Treatment of Radiation Proctitis in Prostate Cancer Patients with a Novel Inducer of Autophagy
Abstract
Prostate cancer is the most common cancer diagnosis among U.S. male Veterans and military members, with over 12,000 new diagnoses annually. Prostate cancer is commonly treated with radiation delivery to the pelvis. An unfortunate but common complication of radiation treatment is chronic inflammation of the rectum, which is located adjacent to the prostate. Therapeutic options are limited for inflammation of the rectum, also called radiation proctitis. Furthermore, little is known about how radiation proctitis develops. Thus, there is a critical need to develop novel strategies to protect normal rectal tissue from radiation during pelvic radiotherapy and to treat chronic radiation proctitis. Autophagy is a basic biological process by which cells break down their own components that are not working or are not needed. Accumulating evidence suggests that defective autophagy contributes to the development of inflammatory bowel disease, a disorder that is similar to radiation proctitis. Therefore, we predict that compounds that induce autophagy in the rectum will effectively treat radiation proctitis. With this goal, we developed a novel autophagy inducer compound named DK520. DK520 is a prodrug of a Food and Drug Administration-approved anthelminthic drug called niclosamide. DK520 is metabolized into niclosamide after administration by mouth and has an excellent safety profile in animal studies. We found that DK520 effectively treats a mouse model of colitis and potently induces autophagy in intestinal tissue. We also developed a new way to study radiation proctitis in mice that is very similar to human disease. We hypothesize that radiation causes defects in autophagy, and DK520 induces autophagy and effectively treats radiation proctitis. In this application, we will use our mouse model of radiation proctitis and patient-derived rectal cultures to study how autophagy contributes to the development of radiation proctitis, and the effectiveness of DK520 in treating radiation proctitis. Our results will have an important positive impact by providing scientific justification of developing DK520 to treat radiation proctitis in prostate cancer patients. This project will directly address two of the FY19 PCRP Overarching Challenges: (1) improve the quality of life for survivors of prostate cancer and (2) develop treatments that improve outcomes for men with lethal prostate cancer. By completion of this project at year 3, we will begin Phase I/I clinical trials for treatment of radiation proctitis in prostate cancer patients with DK520. This process will be accelerated because DK520 is a derivative of a safe and commonly used medication (i.e., niclosamide).
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010203
Entities
People
- Jatin Roper
Organizations
- Duke University
- United States Army