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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 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.

Final Agenda


Monday, September 21

7:00 am Registration and Morning Coffee


UNDERSTANDING CELLULAR CROSS-TALK

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


EXPLORING BIOLOGY FOR EFFECTIVE THERAPIES

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


PROBING NEW HDAC CHEMISTRIES & FUNCTION

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

Inhibition 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

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

Histone 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


HDACi FOR CANCER IMMUNOTHERAPY

3:20 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. 

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

Epigenetic 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 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

The effects of HDAC inhibitors (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.

4:50 Close of Symposium


* Separate Registration Required for Next-Generation Histone Deacetylase Inhibitors Symposium


Suggested Event Package:

September 21 Symposium: Next Generation Histone Deacetylase Inhibitors

September 22-23 Conference: Targeting Epigenetic Readers and Chromatin Remodelers

September 23-24 Conference: Targeting Histone Methyltransferases and Demethylases

 

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SPONSORSHIPS & EXHIBITS

The exhibit hall was sold out in 2014, so please contact us early to reserve your place. To customize your sponsorship or exhibit package for 2015, contact:

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781-972-5483
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September 21 

Next-Generation Histone Deacetylase Inhibitors Symposia 

Strategies for Rare Diseases Symposia 

September 22 

Developing CRISPR-Based Therapies Symposia 

September 22 - 23 

Targeting Epigenetic Readers and Chromatin Remodelers 

Targeting the Ubiquitin Proteasome System 

Targeting the Microbiome 

GPCR - Based Drug Discovery - Part 1 

Antibodies Against Membrane Protein Targets - Part 1 

RNAi for Functional Genomics Screening 

Gene Therapy Breakthroughs 

Targeting Ocular Disorders 

September 23 - 24 

Targeting Histone Methyltransferases and Demethylases 

Targeting the Unfolded Protein Response 

Kinase Inhibitor Discovery 

GPCR-Based Drug Discovery - Part 2 

Antibodies Against Membrane Protein Targets - Part 2 

New Frontiers in Gene Editing 

Quantitative Systems Pharmacology 

Short Courses 

SC1: Cancer Metabolism: Pathways, Targets and Clinical Updates 

SC2: Leveraging Data and Analytics for Drug DiSCovery 

SC3: Setting Up Effective Rnai SCreens: From Design to Data to Validation 

SC4: Phenotypic SCreening and Chemical Probe Development 

SC5: GPCR Structure-based Drug Discovery 

SC6: Targeting of GPCRs with Monoclonal Antibodies 

SC7: Setting Up Effective Functional SCreens Using 3D Cell Cultures 

SC8: Targeting Protein-protein Interactions: Biophysical Approaches 

SC9: Preclinical Animal Models for Ocular Indications 

SC10: Introduction to Allosteric Modulators and Biased Ligands of GPCRs 

SC11: Introduction to Targeted Covalent Inhibitors 

SC12: Assays and High-throughput SCreening for Novel Epigenetic Inhibitors 

SC13: Gamification and Drug Target Challenges 

SC14: A Primer to Gene Editing: Tools and Applications 

SC15: Using Mechanistic Physiological Models In Drug Development