Targeting Proliferating Cell Nuclear Antigen for Enhancing Efficacy of Radiotherapy in Prostate Cancer
Abstract
Androgen receptor signaling is required for growth and survival for most prostate cancer cells. Radiotherapy combined with long-term androgen deprivation therapy (ADT) targeting androgen receptor activity is currently the standard of care for patients with high-risk and very high-risk prostate cancer. The combination therapy is also used for management of other advanced prostate cancer, such as postoperative adjuvant therapy for metastatic prostate cancer and oligometastatic prostate cancer. It becomes clear now that although ADT by inhibition of androgen synthesis or blockade of androgen receptor activity is very effective initially, almost all tumors progress to castration-resistant prostate cancer (CRPC). The current ADT approaches often lead to the overexpression of androgen receptor or expression of the mutated constitutively active androgen receptors that do not require androgen stimulation, which cause therapy failure. Importantly, most CRPC cells still rely on androgen receptor activity for growth and survival, while no therapy currently is available targeting the constitutively active androgen receptors for prostate cancer therapy. Therefore, there is an urgent need to develop new approach for targeting androgen receptors. Proliferating cell nuclear antigen is a protein essential for cell growth and survival as well as DNA repair. It is overexpressed in all cancer cells. Our recent studies show that it interacts with androgen receptor, including the mutated constitutively active androgen receptor, leading to an elevated androgen receptor activity. We have developed a series of novel small molecules and a peptide that inhibit the function of proliferating cell nuclear antigen. Targeting proliferating cell nuclear antigen using the small molecule PCNA-I1S and a peptide R9-AR- PIP blocks the activities of both androgen receptor and the constitutively active androgen receptors, inhibits the expression of androgen receptor regulated genes, and prostate cancer cell growth. Given that both proliferating cell nuclear antigen and androgen receptor are involved in DNA repair, the proposed research will develop novel therapies that targeting proliferating cell nuclear antigen using the small molecules and a peptide to sensitize prostate cancer to radiotherapy. Unlike the current ADT and most androgen receptor inhibitors are not effective in CRPC expressing the mutated constitutively active androgen receptors, our novel approach will not only provide a more efficacious ADT, but also prevent the development of CRPC. Since prostate cancer cells, especially advanced prostate cancers, overexpress both the mutated constitutively active androgen receptors and proliferating cell nuclear antigen, this novel combination therapy will preferentially inhibit androgen receptor activity in cancer cells and, therefore, produce much fewer side effects relative to those caused by the current ADT and should significantly improve the life quality of patients with high-risk prostate cancer and advanced prostate cancer. This research addresses the FY21 PCRP Overarching Challenges to improve quality of life to enhance outcomes and overall health and wellness for those impacted by prostate cancer and to develop treatments that improve outcomes for men with lethal prostate cancer with focus areas of impacting quality of life considerations on decision-making after diagnosis and/or treatment for patients with high-risk PC and CRPC. The small molecule proliferating cell nuclear antigen inhibitor and peptide inhibitor used in the therapy studies were developed in our laboratory. Our institution was granted with a US patent (serial no. 9,895,363, 2/20/2018) for cancer therapeutic application of the small molecule proliferating cell nuclear antigen inhibitors. A provisional patent application (#63129052) was recently filed by our institution for the development and cancer therapeutic applications of this novel peptide. Moreover,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210815
Entities
People
- Zhongyun Dong
Organizations
- United States Army
- University of Cincinnati