Antagonizing CD105 Can Support Radiation Sensitivity in Prostate Cancer
Abstract
Prostate cancer is the second leading cause of cancer in men. Radiation therapy is an option for nearly half of the patients with localized advanced prostate cancer and is an adjuvant therapy for patients that undergo surgery. Multiple randomized trials have shown that higher radiation doses leads to improved disease-free survival in prostate cancer patients. However, administration of higher doses of radiation has also been shown to increase toxicity to non-cancerous tissue. The inability to administer higher doses has been an obstacle in radiotherapy, making the need to identify a co-therapeutic a necessity. Another obstacle is that prostate cancer can be supported by surrounding non-cancerous fibroblasts. The objective of this proposal is to determine whether CD105 is involved in radiation resistance and whether targeting CD105 in prostate cancer and surrounding fibroblasts could be a feasible co-therapy. Rationale: CD105 is highly expressed in prostate cancer and fibroblasts surrounding prostate cancer compared to benign tissue. In our hands, we also see an increase in CD105 expression when we treat prostate cancer cell lines or prostatic fibroblasts with radiation. We rationalized that the increased CD105 expression in aggressive cancers and when cells are treated with radiation may be a mechanism by which prostate cancer undergoes radiation resistance. Further, our preliminary data show that increased CD105 expression during radiation results in changes in metabolism. Cancers are reliant on metabolic changes that aid in their growth, leading to survival and progression of the disease. We propose using a first-in-line therapeutic, TRC105, to target CD105. TRC105 has undergone a number of Phase I clinical trials in cancers, including prostate cancer, and has been shown to be safe for patients. Further, TRC105 is currently in a Phase I trial at Cedars-Sinai in combination with anti-hormonal therapy for advanced prostate cancer. This makes the findings of this proposal extremely applicable to the clinic. Findings from this proposal can determine the feasibility of TRC105 and radiation co-therapy in patients. I have had a long vested interest in prostate cancer resistance. My first exposure to prostate cancer research was as an undergraduate where I studied prostate cancer resistance to anti-hormonal therapy. I went on to study the resistance of prostate cancer to conventional therapeutics such as chemotherapy during my master?s thesis. I joined Cedars-Sinai Graduate Program in Biomedical and Translational Research due to its strong focus in prostate cancer research. My goal upon completion of my doctoral degree is to join a prostate cancer metabolism laboratory as a post-doctoral scientist. The proposed project will give me the necessary skills and conceptual knowledge in understanding prostate cancer metabolic changes as a mechanism for resistance. I will be guided by my mentor, Dr. Neil Bhowmick, who is the Director of the Cancer Biology Program at Cedars-Sinai and has expertise in how the tumor microenvironment, such as fibroblasts, influences the progression of prostate cancer. Additionally, I will be co-mentored by Dr. Roberta Gottlieb who is an expert in metabolism and is the Director of the Metabolism and Mitochondria Core at Cedars-Sinai. With these resources at our disposal, we will be able to confidently dissect the role of CD105 in radiation resistance.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710125
Entities
People
- Anisha Madhav
Organizations
- Cedars-Sinai Medical Center
- United States Army