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Back-to-Back with Cancer Immunotherapeuitcs Conference

Day 2

September 21

7:15 Morning Coffee

7:55 Chairperson's Remarks
Dr. William Westlin, Vice President, Preclinical Research, Praecis Pharmaceuticals, Inc.

Anti – Angiogenesis

8:00 New Tumor Vascular Drug Targets from Human Tumor Endothelial Cells: Discovery and Validation
Dr. Rebecca Bagley, Staff Scientist II, Genzyme Corp
Through serial analysis of gene expression methodology of endothelial cells isolated from fresh samples of human tumor and normal tissues less than 24 hrs from the patient, new therapeutic targets have been identified. By examining the gene highly expressed in tumor endothelial cells from several tumor types compared to normal endothelial cells from the corresponding tissues, it has been possible to determine a small cohort of therapeutic targets that are very selectively expressed by the endothelium of malignant tissue. Interestingly, the cell-types classically used in the study of angiogenesis do not express these targets or express them at very low levels. Therefore, cells that better model tumor endothelium were identified for use in functional assays. While some of these targets are suitable for small molecule drug discovery, others of the targets were more suitable for monoclonal antibody therapeutics. In vivo efficacy testing in syngeneic tumor models and human tumor xenografts demonstrate that targets identified by this method can lead to potentially useful therapeutics.

8:25 Inhibitors of Methionine Aminopeptidase-2 in the Treatment of Non-Hodgkin's Lymphoma
Dr. William Westlin, Vice President, Preclinical Research, Praecis Pharmaceuticals, Inc.
Methionine aminopeptidase-2 (MetAP2) is an important regulator of cell proliferation in tumor cells and highly proliferative endothelial cells participating in the angiogenic process. MetAP2 is highly expressed in human germinal center B cells and their neoplastic counterparts, non-Hodgkin's lymphoma (NHL) cells such as Diffuse Large B Cell Lymphomas and Follicular Lymphomas. PPI-2458 is a selective and irreversible inhibitor of MetAP2 that has been demonstrated to reduce the formation of germinal centers in lymphoid tissues in vivo and has direct anti-proliferative activity on NHL cells in vitro and in vivo. The anti-tumor activity of PPI-2458 was dose-dependent in these models and is directly correlated with the level of molecular target MetAP2 enzyme inhibition in tumor tissues as determined by a sensitive pharmacodynamic assay. This molecularly targeted therapy is currently undergoing clinical evaluation for the treatment of NHL and advanced solid tumor indications.

HDAC

8:50 Novel Histone Deacetylase Inhibitors: Differential Effects on Protein Acetylation and HDAC Enzyme Selectivity 
Dr. Keith Glaser, Group Leader, Cancer Research, Abbott Laboratories
Histone deacetylase (HDAC) inhibitors induce the hyperacetylation of nucleosomal histones in carcinoma cells resulting in the expression of repressed genes that cause growth arrest, terminal differentiation and/or apoptosis. We have studied the in vitro selectivity of several novel hydroxamate HDAC inhibitors including succinimide macrocyclic hydroxamates and the non-hydroxamate a-ketoamide inhibitors using isolated enzyme preparations (HDAC1 /2, 3, 4/3, and 6) and did not observe HDAC enzyme selectivity for these HDAC inhibitors or the reference HDAC inhibitors, MS-275 and SAHA. In cellular assays these compounds cause the accumulation of acetylated histones H3 and H4; however, the succinimide macrocyclic hydroxamates and the a-ketoamides did not cause the accumulation of acetylated a-tubulin, similar to results with MS-275. This observation matches our previous findings where MS-275 was found to have a different gene expression profile compared to hydroxamate-based HDAC inhibitors. These data suggest "selectivity" can be observed at the cellular level with HDAC inhibitors and that the nature of the zinc-chelating moiety is an important determinant of activity against tubulin deacetylase and gene expression in response to that HDAC inhibitor.

