Cotargeting the Trinity of DNA Damage Repair Sensing Kinases in Prostate Cancer
Abstract
For one-half of the ~25,000 American men each year diagnosed with high-risk, organ-confined prostate cancer, definitive local management with surgery and/or radiation and androgen deprivation therapy can be curative. However, for the other 50%, biochemical recurrence and disease progression to incurable metastasis is common, with significant risk of morbidity and mortality. There is a significant unmet need for more effective and curative therapies for this large cohort of men. Therapies like radiation and chemotherapy cause cell death by damaging and causing breaks in the DNA of the prostate cancer cell. If unrepaired, this DNA damage makes the cancer cell undergo programmed cell death or apoptosis. However, the prostate cancer cell has an enhanced DNA damage repair mechanism that enables repair of the radiation-induced DNA damage and allows the cancer cell to survive. Strategies to block DNA damage repair in cancer cells can enhance DNA damage and increase cancer cell death. Prior studies have identified that three protein kinases known as ATM, ATR, and DNA-PKc are known to be important in DNA damage repair within the cancer cell. Our preliminary data indicate that, in prostate cancer, these three protein kinases are functionally redundant and that any one active kinase can adequately compensate for the loss of the other two kinases. Our findings imply that only therapeutic strategies that effectively knock out all three kinases can ensure that DNA damage is not repaired and have clinical utility in prostate cancer. However, combination therapies with inhibitors of these protein kinases is likely to be limited by toxicity and a novel approach to targeting all three kinases is necessary. We have identified that a novel compound, named Compound B, that targets a protein called RUVBL1/2 also dramatically decreases the expression of all three protein kinases: ATM, ATR, and DNA-PKc. We have shown that pretreatment of cancer cells with Compound B blocks DNA damage repair in cancer cells and increases cell death after radiation. Compound B has favorable pharmacologic properties, can be orally given to mice safely, and is not toxic. Further, Compound B appears to enhance the immunogenic profile of the cancer cell, such that it can be recognized and cleared by the body’s immune system. We thus hypothesize that the addition of Compound B to DNA damaging agents such as radiation or chemotherapy will enhance the likelihood of cancer cell kill and immune clearance. In this grant, we will systematically examine the effect of Compound B on the expression of all three protein kinases, DNA damage repair, induction of cell death, and the immunogenic profile of the cancer cell in multiple preclinical models of prostate cancer. We will validate the effect of Compound B in combination with radiation therapy or chemotherapy in animal models. We will examine preclinical models where the immune system is intact to evaluate whether the effect of Compound B in making the tumor cell more immunogenic translates into an immune response. Our studies will establish the preclinical basis for translation of our findings to clinical trials. Our overall goal is to enhance the effect of DNA damaging agents in prostate cancer. For the man with high-risk, clinically localized prostate cancer, our findings could translate into the addition of RUVBL1/2 inhibitors to radiation therapy. Our studies are applicable for men with advanced metastatic prostate cancer, and the addition of RUVBL1/2 inhibitors to chemotherapy may enhance cancer cell kill and increase the response to chemotherapy. Overall, our project has the potential to significantly enhance the outcome of men with prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110687
Entities
People
- Ganesh V Raj
Organizations
- United States Army
- University of Texas Southwestern Medical Center