HDAC Inhibitors


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TUESDAY, NOVEMBER 2

7:00 am Conference Registration and Morning Coffee

 

Exploring Efficacy and Specificity of HDAC Inhibitors

8:30 Chairperson’s Opening Remarks

James Bradner, M.D., M.Sc., Instructor in Medicine, Harvard Medical School and Dana-Farber Cancer Institute     

8:40 What’s Next for HDAC Inhibitors - Better Combinations or Better Specificity?      

Sriram Balasubramanian, Ph.D., Senior Director, Translational Research, Pharmacyclics, Inc.

HDACi are remarkably pleiotropic in their mechanisms of action, and yet despite this pleiotropy, HDACi have achieved success as single
agents only in rare types of lymphomas, while displaying modest activity in solid tumors. But they are capable of potentiating commonly
used cancer therapeutics and many of these combinations are now being explored in the clinic. At the same time, a new generation of
isoform-selective inhibitors are being developed. This talk will highlight progress in both these directions, using as examples the combination strategies being adopted with a pan-HDAC inhibitor PCI-24781, as well the development of inhibitors specific for one isoform, HDAC8.     

9:10 Proteomic Approach to Define the Anti-Tumor Effects of an HDACi as Single Agent or in Combination Treatment    

Alfredo Budillon, M.D., Ph.D., Chief, Experimental Pharmacology Unit, National Cancer Institute, G. Pascale, Italy  

Recently we analyzed the anti-tumor effect of the HDACi vorinostat in combination with the orally active EGF-R tyrosine kinase inhibitor gefitinib in a panel of head and neck squamous cell carcinoma cell lines, demonstrating a synergistic anti-tumor effect also in the gefitinib-resistant cells characterized by mesenchymal markers and phenotype. We also provided evidence that the mechanism of the synergistic interaction is related to the ability of vorinostat to modulate the expression and the activity of erbB receptors (EGFR, ERBB2 and erbB3) together with reversing epithelial to mesenchimal transition (EMT).   

9:40 Augmenting the Efficacy of HDAC Inhibitors 

Joya Chandra, Ph.D., Associate Professor of Pediatrics Research, Children’s Cancer Hospital, M.D. Anderson Cancer Center, University of Texas

Combinatorial chemotherapeutic strategies that include the HDAC inhibitors are showing promise in a number of in vitro and in vivo malignancies. By identifying agents that demonstrate strong synergy with HDAC inhibitors, lower doses can be delivered which is ideal for pediatric cancers such as leukemias and brain tumors. In these models, we find that inhibition of the proteasome, inhibition of lysine specific demethylase, or agents that induce oxidative stress are able to significantly augment the cytotoxicity of HDAC inhibitors.

10:10 Grand Opening Coffee Break in the Exhibit Hall

10:40 Non-Peptide Macrocyclic Histone Deacetylase Inhibitors for Targeted Cancer Treatment

Yomi Oyelere, Ph.D., Assistant Professor of Chemistry and Biochemistry, Georgia Institute of Technology

Most HDACi non-selectively inhibit several HDAC isoforms; and a large number of these agents have not progressed beyond pre-clinical characterizations. If there is no significant paradigm shift in the current molecular design approaches, the vast therapeutic potentials of HDAC inhibition may remained largely untapped. We are developing novel approaches for organ-selective delivery of HDACi for potential use in targeted cancer therapy. I will discuss the discovery and SAR studies and evidence for lung selective accumulation of a new class of macrocyclic HDACi. The prospect of tissue-selective HDAC inhibition is a particularly enticing alternative to isoform selective inhibition.

Sponsored by
PromegaNEW 
11:10 Sensitive HTS Assays to Interrogate Histone Deacetylase (HDAC) & Sirtuin Enzymes

Andrew Niles, Senior Research Scientist, Promega
Histone deacetylase (HDAC) enzymes exert control over gene transcription and cell cycle progression and are implicated in cancer and metabolic diseases. There is strong interest in drug discovery programs in better understanding this important class of enzymes. Promega has developed two homogeneous bioluminescent assays for the sensitive and robust interrogation of HDAC Class I/II or Sirtuin enzyme activities, and we will describe their utility with various biochemical and cell-based models.

