Targeting the Unique Biology of Ductal Prostate Cancers Using Poly ADP-Ribose Polymerase (PARP) Inhibitor and Androgen Signaling Inhibitor Combination Therapy
Abstract
Ductal prostate cancer (DAC) is an aggressive type of cancer occurring in up to 12% of all prostate tumors. When present in a prostate tumor, DAC causes a poor response to traditional treatments such as surgery, radiation, and hormonal treatment. Even in its early stages, DACs have properties similar to very advanced prostate cancers causing early spread (metastasis) into organs such as the lung and are almost universally fatal. Therefore, understanding the cellular pathways driving these ductal cancers is crucial in treating this disease. Dysfunction of the DNA damage repair pathway in particular is seen in approximately half of the patients with ductal prostate cancer. A type of medication called PARP enzyme inhibitors has been used successfully in patients with other cancers (including prostate cancer) who have dysfunction of the DNA damage repair pathway. Our preliminary work has also shown that, when combined with newer-generation hormone therapies, these PARP enzyme inhibitors effectively kill DAC cells even when there is no dysfunction of the DNA damage repair pathways. Therefore, we hypothesize that targeted treatments with PARP enzyme inhibitors with newer-generation hormone therapies can improve the response of DACs. Contributions of This Study to PCRP Overarching Challenges: No current therapies effectively treat these lethal DACs. This study will provide an understanding of its biology, identify any genes driving these cancers, and assess whether targeted PARP enzyme inhibitor therapy with hormone therapy can be used to treat these lethal cancers. If proven to be effective, these already FDA-approved treatments can help improve the effectiveness of surgery when treating patients with DAC and improve survival. A clinical trial for using these medications for DAC before surgery has already been planned and is awaiting this data so that it can be readily expedited at a large tertiary U.S. academic center that regularly treats patients with DAC. Ultimate Applicability of the Research: What Types of Patients Will It Help? Our research will benefit patients with DAC who are highly likely to spread and die from their disease. How Will It Help Them? Our study will identify whether the targeted therapies of PARP enzyme inhibitors combined with newer generation hormone therapies are successful in treating patients with DAC. Potential Clinical Applications, Benefits, and Risks. PARP enzyme inhibitors combined with newer-generation hormone therapies have already been successfully used in clinical trials. Therefore, if our results demonstrate that these therapies can effectively treat DACs, this will help start an already designed clinical trial where patients with DAC can receive these therapies before surgery to improve the outcomes of surgery and survival of the patients. Projected Time to Achieve a Patient-Related Outcome. In 3 years, we will know whether using PARP inhibitors with hormone therapy can target DACs. Our collaborative large tertiary academic center has a history of rapidly translating scientific advances to clinical trials in men with DAC, so our results could lead to patient benefit soon after completion of our studies, should they prove successful. Principal Investigator (PI) Career goals: The PI is a surgeon-scientist (urologist) who has expertise and has published high-impact papers in the field of DAC. He currently holds several academic, clinical, local, and national leadership roles and actively engages in prostate cancer consumer groups. His short-term academic goal is to build on this project to establish a fully functional scientific lab and a 10-year plan for achieving an international leadership role in urology with a professorial appointment at an academic center. Research Plan: The primary mentor holds professorial appointments at two of the country s top eight universities and has more than 30 years of scientific research experience. The PI’s co-ment
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310225
Entities
People
- Weranja Ranasinghe
Organizations
- Monash University
- United States Army