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

摘要 60%以上的转移性去势抵抗性前列腺癌（CRPC）含有PTEN和TP 53基因 缺失和突变。迄今为止，这种分子亚型的治疗选择有限。整体 本申请的目的是阐明B7-H3信号传导在前列腺癌（PCa）中的复杂作用 为CRPC开发生物标志物驱动的B7-H3靶向治疗。我们的初步研究表明， PTEN/TP 53缺陷诱导B7-H3在癌细胞中的过度表达和B7-H3的显著缺失 体内PTEN/p53缺陷型PCa的进展受损。质谱细胞仪分析显示B7-H3信号转导 参与调节PCa肿瘤微环境（TME）中的免疫抑制性骨髓细胞。在这里， 中心假设是B7-H3信号传导有助于含有PTEN/p53的PCa的进展 在PCa TME的免疫抑制性骨髓细胞的重编程中起关键作用。的 中心假设将通过追求以下具体目标来检验。目标1.说明B7-H3对 含有PTEN/TP 53缺失的晚期PCa的进展。这个目标的假设是，B7-H3起着关键作用， 在PCa进展和ADT抗性中的作用，并且PTEN/TP 53缺陷使CRPC对 B7-H3靶向治疗。为此，我们已经产生了一种新的GEMM与前列腺特异性共缺失的 Pten/Trp53/Cd276。这种最先进的自发GEMM提供了一个独特的工具来剖析B7-H3的作用， PCa发展和治疗抗性中的信号传导。机制研究将阐明PTEN和p53 途径控制B7-H3表达。B7-H3表达、PTEN/TP 53状态和 将在人CRPC中评估疾病进展。B7-H3靶向治疗也将在各种不同的临床试验中进行测试。 含有PTEN/TP 53缺失的转移性CRPC的临床前模型。目标2.了解B7-H3信号传导 调节CRPC中的免疫抑制性骨髓细胞。假设是B7-H3信号传导有助于 PCa TME中骨髓细胞的重编程。单细胞转录组学分析将在上文中进行 宝石。功能研究将解决B7-H3信号传导如何介导癌细胞之间的串扰， 免疫抑制骨髓细胞。骨髓细胞中的B7-H3受体和下游信号通路 也将被定性。最后，共靶向B7-H3和免疫抑制剂的治疗潜力被证实是有效的。 将在CRPC的临床前模型中评价骨髓细胞。这些研究预计将具有重大意义。 积极的影响，包括促进对癌症中B7-H3生物学的理解， 使用PTEN和TP 53缺陷作为预测对以下反应的分子生物标志物的令人信服的理由： CRPC患者的B7-H3靶向治疗。拟议的研究还将首次建立 B7-H3信号转导在TME中重编程骨髓细胞中的作用，并开发有效的组合治疗。 针对B7-H3的免疫疗法。

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.