Awardees

Mengdie Wang  |  Mercurio Research Group  |  U.S. Department of Defense Prostate Cancer Research Program, Early Investigator Award

Neuroendocrine prostate cancer (NEPC) is an aggressive form of PCa that is associated with rapid progression, drug resistance and a very poor prognosis. It most commonly evolves from pre-existing adenocarcinoma by upregulation of regulators that drive stemness and lineage plasticity in response to pressure from therapies. Our lab discovered that vascular endothelial growth factor (VEGF) signaling in tumor cells is mediated primarily by neuropilins-2 (NRP2). VEGF/NRP2 signaling contributes to stemness associated with aggressive cancer cells. Interestingly, the genes for NRP2 and VEGF-A are significantly amplified in NEPC.  Further, VEGF/NRP2 signaling regulates programmed cell death 1 ligand (PD-L1), which contributes to tumor progression cell-autonomously by promoting stemness and inhibiting anti-tumor immunity non-autonomously. Currently, there are no established therapies for treating NEPC. Importantly, treatments that can reverse stemness could sensitize NEPC cells to therapies. NRP2 can be an effective therapeutic target using function-blocking Abs, making it a promising target to reduce the aggressive behavior of NEPC and sensitize it to other therapies. I hypothesize that VEGF/NRP2 signaling contributes to the aggressive behavior of NEPC by sustaining the expression of PD-L1, which contributes to both stemness and immune evasion. Consequently, targeted inhibition of NRP2 is a promising therapeutic strategy for NEPC to inhibit stemness, activate anti-tumor immunity and synergize with PD pathway blockade. The objective of this proposal is to understand the role of VEGF/NRP2 signaling in regulating stemness and aggressive behavior of NEPC cells and to develop new therapeutic strategies for NEPC.