Novel Approaches Targeting B7-H3 in Castration-resistant Prostate Cancer

点击翻译按钮获取中文摘要

ABSTRACT More than 60% of metastatic castration-resistant prostate cancers (CRPC) contain PTEN and TP53 gene deletions and mutations. To date, there are limited treatment options for this molecular subtype. The overall objective of this application is to elucidate the complex role of B7-H3 signaling in prostate cancer (PCa) as well as develop biomarker-driven B7-H3 targeted therapy for CRPC. Our preliminary studies demonstrated that PTEN/TP53 defects induce B7-H3 overexpression and that depletion of B7-H3 in cancer cells remarkably impaired progression of PTEN/p53-deficient PCa in vivo. Mass cytometry analysis revealed that B7-H3 signaling is involved in modulating immunosuppressive myeloid cells in the PCa tumor microenvironment (TME). Here, the central hypothesis is that B7-H3 signaling contributes to the progression of PCa containing PTEN/p53 deficiencies and plays a key role in reprogramming immunosuppressive myeloid cells in the PCa TME. The central hypothesis will be tested by pursuing the following specific aims. Aim 1. Elucidate B7-H3’s impact on progression of advanced PCa containing PTEN/TP53 loss. The hypothesis in this aim is that B7-H3 plays a key role in PCa progression and resistance to ADT and that PTEN/TP53 defects render CRPC more responsive to B7-H3 targeted therapy. To this end, we have generated a novel GEMM with prostate-specific co-deletion of Pten/Trp53/Cd276. This state-of-the-art spontaneous GEMM provides a unique tool to dissect the role of B7-H3 signaling in PCa development and therapeutic resistance. Mechanistic studies will illuminate how PTEN and p53 pathways control B7-H3 expression. Clinical relevance among B7-H3 expression, PTEN/TP53 status, and disease progression will be assessed in human CRPCs. B7-H3 targeted therapies will also be tested in various preclinical models of metastatic CRPC containing PTEN/TP53 loss. Aim 2. Understand how B7-H3 signaling modulates immunosuppressive myeloid cells in CRPC. The hypothesis is that B7-H3 signaling contributes to the reprogramming of myeloid cells in the PCa TME. Single-cell transcriptomics analysis will be performed in above GEMMs. Functional studies will address how B7-H3 signaling mediates the crosstalk between cancer cells and immunosuppressive myeloid cells. B7-H3 receptor(s) and the downstream signaling pathway(s) in myeloid cells will also be characterized. Finally, the therapeutic potential of co-targeting B7-H3 and immunosuppressive myeloid cells will be evaluated in preclinical models of CRPC. These studies are expected to have significant positive impacts, including advancing the understanding of B7-H3 biology in cancers and providing a compelling rationale for the use of PTEN and TP53 defects as molecular biomarkers for predicting response to B7-H3-targeted therapy for patients with CRPC. The proposed research will also establish, for the first time, the role of B7-H3 signaling in reprogramming myeloid cells in the TME and develop effective combinatorial immunotherapy targeting B7-H3.