This project is designed to develop a new approach to cancer treatment through the study of growth, survival, and metastasis regulatory signal transduction events that identify molecular targets for anticancer drug development. Our work is divided into basic research and translational research through the Preclinical Development Research Core, a translational drug development facility that we have established. Our work is currently focused on (1) the development of novel antiandrogens targeting the Hsp90-Hsp70 supramolecular complex, and (2) development and implementation of pharmacodynamic assays for targeted therapy trials, including assays for response to antiangiogenics, histone deacetylase inhibitors, Hsp90 inhibitors, immune-targeting agents, and detection of circulating epithelial tumor cells (CTCs) pre- and post-drug therapy, and, in collaboration with Dr. Peter Pinto of the Urologic Oncology Branch, CTC assays pre- and post-surgery. (1) Prostate cancer is the most common malignancy and second leading cause of cancer-related death in men in the United States. Androgen deprivation is the mainstay of treatment for men with metastatic prostate cancer, but almost all men treated with hormonal therapy will progress to a castrate-resistant state (CRPC). Once CRPC develops, responses to second-line treatment are limited and median survival is currently approximately 12 to 18 months. Clearly a new therapeutic approach is needed for the treatment of CRPC. Once thought to reflect an androgen-independent state, it is now appreciated that CRPC is driven by androgen receptor (AR) signaling, and that more effective blockade of this pathway would be of enormous value in improving the efficacy of CRCP therapy. In the past three years we have performed high-throughput screens and structure-activity relationship analyses (SAR), and have developed several novel antiandrogens for which the NIH has filed for intellectual property protection. In the first project we worked in collaboration with a number of labs including Len Neckers of the Urologic Oncology Branch, NCI and Marc Cox of the University of Texas, El Paso. We contributed to the SAR by identifying the most potent compound, and we performed all of the AR-driven gene expression studies. This project identified the mechanism of action of the active molecule as targeting of the Hsp90-AR complex with FKBP52, by binding to the Hsp90-FKBP52 interface. As a result of this binding Hsp90 does not release AR in response to androgen binding. Thus AR does not enter the nucleus and AR signaling is inhibited. We published a report on this work in PNAS this year, and NIH filed for patent on the compound. As a result of an SAR on a different chemical library we have identified a new antiandrogen with a novel chemical scaffold and a unique mechanism of action. Compound syntheses were guided by the results of our gene expression analyses, and performed by Sanjay Malhotra and Vineet Kumar of the NCI-Frederick Laboratory of Synthetic Chemistry. My laboratory is working on elucidating the mechanism of action of compounds with this scaffold, and NIH has filed a second antiandrogen patent for these compounds. Our data thus far demonstrate that these compounds have the unique ability to cause degradation of Hsp90 clients, including AR, without binding to either the N-terminal or C-terminal of Hsp90 itself. (2) The Preclinical Development Research Core has been working with intramural, extramural and industry investigators on a range of phase I and phase II clinical trials. I am an associate investigator on 40 clinical trials. For each of these trials we work with the PI to develop novel pharmacodynamic endpoints, including analysis of circulating endothelial progenitor cells, mature endothelial cells, circulating epithelial tumors cells and a wide range of rare immune subsets. This year we have analyzed over 120 patients for these parameters. Our analysis of circulating endothelial cell subsets in Our basic research on signal transduction pathways that can inhibit the growth of hormone-refractory prostate cancer cells led us to the identification of histone deacetylase as a critical target in this neoplasm. We have developed a novel pharmacodynamic assay for assessment of HDAC inhibitor activity in vivo. The NCI has applied for a patent on our work, which is uniquely capable of analyzing HDAC inhibitor activity in as little blood as in a finger-stick, and can look at combination therapy pharmacodynamic responses by examining 10 parameters simultaneously. We have implemented this technology in several published clinical trials (Gojo et al. Blood 109:2781-2790, 2007 and Kummar et al., Clin. Cancer Res. 13:5411-5417, 2007) and this year in a phase II trial of belinostat in thymic malignancies (J. Clin. Oncol., 29:2052-2059, 2011), in which we also published data using our pharmacodynamic assay for regulatory T cell (Treg) subsets. We have established a collaboration with Drs. Jay Bradner and Stuart Schreiber of the Broad Institute to use our technology to develop new HDAC inhibitors, and a collaboration with Dr. Michael Palladino of Nereus Pharmaceuticals to study HDAC inhibitors in combination with the novel Nereus proteasome inhibitor NPI-0052. This year we have a CRADA agreement with Syndax Pharmaceuticals to support HDAC inhibitor research in the lab. We have analyzed recent progress in HDAC as a molecular target in Current Opinion in Oncology (20:639-649, 2008) and we have reviewed progress in Hsp90 inhibitors in clinical trial in Curr Top Med Chem (9:1479-1492, 2009) and Nat Rev Cancer (10:537-549, 2011). This year we have also had a CRADA agreement with Macrogenics, Inc. for development and implementation of pharmacodynamic assays for the assessment of their Fcgamma receptor-optimized anti-HER2 therapeutic antibody MGAH22. The assays we have developed and implemented include molecular assessment of Fcgamma receptor polymorphisms conferring enhanced binding of IgG1 monoclonal antibodies. Working with surgeons in the Urologic Oncology Branch we have developed assays for rare immune subsets inflitrating the tumor microenvironment, and will be employing these assays in upcoming clinical trials in urologic malignancies where they have been written in as exploratory endpoints. We have been working intensively on development of a new platform for detection of circulating epithelial tumor cells, and we are currently implementing this endpoint in five open clinical trials.
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