Scientific Objective and Rationale: There are two major issues in the field of prostate cancer that need to be addressed through basic and translational research. First, we lack the ability to predict which men will go on to have aggressive, lethal prostate cancer and which men will survive with relatively indolent tumors. The standard treatment for men with advanced disease is hormonal (androgen-deprivation) therapy, which causes tumors to shrink but is not curative. Tumors grow back into the form of the disease called castration-resistant prostate cancer. The second important issue in the field is the lack of effective treatments that can prolong life for men who have lethal castration-resistant prostate cancer.

One way to tackle both issues is to determine which type of cell in the tumor is most responsible for generating aggressive, lethal prostate cancer. When patients undergo biopsy for prostate cancer at an early stage, perhaps the presence or abundance of that cell in biopsy tissues would predict the outcome of the tumor. Importantly, targeting and eliminating that cell would likely prevent the development of lethal disease.

Our laboratory has recently identified a type of cell (intermediate luminal progenitor) that has an incredible capacity to grow and importantly does not depend on androgen for survival, suggesting that hormonal therapy does not target this cell. Therefore, these surviving cancer cells may be able to regenerate the tumor in the lethal castration-resistant form.

In this proposal, we will test the hypothesis that intermediate luminal progenitor cells in prostate cancer can survive castration and regenerate castration-resistant prostate cancer. We will then develop methods to both detect and target these cells in tumors.

Clinical Applications: We predict that having an increased number of these intermediate luminal progenitor cells in early-stage tumors will predispose that patient to aggressive disease, as these cancer cells cannot be targeted by standard therapies. The results from this study may lead to the further development, validation, and clinical use of biomarkers to help predict aggressive from indolent disease in the next 3-5 years. Such clinical applications would be relevant for men with early-stage tumors deciding between surgical procedures or watchful waiting.

We hypothesize that elimination of these cells through specific targeted therapies in combination with hormonal therapy will prevent or delay the onset of castration-resistant prostate cancer. As we have found luminal progenitor cells to express therapeutic targets already being tested in clinical trials for other malignancies, our studies could accelerate the use of these agents in prostate cancer trials in the next 5-10 years for men with advanced prostate cancer.

Contributions to the Field of Prostate Cancer Research: Identifying the cells that survive hormonal therapy and contribute to the re-growth of tumors in the castration-resistant form will significantly advance the field of prostate cancer research and allow other investigators to study mechanisms used by these cells to escape hormonal therapy. Importantly, this finding will allow researchers who specialize in therapeutic targeting to test drugs and other inhibitors for the ability to eliminate these cells.