11:25 Sponsored Presentation (Opportunity Available)

11:40 New HDAC Inhibitors for Hematologic Malignancies     

James Bradner, M.D., M.Sc., Instructor in Medicine, Harvard Medical School and Dana-Farber Cancer Institute 

The therapeutic potential of histone deacetylase inhibitors has been limited principally by class-associated side effects. To expand the
therapeutic index of HDACi, we have undertaken to design isoformselective and retrometabolic HDACi for broad use in neoplastic and inflammatory diseases. Proof-of-concept molecules have demonstrated robust activity in translational models of cutaneous T-cell lymphoma and multiple myeloma. Lead optimization has produced small molecules poised for human clinical investigation.    

12:10 pm Panel Discussion: HDACi: What Do We Really Need? Efficacy, Specificity or Both?

Moderator: James Bradner, M.D., M.Sc., Instructor in Medicine, Harvard Medical School and Dana-Farber Cancer Institute

12:40 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on your own

 

Understanding the Cellular Effects of HDACs

2:20 Chairperson’s Remarks

Stanley Spence, Ph.D., Executive Director, Preclinical Safety Assessment, Novartis Institutes of Biomedical Research     

2:25 Inherent Epigenetic Make-Up of Cancer Cells and their Predisposition to HDACi Sensitization        

France Carrier, Ph.D., Associate Professor, Radiation Oncology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland

The reasons for HDACi sensitization of cancer cells to conventional anti-cancer therapies are not known. Our data indicate that intrinsic differences in chromatin structure favor HDACi selectivity for cancer cells. Our newly developed PCR-Stop-RT-PCR assay indicate that HDACi increase the DNA cleavage efficiency of anti-cancer drugs at drugs targeted sites in cancer but not normal cells. Moreover, protein chips arrays identified differences in five basal and three treatment specific histone post-translational modifications, associated with chromatin compaction. These could provide new markers to help predict the benefit of using HDACi in drug combination therapies.

2:55 Pre-Clinical Cardiac Risk Assessment of Histone Deacetylase Inhibitors: An Integrated Assessment

Stanley Spence, Ph.D., Executive Director, Preclinical Safety Assessment, Novartis Institutes of Biomedical Research

In the clinical setting a number of HDACi are associated with slight dose- and schedule-dependent prolongation of the QTc interval and
isolated anecdotal reports of torsade de pointe at high doses. To identify the potential mechanism(s) responsible for these effects
we performed an extensive assessment of non-clinical cardiac safety studies. HDACi of diverse structures, specificities and potencies
were assessed in numerous assays including: HDAC isotype profiling, cytoxicity, hERG, Nav1.5 and Cav1.2 binding and patch clamp, hERG trafficking and maturation, and comparative dog telemetry. Common themes of HDACi on the hERG channel and cardiac repolarization will be presented and discussed.

3:25 Networking Refreshment Break in the Exhibit Hall

4:05 KEYNOTE PRESENTATION: Function, Mechanism of Action, and Regulation of HDACs

Edward SetoEdward Seto, Ph.D., Chairman, Department of Molecular Oncology, H. Lee Moffitt Cancer Center

The focus of our research is: 1) Identify the underlying mechanisms by which HDACs repress gene transcription; 2) Determine the mechanisms by which HDAC inhibitors regulate the expression of genes involved in growth and proliferation; 3) Identify and comprehensively analyze non-histone substrates of HDACs; and 4) Clarify the role of HDACs in DNA damage repair. Abnormal HDACs are strongly correlated with many human maladies. Therefore, a thorough understanding of the biology of HDACs will provide not only tremendous insights into epigenetics and gene regulation, but also provide potential diagnostic and therapeutic approaches for the treatment of diseases.

5:05 Interactive Breakout Discussion Groups

6:15 – 7:15 Happy Hour in the Exhibit HallSponsored by
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The exhibit hall was sold out in 2013, so please contact us early to reserve your place. To customize your sponsorship or exhibit package for 2014, contact:

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781-972-5483
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