Combining Targeted Radionuclide Therapy and Epigenetic Regulators for the Treatment of Castration-Resistant Prostate Cancer
Abstract
Prostate cancer remains a leading cause of cancer-related death in men in the United States. Although most patients initially respond very well to chemical castration with drugs that lower body’s testosterone levels, eventually, cancer comes back in nearly all men treated. Recurring tumors typically reappear at various places around the body, showing more aggressive traits like resistance to chemical castration. This stage of the disease, which is called metastatic castration-resistant prostate cancer mCRPC, is the lethal form of prostate cancer. Because more than half of mCRPC patients die within three years despite intense chemotherapy, there is an urgent need for better treatments that can treat this stage of disease more effectively. Therefore, our goal is to develop a highly effective therapy regime that will eradicate lethal mCRPC. To achieve this goal of eliminating the mortality of mCRPC, we will implement an innovative therapy approach combining a cancer-seeking radioactive drug with two other drugs that sensitize cancer cells to radiation. Sensitizing tumor cells to radiation will be attained by administering a combination of drugs that block PARP and BET, two proteins that play an essential role in repairing DNA damage. Although blocking of PARP and BET can kill tumor cells on its own, because these two drugs are non-tumor selective, normal cells can also be affected, limiting the utility of this treatment. Our realization that PARP and BET blocking combination lacks a third fundamental component granting tumor selectivity to the treatment is the major innovation of this proposal. Using an injectable radioactive drug (IRD) that finds and binds a protein that is only present in tumor cells, we can selectively deliver significant amounts of DNA damaging radiation to tumors without affecting surrounding normal tissues. Therefore, the radiation sensitizing effects of PARP + BET blocking will be leveraged by IRD exclusively in tumor cells instead of normal cells. This proposal sets out to investigate whether this triple combination of IDR with PARP + BET blocking is the ideal treatment that eradicates mCRPC. This combination therapy is highly innovative as the radiosensitizing potential of PARP + BET blocking has not been explored to date. We anticipate that our proposed combination therapy will improve survival and quality of life of mCRPC patients by (1) leveraging the synergy between BETi, PARPi, and IRD; (2) reducing toxicity compared to other chemotherapies; and (3) overcoming resistance to current standard therapies. We also anticipate that this treatment can transgress the mCRPC setting and become a viable therapeutic option for all aggressive prostate cancers. Importantly, since the three drugs employed in our treatment combination are either FDA-approved or in advanced stages of clinical testing, our approach has immediate clinical relevance to mCRPC patients. It is conceivable that upon demonstrating therapeutic benefits, evaluation of this combination in clinical trials could follow reasonably quickly. Our purpose is that animal data garnered in this proposal will be informative to those trials on how to combine the treatments optimally to achieve cure in mCRPC patients. Additionally, it will study any toxicities associated with the combination of radiosensitizing PARP + BET blocking and IRD to shed light on potential organs at risk. This information is paramount to guaranteeing the successful approval and clinical adoption of this paradigm. Given that mCRPC is responsible for most prostate cancer-related death, our proposal tackles a major unmet clinical need in prostate cancer. Our combination approach can have a considerable impact on the current management of mCRPC by allowing these patients to respond and benefit from potentially curative combination therapy. Since our proposal seeks to expand our understanding of prostate cancer radiobiology and devise improved therapeutic st
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110729
Entities
People
- Reinier Hernandez
Organizations
- United States Army
- University of Wisconsin–Madison