2017 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 preclinical and clinical stages. HDACi were primarily developed as anti-tumor agents for cancer, but many are now being explored for treating neurologic, 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. Cambridge Healthtech Institute’s conference on 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. The interactive sessions and panel discussions are all geared to provide ample opportunity for active networking, brainstorming and collaborating.
Final Agenda
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Wednesday, September 27
11:50 am Conference Registration Open
12:35 pm Plenary Keynote Program
(click here for details)
2:00 Refreshment Break in the Exhibit Hall with Poster Viewing
2:45 Welcome Remarks
Tanuja Koppal, Ph.D., Conference Director, Cambridge Healthtech Institute
2:50 Chairperson’s Opening Remarks
Timothy A. McKinsey, Ph.D., Associate Professor and Associate Division Head for Translational Research, Director, Consortium for Fibrosis Research and Translation, Department of Medicine, Division of Cardiology, University of Colorado Denver
2:55 Photo-Activatable HDAC Inhibitors for Modulating Inflammation
Pamela Chang, Ph.D., Assistant Professor, Department of Microbiology and Immunology, Cornell University
The immune system is an essential component of host defense that is mediated by inflammatory molecules produced by immune cells. These inflammatory mediators are regulated at the transcriptional level by chromatin-modifying enzymes including histone deacetylases (HDACs). Here we describe a strategy to regulate inflammation and immunity with photo-controlled HDAC inhibitors, which can be selectively delivered to target cells by light irradiation to minimize off-target effects.
3:25 HDAC Inhibitors for Non-Oncology Indications: Focus on Heart, Kidney and Fat
Timothy A. McKinsey, Ph.D., Associate Professor and Associate Division Head for Translational Research, Director, Consortium for Fibrosis Research and Translation, Department of Medicine, Division of Cardiology, University of Colorado Denver
Obesity is a major risk factor for the development of diabetes, heart failure and chronic kidney disease. I will discuss our recent findings that suggest novel roles for specific HDAC isoforms in the control of obesity, glucose tolerance and cardiorenal disease, and the potential for isoform-selective HDAC inhibitors for the treatment of heart, kidney and metabolic dysfunction.
3:55 Drug Safety for Epigenetic Drugs: What Should Be Done?
Kevin S. Sweder, Ph.D., DABT, Director, The Forensic and National Security Sciences Institute, Center for Science & Technology, Syracuse University
The ability of non-genotoxic agents to induce cancer has been documented and a reassessment of testing for environmental and human safety is required. Drug safety testing has relied on genetic toxicology assays designed to detect DNA damage leading to mutation and cancer, which are not suitable for compounds that function through epigenetic changes. How then might we predict long-term downstream effects through epigenetic mechanisms?
4:25 Refreshment Break in the Exhibit Hall with Poster Viewing
5:00 HDAC Inhibition in Pulmonary Arterial Hypertension
Hyung J. Chun, M.D., FAHA, Associate Professor of Medicine, Section of Cardiovascular Medicine, Yale School of Medicine
Pulmonary arterial hypertension (PAH) is a rare disease involving the remodeling of the pulmonary arterioles that leads to increased pulmonary vascular resistance and right heart failure. Emerging studies have demonstrated efficacy of HDAC inhibitors as a therapeutic strategy in experimental models of PAH. Recent evidence supporting the role for selective HDAC class IIA inhibition will be discussed.
5:30 HDAC6 Inhibitors, Autophagy, Mitochondrial Movement, and Disease Modification
Alan P. Kozikowski, Ph.D., CEO and President, StarWise Therapeutics LLC
In this lecture I will present information on the design, synthesis, and testing of ligands that are highly selective for HDAC6 inhibition and show the effects of these compounds in animal models of diseases such as Rett syndrome, Alzheimer’s disease, Charcot Marie Tooth disease, cancer, and stroke.
6:00 Close of Day
6:30 Dinner Short Course Registration
Click here for details on short courses offered.
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Thursday, September 28
7:30 am Registration Open
8:00 Interactive Breakout Discussion Groups with Continental Breakfast
Grab a cup of coffee and join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Details on the topics and moderators are below. Please click here for full details on all breakouts.
Non-Oncology Indications for HDAC Inhibitors
Moderator: Timothy A. McKinsey, Ph.D., Associate Professor and Associate Division Head for Translational Research, Director, Consortium for Fibrosis Research and Translation, Department of Medicine, Division of Cardiology, University of Colorado Denver
- Are isoform-selective HDAC inhibitors really necessary?
- Can we improve the therapeutic index of HDAC inhibitors with episodic dosing and/or combination therapy?
- Why do HDAC inhibitors work in so many preclinical models?
HDAC Inhibitors in Immuno-Oncology
Moderator: Alejandro Villagra, Ph.D., Assistant Professor, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University
- Rationale for new combination therapies using
immune check-point blockade and HDAC inhibitors
9:00 Chairperson’s Remarks
Stephen Shuttleworth, Ph.D., COO and CSO, Karus Therapeutics Ltd.
