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
Histone deacetylase inhibitors (HDACi’s) are studied in models of a broad spectrum of diseases, which are not related to the pro-apoptotic properties used to treat cancer. The spectrum of diseases is for the most part due to anti-inflammatory and immunomodulatory properties of HDACi’s, often observed in vitro but also in animal models. One unifying property is a reduction in cytokine production as well as inhibition of cytokine post-receptor signaling. 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 Design and Development of Novel, Selective Orally-Active HDAC6 Inhibitors
Stephen Shuttleworth, Ph.D., CSO, Karus Therapeutics Ltd.
Despite its name, HDAC6 is primarily a tubulin–not a histone deacetylase, and is structurally unique and phenotypically distinct from other zinc dependent HDACs. Therapeutically, HDAC6 is a target of great potential in oncology, immune-inflammatory and CNS disorders. Our focus has been on the design and development of highly selective, orally active inhibitors of HDAC6, primarily for immune disorder and cancer therapy.
10:10 Networking Coffee Break
10:40 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
Heart failure (HF) afflicts ~6 million people in the U.S. alone, and is associated with a 5-year mortality rate that approaches 50%. HF is typically classified as either systolic (reduced ejection fraction [EF]) or diastolic, which is also referred to as HF with preserved EF (HFpEF). I will discuss roles of specific HDAC isoforms in HF pathogenesis, and highlight our recent studies of HDAC inhibitors in models of HFpEF.
11:10 Targeting Immunologic and Epigenetic Resistance in Solid Tumors Using HDAC1 Selective Inhibitor Entinostat
Peter Ordentlich, Ph.D., CTO and Founder, Syndax Pharmaceuticals
Entinostat, an oral, highly selective HDAC inhibitor with epigenetic and immunomodulatory activity has been designated a Breakthrough Therapy by the FDA and a pivotal Phase 3 clinical study combining entinostat with exemestane for the treatment of hormone receptor-positive metastatic breast cancer is currently enrolling. Entinostat is also being developed as an immuno-oncology platform to improve responsiveness to checkpoint inhibitors based on entinostat’s ability to down-regulate immune suppressor cells.
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
of HDACs is being pursued as a therapeutic strategy and yet we do not know for
most diseases the relationship between HDAC density or function and disease
progression. 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. The
possible mode of action of certain HDACi in depression will also be analyzed.
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
deacetylase inhibition has shown promise as a therapeutic approach towards
numerous neurological diseases including stroke, Alzheimer’s and learning and
memory disorders. Neuronal loss due to
oxidative stress underlies the pathophysiology in many of these diseases and
HDAC inhibitors have demonstrated an ability to protect neurons 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 Epigenetic Priming for Immunotherapy in Breast Cancer
Pamela Munster, M.D., Professor of
Medicine, Program Leader Development Therapeutics and Director of Early Phase
Clinical Trials' Program, Helen Diller Cancer Center, University of California, San Francisco
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
therapy is emerging as a novel targeted therapy for cancer. HDAC inhibitors are
well known to affect cancer cell viability and biology. Immunotherapy is
effective in selected cancer patients. The direct effects of HDAC inhibitors on
immune cell function, however, remain largely unexplored. We investigated the
potential of HDAC inhibitors in immuno-combination therapy of cancer in
preclinical tumor models.
4:20 FEATURED PRESENTATION: Role of Selective HDAC6 Inhibitors in Cancer Immunotherapy
Eduardo Sotomayor, M.D., Director, GW Cancer Center, and Professor of Medicine, Division of Hematology/Oncology, George Washington University
We have found that genetic (HDAC6 knock-down) or pharmacologic disruption of HDAC6 (with novel isotype-selective inhibitors) resulted in augmentation of tumor immunogenicity. In the absence of functional HDAC6, the STAT3/IL-10 immunosuppressive axis is disrupted resulting in increased tumor immunogenicity. The additional 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.
4:50 Close of Symposium
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