The proposed research project is responsive to the overarching challenge to "develop effective treatments and address mechanisms of resistance for men with high-risk or metastatic prostate cancer" and to the focus area on "mechanisms of resistance" and "therapy." Prostate cancer is the most common male malignancy in the United States, with 233,000 cases, of which 20% to 30% have high-risk features, and 29,480 deaths are expected in 2014. For patents with high-risk prostate cancer, standard treatment is combined radiotherapy (RT) and androgen deprivation therapy (ADT). Despite combined therapy, eventually the tumor cells become resistant and regrow in approximately half of patients with high-risk prostate cancer. These key statistics highlight a critical unmet need to determine the causes of radioresistance and to identify means to improve long-term outcomes following combined RT and ADT.

Previous studies have shown that signaling driven by the androgen receptor regulates RT-induced DNA repair pathways and reduce the efficacy of RT. In addition, shortened forms of androgen receptor play a key role in the progression of the disease and development of resistance to treatment. Significantly, recent studies showed that increase expression of shortened forms of different genes is a critical mechanism for response to DNA damage. Because radiation relies upon DNA damage in tumors for its effectiveness, RT in high-risk PCa may regulate shortened forms of androgen receptor, which enables the prostate cancer cell to maintain critical DNA repair pathways and promote resistance to combined RT and ADT.

The objective of this application is to determine if expression of shortened forms of androgen receptor function as the determinant of response to combined RT and ADT in localized high-risk prostate cancer. In the study proposed here, the initial experiment will be to exam the expression of shortened forms of androgen receptor in surgical removed tissue samples from patients who failed combined RT and ADT. Then, biopsy samples that were originally taken before combined RT and ADT to diagnose the cancer will be analyzed for the presence or absence of shortened forms androgen receptor that may predict for sensitivity of combined RT and ADT. The patients selected to be studied will all have been treated 5 or more years ago, so it will be known whether or not their tumors were controlled with combined RT and ADT. The presence or absence of the shortened forms of androgen receptor in each patient's tumor will be compared with how well the tumor was controlled. It is hoped that strong relationships between shortened forms of androgen receptor and the success rate with combined RT and ADT will be identified. The functional significance of shortened forms of androgen receptor expression will be further tested by sophisticated molecular biology techniques in prostate cancer cell line and surgically removed human prostate tissues. If overexpression of shortened androgen receptor is confirmed to result in radioresistance, therapeutic approaches that target shortened androgen receptor will be tested to determine their radiosensitizing properties for combined RT and ADT.

This novel research may have a significant impact on the risk assessment and individualization of combined RT and ADT for high-risk prostate cancer patients. If successful, status of shortened forms of androgen receptor may be used to determine which patients should have treatment with combined RT and ADT and which patients should be spared the toxicity associated with combined RT and ADT. Additionally, this research would provide strong rationale for targeted radiosensitization of shortened androgen receptor-positive high-risk patients through inhibition of shortened androgen receptor, opening a realm of possible treatment options for these patients.