9:15 Epigenetic Silencing of Tumor Suppressor Genes through Aberrant Acetylation of Associated Histones Plays an Important Role in the Etiology of Cancer
Dr. Jeffrey M. Besterman, Senior VP, R&D, MethylGene Inc.
Targeting histone deacetylases (HDACs) is a new approach in human cancer therapy. Several HDAC inhibitors have been advanced into human clinical trials including MGCD0103. We rationally designed MGCD0103, a non-hydroxamate small molecule HDAC inhibitor, as a novel anti-cancer therapeutic. MGCD0103 selectively targets certain specific class I HDAC isoforms at submicromolar IC50s in vitro and induces hyperacetylation of histones in vivo. 
Comparing MGCD0103 with other HDAC inhibitors in clinical development by cDNA array analysis indicates that MGCD0103 regulates transcription of a smaller set of genes, reflecting the isotype inhibitory specificity of MGCD0103 compared to the pan-inhibitory character of other HDAC inhibitors. In vivo, MGCD0103 significantly inhibits growth of human tumors in various xenograft models in nude mice in a dose-dependent manner with minimal toxicity. Phase I clinical trial results for MGCD0103 will be presented.

9:40 Poster Snapshots
Several poster presenters will be given the opportunity to present a brief oral presentation of their work. The presentations will be selected from all abstracts submitted prior to the deadline on August 29. 

10:00 Coffee Break, Poster  Viewing

Signal Transduction

11:00 Inhibition of IGF-1R Signaling and Tumor Cell Proliferation by a Fully Human Neutralizing anti-IGF-1R Antibody
Dr. Yan Wang, Principal Scientist, Department: Oncology, Schering-Plough Research Institute
Insulin-like growth factor 1 receptor (IGF-1R) plays an important role in tumor cell growth and survival. We describe development of a fully human anti-IGF-1R monoclonal antibody 19D12 that inhibits IGF binding and autophosphorylation of both IGF-1R:IGF-1R homo-dimers and IGF-1R:insulin receptor (IR) hetero-dimers. In addition to inhibiting IGF-1R autophosphorylation, 19D12 also inhibits IRS-1 phosphorylation and activation of the major downstream signaling molecules, AKT and ERK1/2. Furthermore, the antibody down-modulates the total IGF-1R protein level, and can induce ADCC in vitro in the presence of isolated human natural killer cells. In vivo, 19D12 inhibits the tumor growth of various xenograft models. These data support the development of the anti-IGF-1R monoclonal antibody as a promising anti-cancer agent.

11:25 TGFbRI Kinase Inhibitors for Cancer
Dr. Kam Cheung, Scientist, Validation Biology, Biogen Idec Inc.
The TGFbeta pathway has emerged as an attractive target in oncology. Recent findings show that potent, selective TGFbeta type I receptor kinase inhibitors can inhibit tumor growth and provide a novel approach to cancer therapy.

11:50 Immunoaffinity Profiling of Tyrosine Phosphorylation in Cancer Cells
Dr. Christopher Bunker, Director, New Business Development, Cell Signaling Technology Inc.
Tyrosine kinases play a prominent role in human cancer. Profiling tyrosine phosphorylation has been difficult due to low cellular levels of tyrosine phosphorylation. Global phosphoproteomic approaches typically reveal small numbers of peptides containing phosphotyrosine. We have developed a strategy that emphasizes the phosphotyrosine component of the phosphoproteome and identifies large numbers of tyrosine phosphorylation sites. Peptides containing phosphotyrosine are isolated directly from protease-digested cellular protein extracts with a phosphotyrosine-specific antibody and are identified by tandem mass spectrometry. Using this approach with cancer cell lines and tissues, we can identify activated protein kinases and downstream proteins, and when coupled to quantitative methods our technology can help identify phosphorylation signatures of drug response. In collaboration with Al Moritz, Kim Lee, Ailan Guo, Valerie Goss, Erik Spek, John Rush and Michael Comb.