This project is designed to develop new approaches 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 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 most men treated with hormonal therapy will progress to a castrate-resistant state (CRPC). Once CRPC develops, treatment options are limited and median overall survival is currently approximately 32 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. 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 the Hsp90-AR-FKBP52 complex 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 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. These compounds have the ability to cause degradation of AR splice variants characteristic of CRPC and are cytotoxic to CRPC cells driven by ligand binding domain (LBD) mutant AR and splice variant AR. In addition, we performed SAR studies on a novel series of dihydropyridones and identified an antiandrogen with potency comparable to enzalutamide (J Med Chem 56:8280-8297, 2014). (2) The Preclinical Development Core has been working with intramural, extramural and industry investigators on a range of phase I, phase II and phase III clinical trials. I am an Associate Investigator on 50 clinical trials either open to accrual or open for analysis this year. 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 tumor cells (CTCs) and a wide range of rare immune subsets, as well as various molecular analyses. This year we have analyzed over 300 patients for these parameters. Our analyses of circulating endothelial cell subsets, circulating tumor cells and rare immune subsets including analysis of immune checkpoint receptor expression have shown statistically significant correlation with clinical outcome in phase I and phase II trials. 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, Kummar et al., Clin. Cancer Res. 13:5411-5417, 2007), 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, and in a randomized phase II trial of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor (J. Clin. Oncol. 31:228-2135, 2013). This year this assay is being tested as a predictive biomarker of HDAC inhibitor plus exemestane response in a randomized phase III trial of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. 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 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), Nat Rev Cancer (10:537-549, 2011) and Clinical Cancer Research (20:275-277, 2014). This year we have also had a CRADA agreement with Macrogenics, Inc. for development and implementation of pharmacodynamic assays for the assessment of their Fc 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 and medical oncologists in the Genitourinary Malignancies Branch we have developed assays for rare immune subsets infiltrating the tumor microenvironment, and we are employing these assays in a clinical trial in a randomized phase II study of androgen deprivation therapy and radiation therapy with or without Stimuvax vaccine in high-risk prostate cancer. We have been working intensively on development of a new platform for detection of circulating epithelial tumor cells (CTCs), and we are currently implementing this endpoint in 24 clinical trials.
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