High Fidelity Drug Repurposing, Molecular Profiling, and Cell Reprogramming
Abstract
Despite decades of research into the causes and possible cures for prostate cancer, over 26,000 men die each year from this disease in the United States alone. While many of the studies performed over the years have identified important genes and signaling pathways involved in prostate carcinogenesis, the fact remains that due to the limited and suboptimal prostate cell lines available for correlative analyses, significant unmet needs exist in validating clinical findings. Confounding the need to effectively treat prostate cancer, the development, phased clinical testing, and finally Food and Drug Administration (FDA) approval can take decades, and over 90% of the compounds tested fail to become approved drugs. Quite possibly, the only useful and valid tissue for understanding prostate cancer and designing effective treatments is the patients own cells. However, the long-termed culturing of prostate epithelial cells has not been previously possible without drastic modifications to the cellular and genetic machinery, such as transformation with powerful oncogenes, irreversibly compromising the integrity of the cells and hence the data itself. Furthermore, thousands of FDA-approved and experimental drugs are available that, if properly interrogated and tested, could, in theory, be "repurposed for treating prostate cancer." We have developed two groundbreaking methodologies that allow for the first time: (1) the establishment of stable, long-term cultures of both normal and cancerous prostate epithelial cells, termed conditionally reprogrammed cells (CRCs) and (2) the identification of approved drugs though the in silico prediction of new targets for the drug using a platform referred to as Train, Match Fit and Streamline (TMFS). We have shown that TMFS can accurately predict the efficacy of the anti-malarial mebendazole to inhibit several kinases (e.g., VEGFR2) and confirmed this using patient-derived melanoma cells. Also, our TMFS modeling data predicted that combining mebendazole with a MEK inhibitor trametinib would suppress the observed resistance to each drug alone. We found that mebendazole synergizes with trametinib to inhibit the growth of drug-resistant human melanoma cells in vitro and in vivo as xenografts. With support from the Department of Defense, we now have seven matched sets of normal and malignant prostate cells growing as CRCs, and expect at least 10 more over the next 2 years. Also, in 2012, we established that the CRC approach could be rapidly (14 days) used for identifying a "repurposed" drug, vorinostat, for the successful treatment of a lethal case of recurrent respiratory papillomatosis. The patient remains alive to date. Our proposal will link our in silico approved drug repurposing software and databases with our breakthrough CRC technology to hopefully allow for bedside to bench to bedside personalized cancer treatments for all stages of the disease and, when applied to early-stage disease, may eventually delay or negate the need for androgen depravation therapy, the major cause of the progression to lethal androgen-independent prostate cancer. Success in our proposal, we firmly believe, will establish the CRC technology in combination with TMFS as a viable new approach for personalized prostate cancer research and treatment. Since the drugs identified and validated in the CRCs will all be FDA-approved, rapid translation into the clinic is highly anticipated.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510288
Entities
People
- Christopher Albanese
Organizations
- Georgetown University
- United States Army