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ThermoScientific

HDAC Inhibitors: Targeting Oncology and Beyond - Day 2

 Day 1  |  Day 2  |  Download Brochure 

 THURSDAY, OCTOBER 23

7:30am – 3:40pm Registration Open

7:30            Morning Coffee

Mechanistic Insights into HDAC Inhibition

8:35            Chairperson’s Remarks

8:40            Rational Approaches to Combining HDAC Inhibitors  (HDACIs) with other Targeted Agents in the Treatment of  Malignant Diseases
Steven Grant, M.D., Professor of Medicine, Biochemistry, and Pharmacology, Associate Director for Translational Research, Massey Cancer Center and Virginia Commonwealth University
While HDACIs have already shown promise in the treatment of various human malignancies (e.g., cutaneous T-cell lymphoma), their ultimate role may be in combination with other agents. Because HDACIs act through multiple mechanisms in addition to modulation of gene expression to kill tumor cells (e.g., induction of ROS and death receptors, acetylation of chaperone and DNA repair proteins etc), it is noteworthy that synergistic interactions have been observed with multiple other targeted agents (e.g., CDK inhibitors, Hsp90 antagonists, NF-κB and proteasome inhibitors etc.).  A summary of promising preclinical findings and emerging clinical initiatives in this field will be presented.

9:10            Discovery, Preclinical and Initial Phase I Development of CS055/HBI-8000, a Novel  Benzamide Class HDAC Inhibitor
Michael J. Newman, Ph.D., Executive Vice President, Oncology, HUYA Bioscience International, LLC
CS055/HBI-8000 was discovered using a computer-aided rational drug design approach.  This novel benzamide is a selective, low nanomolar inhibitor of several class I HDAC enzymes, enhances histone acetylation in tumor cells in the nanomolar range, and exhibits broad-spectrum in vitro and in vivo anti-tumor activity.  The compound is orally bioavailable, with an attractive preclinical safety and PK profile, and has been evaluated under a Phase I protocol in patients with advanced solid tumors.  Preclinical pharmacology, efficacy and safety data, as well as the results of the Phase I trial will be presented.

9:40            A New Generation of HDAC Inhibitors Based on Synthetically Optimized Natural Products
Simon Kerry, Ph.D., MBA, Chief Executive Officer, Karus Therapeutics Ltd.
We have developed a novel class of potent non-hydroxamate, non-benzamide HDAC inhibitors with distinct subtype selectivities. These compounds display high in vitro anti-proliferative activities in a diverse range of tumor cell lines, and exhibit potent PD effects. Advanced leads, with promising physicochemical and ADMET properties, confer potent tumor growth inhibition in a PC3 xenograft model and exhibit high tolerability. Additionally, several leads display potent in vitro anti-proliferative and anti-inflammatory activity, and high in vivo efficacy in models of immune/inflammatory diseases has been observed. These compounds represent an important class of novel therapeutics; clinical studies will be initiated in 2009.

10:10         Networking Coffee Break in the Exhibit Hall 

10:55         Targeting Individual HDACs: Insights From Pediatric Cancer Models
Olaf Witt M.D., Professor for Pediatric Oncology, Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center
Expression analysis of HDAC1-11 in 200 neuroblastoma samples revealed that only HDAC8 expression correlates with disease progression and long term survival. Targeting of HDAC8 using siRNAs or selective chemical inhibitor induces differentiation in cultured cells without altering global HDAC activity. In contrast, targeting other class I HDACs induces apoptosis. In medulloblastoma however, expression of distinct class II HDACs correlates with survival of patients and exhibit specific functions in these cells. Thus, pediatric cancer models uncover single HDACs as prognostic markers of patient survival and selective targeting exerts differentiation or apoptotic programs depending on the cellular context.

