Division of Cardiology, University of Colorado Denver
10:10 Networking Coffee Break
10:40 Design and Development of Novel, Selective Orally-Active HDAC6 Inhibitors
Stephen Shuttleworth, Ph.D., CSO, Karus Therapeutics Ltd.
11:10 Targeting Immunologic and Epigenetic Resistance in Solid Tumors Using HDAC1 Selective Inhibitor Entinostat
Peter Ordentlich, Ph.D., CTO and Founder, Syndax Pharmaceuticals
11:40 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own
1:10 pm Chairperson’s Remarks
Alan P. Kozikowski, Ph.D., Professor, University of Illinois, Chicago
1:20 Imaging HDAC Density and Drug Inhibition in the Human Brain
Jacob Hooker, Ph.D., Assistant Professor, Department of Radiology, Harvard Medical School
We have developed an imaging agent, [11C]Martinostat, to quantify HDAC isoforms non-invasively in humans and are using quantitative imaging to determine the relationships between HDAC and disease in the brain and in peripheral organ systems.
1:50 Exploration of Some New HDAC inhibitors for Cancer and CNS Diseases
Alan P. Kozikowski, Ph.D., Professor, College of Pharmacy Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago
I will discuss several new chemical scaffolds for HDACi that have been designed and found to be highly selective for HDAC6 inhibition. These new inhibitors have been examined using both thiol and hydroxamate based zinc binding groups. Some of the compounds have the ability to penetrate the BBB, and are being studied for effects in CMT, Rett syndrome, Alzheimer’s, and cancer as well as immune responses through control of Treg populations.
2:20 Defining the HDAC Independent Effects of Hydroxamate-Based Inhibitors in Neuroprotection
Edward Holson, Ph.D., Director, Medicinal Chemistry, Stanley Center for Psychiatric Research and Director, Chemistry, Chemical Biology Platform, Broad Institute
HDACi have demonstrated an ability to protect neuronal loss from multiple forms of oxidative insult. We discovered that several hydroxamate based inhibitors derive their neuroprotective effects through HDAC independent mechanisms driven primarily through their ability to chelate metal ions.
2:50 Refreshment Break
3:20 FEATURED PRESENTATION: Role of Selective HDAC6 Inhibitors in Cancer Immunotherapy
Eduardo Sotomayor, M.D., Susan and John Sykes Endowed Chair in Hematologic Malignancies, Scientific Director, DeBartolo Family Personalized Medicine Institute; Professor of Oncologic Sciences, Pathology and Cell Biology, University of South Florida College of Medicine
We have found that genetic or pharmacologic disruption of HDAC6 resulted in augmentation of tumor immunogenicity. The positive effects of HDAC6 selective inhibition upon immune cells provide the framework for evaluating HDAC6 selective inhibitor(s) alone or in combination with checkpoint antibodies in cancer immunotherapy.
3:50 HDAC Inhibitors for Immuno-combination Therapy of Cancer
Gosse Adema, Ph.D., Professor and Chair in Molecular Immunology, Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, The Netherlands
4:20 HDACi Activate Innate Immune Cells and Regulatory Molecules
Ricky Johnstone Ph.D., Assistant Director of Research Division; Co-Head, Cancer Therapeutics Program, Head, Gene Regulation Laboratory, Peter MacCallum Cancer Centre, Australia
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.
4:50 Close of Symposium
* Separate Registration Required for Next-Generation Histone Deacetylase Inhibitors Symposium