9:05 Epigenetic Targeting of Foxp3+ Treg Cells to Promote Anti-Tumor Immunity
Wayne W. Hancock, M.D., Ph.D., Professor of Pathology and Chief of Transplant Immunology, Children’s Hospital of Philadelphia and University of Pennsylvania
HDACs such as HDAC1, HDAC2 and HDAC3 function as part of large multi-molecular complexes. We have begun to study the effects of targeting individual HDACs or co-associated proteins within these complexes. This presentation will deal with our successful targeting of individual members of the CoREST complex during cancer and inflammatory responses.
9:35 Epigenetic Priming with New HDAC Class I Inhibitor 4SC-202 Sensitizes Tumor for Anti-PD-1/PD-L1 Therapy
Svetlana Hamm, Ph.D., Head of Translational Pharmacology, 4SC AG
Epigenetic drugs were shown to increase immunogenicity and recognizibility of tumors by immune cells, and there is growing evidence that combination of epigenetic modulators with different cancer immunotherapies results in increased clinical benefit. We have found that 4SC-202, a new oral HDAC class I inhibitor, modulates inflammatory networks in the tumor microenvironment, strongly increases tumor infiltration with tumoricidal cytotoxic T cells and synergizes with anti-PD1/PD-L1 therapy.
10:05 Improving Cancer Immunotherapy with Selective HDAC Inhibitors
Alejandro Villagra, Ph.D., Assistant Professor, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University
A considerable number of reports have analyzed the role of the specific inhibition of HDACs in cancer as well as processes of immune regulation. This new collection of information has helped the rational design of improved anti-cancer drug candidates to be used as stand-alone or as combination partners in immunotherapeutic approaches. In here, we will discuss the new functional roles of HDAC6 and other HDAC inhibitors as immune regulators in cancer and immune cells, and the new combination strategies being tested to improve immunotherapy.
10:35 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced
11:20 Promise of HDAC and IKK Inhibition as Combination Therapy for Solid Tumors
Ivana Vancurova, Ph.D., Professor of Biological Sciences, Department of Biology, Laboratory of Cancer Immunology, St. John’s University
We present evidence that may explain the decreased efficacy of HDAC inhibition (HDI) in ovarian cancer (OC), based on our data demonstrating that HDI increases IKK-dependent interleukin-8 expression, which induces OC cell proliferation. Combination of HDI and IKK inhibitors significantly reduces tumor growth in mice, compared to either drug alone, suggesting that IKK inhibitors may increase HDI effectiveness in OC and other solid tumors characterized by increased IL-8 expression.
11:50 Design and Development of KA2507, an Orally-Active HDAC6-Selective Inhibitor with Tumor Immunotherapeutic Activity
Stephen Shuttleworth, Ph.D., COO and CSO, Karus Therapeutics Ltd.
12:20 pm Enjoy Lunch on Your Own
1:50 Refreshment Break in the Exhibit Hall with Poster Viewing
2:35 Chairperson’s Remarks
Ralph Mazitschek, Ph.D., Assistant Professor, Harvard Medical School; Co-Director of the Chemical Biology Platform, Center for Systems Biology, Massachusetts General Hospital
2:40 Non-Catalytic Inhibitors Target the Zinc-Finger Ubiquitin-Binding Domain of HDAC6
Matthieu Schapira, Ph.D., Principal Investigator, Structural Genomics Consortium, University of Toronto
Virtual and fragment-based screens identified a novel class of inhibitors targeting the unique zinc-finger ubiquitin-binding domain of HDAC6. Crystal structures in complex with these screening hits provide a framework for structure-based optimization.
3:10 FEATURED PRESENTATION: Novel Insights about Deacetylation by HDAC6
Patrick Matthias, Ph.D., Senior Group Leader, Friedrich Miescher Institute for Biomedical Research (FMI)
We will present the crystal structure of the two catalytic domains of Histone deacetylase 6 (HDAC6), in complex with the pan-HDAC inhibitor, trichostatin A (TSA) to 1.6Å resolution. The structural backbone of each catalytic domain is highly similar to each other and has overall similarity to other deacetylase domains. We propose a detailed model explaining how HDAC6 can uniquely deacetylate tubulin. We will also discuss the identification of novel substrates and the implications for understanding the activity of this enzyme.
3:40 Session Break
3:55 The Importance of Non-Catalytic Domains of HDAC6 for Interactions with Tubulin
Cyril Bařinka, Ph.D., Principal Investigator, Laboratory of Structural Biology, Institute of Biotechnology, Vestec, Czech Republic
We will present data on interactions between human HDAC6 and tubulin/microtubules. By using single-molecule TIRF microscopy we identified structural features governing HDAC6 binding to assembled microtubules. Furthermore, we detailed the influence of HDAC6 on microtubule assembly and dynamics. Our data show that structural motifs beyond the HDAC6 catalytic domains play an important role in HDAC6/tubulin interactions and influence microtubule dynamics.
4:25 Light-Controlled Epigenetics
Ralph Mazitschek, Ph.D., Assistant Professor, Harvard Medical School; Co-Director of the Chemical Biology Platform, Center for Systems Biology, Massachusetts General Hospital
4:55 Close of Conference
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