11:25         Control of Tissue Growth and Disease by Histone Deacetylases, and Therapeutic Implications
Rusty L. Montgomery, Ph.D., Post-Doctoral Fellow, Laboratory of Dr. Eric Olson, Department of Molecular Biology, University of Texas, Southwestern Medical Center at Dallas
HDAC inhibitors show remarkable therapeutic potential for a variety of disorders, however, the specific HDAC isoforms that mediate their actions are unclear, as are the physiological and pathological functions of individual HDACs in vivo.  To explore the functions of class I HDACs in vivo, we generated conditional knockout alleles for HDAC1, HDAC2, and HDAC3.  Global and tissue-specific deletions reveal partially redundant roles for HDAC1 and HDAC2 in a number of cell types, whereas HDAC3 is an independent regulator of tissue growth and development.  The phenotypes of these genetic studies and underlying mechanistic insights will be discussed.

11:55         The Design, Synthesis, and Biological Study of Isozyme  
Selective HDACIs for Use in Neurodegenerative Diseases, Cancer, and Neglected Diseases

Alan P. Kozikowski, Ph.D., Professor, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago
HDAC inhibitors (HDACIs) are able to reactivate silenced genes, and these compounds have been shown to be of some value in the treatment of cancer [CTCL], and possibly even neurological disorders as well as certain parasitic diseases such as malaria. In our efforts to identify HDACIs that may show an improved therapeutic profile, we have sought to identify compounds that may show enhanced levels of HDAC isozyme selectivity, as it is believed that some of the undesirable side effects of these agents may relate to their overall lack of enzyme selectivity. We have thus been investigating the design, synthesis, and testing of compounds containing various CAP residues that may interact differentially with the surface areas of these enzymes outside their catalytic gorge regions, as well as to more broadly assess the effect of variations in the zinc binding groups. In this presentation I shall summarize our current efforts in this exciting field of research, and present the results from animal studies pertaining to the use of our compounds in oxidative stress, pancreatic cancers, traumatic brain injury, and malaria.

12:25pm    Luncheon Workshop (Sponsorship available) or Lunch on Your Own

12:55         Session Break

 

Novel Mechanisms for Non-Oncology Indications

1:55            Chairperson’s Remarks

2:00            Novel Mechanisms of Action for Broad-Spectrum and Isoform-Specific HDAC Inhibitors Point the Way to New Clinical Indications
Sriram Balasubramanian, Ph.D., Director, Translational Research, Pharmacyclics, Inc.
Histone deacetylase (HDAC) inhibitors are currently in clinical trials for treating a variety of conditions with the focus on neoplasms.  All the HDAC inhibitors in the clinic target multiple isoforms of the HDAC family, including our novel broad-spectrum inhibitor PCI-24781 that is in Phase I and II trials for treating solid and hematologic tumors.  We are also developing isoform-specific inhibitors of HDAC8 such as PCI-34051, which induce anti-apoptotic activity selectively in T-cell derived tumors.  Interestingly we have found that these HDAC8-specific inhibitors decrease the secretion of interleukin 1-beta (IL-1b) by PBMC and primary monocytes, but unlike the pan-HDAC inhibitors, do so by a novel post-translational mechanism without significantly affecting the mRNA expression of IL-1b or other pro-inflammatory cytokines.  We have found that PCI-34051 can decrease IL-1b secretion in PBMC from psoriasis and RA patients, and also decrease IL-1b secretion and inflammation in mouse models.  These findings illustrate the potential of HDAC8 inhibitors in treating autoimmune disease in addition to hematologic malignancies. 

2:30                        HDAC Inhibition in Inflammation
Paolo Mascagni Ph.D., Director of Preclinical Research and Development, Italfarmaco spa
In addition to being anti-tumoral, HDAC inhibitors have anti-inflammatory properties by inhibiting either the synthesis or the post-translational modification of a number of pro-inflammatory cytokines and other inflammatory genes. Inhibition occurs at concentrations generally much lower than those required for cell death in healthy or tumoral cells. in vivo, oral doses of HDACi have shown efficacy in a variety of auto-immunity models and evidence has been produced, which indicates that their mechanism of action involves rebalancing the Th1/Th2 responses and/or the activation of T regulatory cells. On the other hand, reduced HDAC activity has been measured in tissue from patients with auto-immune disease, arguing against the use of HDAC inhibitors in these pathologies. An overview of these apparently opposing evidences will be presented.

