Novel Therapeutic Approaches for Aggressive Prostate Cancer

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Summary The goal of this proposal is to develop a novel therapeutic strategy for the treatment of neuroendocrine prostate cancer (NEPC) that has the potential for translation to the clinic. NEPC is an aggressive form of prostate cancer that is associated with rapid progression, resistance to treatments and a very poor outcome. Currently, there are no effective therapies for treating NEPC. This revised proposal focuses on the hypothesis that programmed cell death 1 ligand (PD-L1) has a causal role in the stemness and metastatic propensity associated with NEPC. Although PD-L1 is best known for its role in immune suppression, its tumor cell intrinsic functions that are independent of immune suppression can also contribute to cancer progression. Specifically, PD-L1 has been implicated in tumor stemness, invasion and metastasis and there is circumstantial evidence that it contributes to these functions in NEPC, although a causal role has yet to be demonstrated. This novel function of PD-L1 can be exploited to improve the therapy of NEPC based on compelling evidence that VEGF/NRP2 signaling sustains the expression of PD-L1 in prostate cancer. Inhibiting VEGF/NRP2 reduces stem cell properties and promotes a more differentiated phenotype that is more susceptible to chemotherapy, and it is likely that the mechanism involves reducing PD-L1 expression. Also, a humanized mAb is available that inhibits the binding of VEGF to NRP2. This mAb does not cause toxicity in mice and non-human primates and is being manufactured for use in clinical trials. Of note, this mAb diminishes the expression of PD-L1 significantly in models of NEPC. Together, these observations formulate a central hypothesis: PD-L1 has a causal role in NEPC by sustaining stemness and facilitating metastasis (cell autonomous PD-L1 function) and by promoting immune cell evasion (non-cell autonomous PD-L1 function). Both critical functions of PD-L1 can be blocked by therapeutic targeting of VEGF binding to NRP2 to improve the morbidity and mortality associated with NEPC. The first specific aim will investigate a therapeutic strategy for inhibiting tumor cell intrinsic functions of PD-L1 to mitigate stemness and metastasis in NEPC that involves blocking the binding of VEGF to NRP2. The second aim will investigate therapeutic strategies that target PD- 1-dependent and PD-1-independent functions of PD-L1 in NEPC by blocking the binding of VEGF to NPR2 using immune competent models. The data generated in this proposal have the potential to provide sufficient evidence to justify the initiation of clinical trials using NRP2 inhibitors, especially the function-blocking Abs that are the focus of the experimental approach.