ZIC SC 006743 (ZIC) | |||
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Title | Signal Transduction Events and the Regulation of Cell Growth | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Trepel, Jane | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $609,397 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2017 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Interferon (1.0%) Metastasis (45.0%) |
Breast (14.0%) Esophagus (1.0%) Kidney Cancer (15.0%) Kidney Disease (15.0%) Leukemia (10.0%) Lung (30.0%) Prostate (30.0%) Urinary System (15.0%) |
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Research Type | |||
Technology Development and/or Marker Discovery Systemic Therapies - Discovery and Development |
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Abstract | |||
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 encompasses preclinical and clinical translational research through the translational drug development facility that I have established. Our work is currently focused on development and implementation of pharmacodynamic (PD) assays for targeted therapy trials, including assays for response to histone deacetylase inhibitors, Hsp90 inhibitors, kinase inhibitors including sunitinib, cabozantinib, the Chk1/2 inhibitor prexasertib, the ATR inhibitor VX-970, PARP inhibitors, the androgen receptor modulator enzalutamide, multiple therapeutic antibodies, including an immunotoxin and the first-in-class photoimmunotoxin, multiple vaccine therapies, and cytotoxic drugs, including MM-398 (nanoliposomal irinotecan), CRLX101 (nanoparticle camptothecin) and the HSP90 inhibitor-SN38 drug conjugate PEN-866. The PD assays we have developed include assays for 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 (J Urol 195:1136-1142, 2016). 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. 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 enzalut |