3:00            Networking Ice Cream Refreshment Break in the Exhibit Hall (Last Chance for Viewing)

3:40            Isotype-Selective HDAC Inhibitors as Therapeutic Agents in Spinal Muscular Atrophy and Inflammatory Diseases
Zuomei Li, Ph. D., Executive Director, Molecular Biology, MethylGene Inc.
Emerging evidence suggests that HDAC pan-inhibitors have efficacy in preclinical models of human non-oncologic diseases, such as the neurodevelopmental disease Spinal Muscular Atrophy (SMA) and inflammatory diseases.  However, the inhibitors being developed for oncology may have risk/benefit profiles that may not be suitable for use in the treatment of patients with chronic non-oncologic diseases.  We aim to develop new classes of HDAC isotype-selective inhibitors to treat these systemic diseases.  A panel of isotype-selective inhibitors with different target specificities and with suitable pharmaceutical properties was used in mouse models of proximal spinal muscular atrophy and human inflammatory diseases for proof-of-concept studies.  Our results suggest that selective HDAC inhibition is efficacious and safe in preclinical models of SMA and inflammatory diseases, and the target HDAC isotype can be different from those required in oncology.

4:10            Acetylation of Cardiac Sarcomeric Proteins Plays a Role in Regulating Myofilament Contractile Activity
Sanjeev G. Shroff, Ph.D., Professor & Gerald E. McGinnis Chair in Bioengineering, University of Pittsburgh
A role of protein phosphorylation in regulating cardiac contraction is well established.  In the present study, we show that reversible protein acetylation carried out by histone acetyltransferases (HATs ) and deacetylases (HDACs) also plays a role in regulating the myofilament contractile activity.  We found that a Class II HDAC, HDAC4, and an HAT, PCAF, associate with cardiac myofilaments.  Primary cultures of cardiomyocytes as well as mouse heart sections examined by immunohistochemical and electron microscopic analyses revealed that both HDAC4 and PCAF associate with the Z-disc and I- and A-bands of cardiac sacromeres.  Increased acetylation of sarcomeric proteins by HDAC inhibition (using class I and II HDAC inhibitors or anti-HDAC4 antibody) enhanced the myofilament calcium sensitivity.  We found that a number of sarcomeric proteins were acetylated, including the Z-disc-associated protein, MLP, a sensor of cardiac mechanical stretch.  We also show that trichostatin-A, a class I and II HDAC inhibitor, increases myofilament calcium sensitivity of wild-type, but not of MLP knock-out mice, thus demonstrating a role of MLP in acetylation-dependent increased contractile activity of myofilaments.  These studies provide the first evidence that HATs and HDACs play a role in regulation of cardiac muscle contraction.

4:40            HDAC as a Potential Anti-Parasitic Drug Target
Babu L. Tekwani, Ph.D., Senior Scientist II, National Center for Natural Products Research, School of Pharmacy, University of Mississippi
The infections with parasitic protozoa are major global health challenges. Emergence of resistant and more virulent strains of the pathogens has further aggravated this problem and underscores discovery of new antiparasitic drugs. A comparative analysis of multiple histone deacetylases (HDACs) from parasitic protozoa has revealed significant distinct features of the enzymes. Evidences have also been gathered that indicate functional expression of HDAC isoforms and their essential role in progression of normal cell cycle of these organisms. Molecular, functional and structural comparisons of HDACs from the parasitic protozoa with the human HDAC’s,  differences in the inhibitor/substrate binding site topology and evaluation of HDAC inhibitors libraries against the parasite enzymes and cultures should identify selective HDAC inhibitors as potential new antiprotozoal drugs.    

5:10pm            Close of HDAC Inhibitors Conference                   

 

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