I have recently started my postdoctoral fellowship in the well-respected prostate cancer laboratory of Dr. Karen Knudsen. I find it thrilling to work in the field of cancer research, in which I have actively participated for the past 6 years. The training environment at the National Cancer Institute-designated Thomas Jefferson University Kimmel Cancer Center is outstanding for investigators who wish to do real bench-to-bedside research, such as myself. It provides many training opportunities to improve my experimental approach, interpretation of results, and presentation skills. I am surrounded with many scientific experts and prostate cancer clinicians, with whom I have continuous dialogue about my project and the field of prostate cancer in general. This helps sharpen ideas and translate lab results into the clinic. The support of the Department of Defense Prostate Cancer Research Program Postdoctoral Training Award would set a solid basis for what will hopefully prove to be a successful and rewarding career in prostate cancer research.

Prostate cancer (PCa) is the most commonly diagnosed malignancy in the United States and second leading cause of male cancer death. Patients with prostate cancer that has not spread can often be cured with surgery or radiation. However, if the cancer has spread outside the prostate into surrounding tissue or to distant sites in the body, other measures need to be taken to try to stop tumor growth. The most common approach is hormone therapy, such as by hormone treatment (e.g., Casodex), which is effective in preventing recurrence of disease for 2-3 years. Unfortunately, many patients relapse and present with hormone therapy resistant cancer, also called castration resistant prostate cancer (CRPC). Only limited treatment options are available for these patients to prolong life, but they ultimately succumb to this more aggressive cancer growing and spreading throughout the body.

This proposal focuses on the RB tumor suppressor, which has potential to dramatically improve the overall survival and quality of life for patients with recurrent disease. We have observed that many CRPC patients have lost RB tumor suppressor function in the tumors. In general, prostate cancer responds poorly to chemotherapy, but we suspect that this group of patients could be more sensitive to certain types of chemotherapy, such as docetaxel (Taxotere) and cabazitaxel (Jevtana). Loss of RB likely decreases the ability of the tumor cell to repair DNA damage induced by these drugs, thereby killing the cells and stopping tumor growth.

This idea will be explored in two main approaches. First, we need to understand better how RB is lost and how this change processes in the tumor cell in such a way that it ultimately leads to hormone therapy resistance. RB controls androgen receptor (AR) activity, which is the protein that is targeted by hormone therapy. When RB is lost, AR becomes insensitive to hormone therapy and elevates other proteins that are responsible for the more aggressive cancer. Better knowledge on what these proteins are will aid in formulating new treatment strategies to increase survival chances for these CRPC patients. We will use PCa cell lines to study changes by removing RB protein and will validate this in animal models, which are more relevant for translational cancer research. Second, we will test different treatment regimens on PCa cells and animal models. We expect that cabazitaxel will effectively block tumor growth when RB is removed. Moreover, when RB is not removed, it can potentially be hyperactivated by a kinase inhibitor, thereby preventing hormone therapy resistance. The results from these experiments are easily translatable to the clinic. First, we will validate these therapeutics on actual tumor material in the lab. Second, we will compare our results with a clinical trial that is running in parallel.

This proposal presents exciting research with outcomes that will directly and rapidly influence treatment options for patients with recurrent, hormone therapy resistant prostate cancer. It provides a means to define which therapeutic strategy is most likely to be successful for the individual patient. Moreover, unnecessary treatment with drugs that are unlikely to be beneficial can be avoided, and hence also their potential adverse side effects. Taken together, patients will directly benefit, as these studies should result in significant increase in survival and quality of life.