Scientific Objective/Rationale: Prostate cancer is the most common non-skin cancer for men in the United States. About 1 man in 6 will be diagnosed with prostate cancer during his life time, and about 1 man in 36 will die of prostate cancer. Prostate cancer is a complex disease. Similar to many other cancer types, prostate tumors are not simply clones of cancer cells. Instead, they represent biologically abnormal organs composed of a variety of cell types and biological molecules as well as cellular matrix that hold them together. Abnormal tumor cells together with other cells and molecules inside a tumor compose the tumor microenvironment. The non-tumor cells, or stromal cells, interact with tumor cells to either prevent or promote tumor growth, invasion, and spread to other organs. Among the stromal cells, one cell type called myeloid-derived suppressor cell is increasingly recognized as an essential regulator of the immune system. These cells increase in number dramatically inside the tumor and block the tumor-killing activity of T cells, a major cell type for adaptive immune response in human. Myeloid-derived suppressor cells can also directly signal to and activate tumor cells. Therefore, if we can target and eliminate these cells, tumors are likely to be killed by the immune system or decline directly. However, it is unclear how prostate tumor cells recruit and activate myeloid-derived suppressor cells within the tumor microenvironment. It is also unclear what the best molecular targets are for these cells. Our goal is to find answers to these questions by using our unique animal model of aggressive prostate cancer and a variety of modern biomedical technologies. We will validate our findings from animal models using human prostate cancer samples, so the molecules that we discover as promising prognostic markers or therapeutic targets will have solid clinical evidence.

Applicability of the Research: Our proposed research is to identify the key molecules mediating signaling and interactions between tumor cells and myeloid-derived suppressor cells, and we will demonstrate that by showing that if we block these molecules we will be able to cause significant shrinkage or elimination of the prostate tumors in our preclinical models. Our ultimate goal is to translate our findings into prognosis or treatment of aggressive prostate cancer including the relapsed cancer after androgen-deprivation therapy. Our strategy of targeting a crucial component of the tumor microenvironment is distinct from the common prostate cancer therapies, like hormone therapy, radiation therapy, or surgery. Therefore, its application may offer a unique complement to the current limited options of prognosis and treatment of patients with advanced prostate cancer. While our approach is expected to have general anti-tumor effect for prostate cancer, we envision it may offer a particular benefit to patients undergoing sipuleucel-T treatment, an immunotherapy recently approved by the U.S. Food and Drug Administration. Because myeloid-derived suppressor cells represent a potent suppressive mechanism for immune system, targeting them is expected to improve the benefits one can get from an immunotherapy.

Within the 3-year period of the proposed study, we will reach our conclusions based on extensive functional validations using preclinical animal models and correlation-based clinical validations. Afterwards, we will spend one more year to collaborate with clinicians at MD Anderson Cancer Center and leverage the clinical resources to further corroborate the clinical value of the study. Next, we will seek the opportunity to register our identified molecule(s) in a clinical trial as either prognostic marker or drug target for lethal prostate cancer at MD Anderson Cancer Center. Therefore, although we are proposing a basic research project, our keen pursuit to realize its clinical application in prostate cancer patient care will drive the bench-to-bedside process in a minimal time, estimated within 5 to 10 years.

Contributions of this proposed study to prostate cancer research. Prostate cancer research has been driven by focusing on tumor cells, in particular, how androgen signaling controls tumor growth and shapes resistance. This tumor cell centric view of cancer has now been shifted to an integrative view of cancer as a complex organ with non-cancer cells playing crucial roles in impacting tumor growth and response to treatment. Our study will represent a first effort to extensively and systematically elucidate the function and molecular mechanisms of myeloid-derived suppressor cells in prostate cancer. Knowledge gained from the proposed study will tremendously enrich and improve the conceptual framework of tumor microenvironment in prostate cancer, and stimulate follow-up studies on more specific details of targeting myeloid-derived suppressor cells as a viable approach to prostate cancer therapy. An additional benefit of the proposed study is that the approach to the tumor-stroma interaction network, including the animal modeling methodology and bioinformatics pipeline, will be valuable tools for the prostate cancer research community.