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

靶向 B7-H3 治疗去势抵抗性前列腺癌的新方法

• 批准号: 10560840
• 负责人: Di Zhao
• 金额: $ 58.81万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560840
• 关键词: Antiandrogen Therapy; Antibody-drug conjugates; Biological; Biological Process; Biology; CD276 gene; CTLA4 blockade; Cancer Patient; Cells; Clinical; Combination immunotherapy; Complex; Cytometry; Data; Defect; Development; Disease; Disease Progression; Gene Deletion; Genetically Engineered Mouse; Goals; Human; Immune; Impairment; In Vitro; Infiltration; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Molecular; Monoclonal Antibodies; Mutation; Myeloid Cells; Myeloid-derived suppressor cells; Nature; Outcome; PTEN gene; Pathway interactions; Patients; Phenotype; Pilot Projects; Play; Pre-Clinical Model; Prostate; RB1 gene; Recurrent Malignant Neoplasm; Research; Resistance; Role; Signal Pathway; Signal Transduction; T cell infiltration; T-Lymphocyte; TP53 gene; Testing; Therapeutic; Time; Tumor-associated macrophages; Variant; advanced prostate cancer; androgen deprivation therapy; antitumor effect; biomarker driven; cancer cell; cancer recurrence; castration resistant prostate cancer; checkpoint therapy; clinically relevant; immune checkpoint; in vivo; inhibitor; molecular marker; molecular subtypes; mouse model; novel; novel strategies; overexpression; patient derived xenograft model; predicting response; predictive marker; programmed cell death protein 1; prostate cancer model; prostate cancer progression; receptor; response; targeted treatment; therapy resistant; tool; transcriptomic profiling; transcriptomics; tumor; tumor microenvironment

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.

抽象的 超过 60% 的转移性去势抵抗性前列腺癌 (CRPC) 含有 PTEN 和 TP53 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 此应用的目的是阐明 B7-H3 信号传导在前列腺癌 (PCa) 中的复杂作用 开发生物标志物驱动的 B7-H3 靶向治疗 CRPC。我们的初步研究表明 PTEN/TP53 缺陷诱导 B7-H3 过度表达，并且癌细胞中 B7-H3 显着缺失 PTEN/p53 缺陷型 PCa 体内进展受损。质谱流式分析显示 B7-H3 信号传导 参与调节 PCa 肿瘤微环境 (TME) 中的免疫抑制性骨髓细胞。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 缺陷，并在 PCa TME 中的免疫抑制骨髓细胞重编程中发挥关键作用。这 将通过追求以下具体目标来检验中心假设。目标 1. 阐明 B7-H3 对 含有 PTEN/TP53 缺失的晚期 PCa 的进展。该目标的假设是 B7-H3 发挥着关键作用 PTEN/TP53 缺陷使 CRPC 对 PCa 进展和 ADT 耐药性更敏感 B7-H3靶向治疗。为此，我们生成了一种新型 GEMM，具有前列腺特异性共缺失 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 发展和治疗耐药中的信号传导。机制研究将阐明 PTEN 和 p53 如何 途径控制 B7-H3 表达。 B7-H3 表达、PTEN/TP53 状态和 将在人类 CRPC 中评估疾病进展。 B7-H3靶向疗法也将在多个领域进行测试 含有 PTEN/TP53 缺失的转移性 CRPC 的临床前模型。目标 2. 了解 B7-H3 信号如何传递 调节 CRPC 中的免疫抑制性骨髓细胞。假设 B7-H3 信号传导有助于 PCa TME 中骨髓细胞的重编程。以上将进行单细胞转录组学分析 GEMM。功能研究将解决 B7-H3 信号如何介导癌细胞和癌细胞之间的串扰。 免疫抑制性骨髓细胞。骨髓细胞中的 B7-H3 受体和下游信号通路 也将被表征。最后，共同靶向 B7-H3 和免疫抑制药物的治疗潜力 骨髓细胞将在 CRPC 临床前模型中进行评估。这些研究预计将具有重大意义 积极影响，包括增进对癌症中 B7-H3 生物学的了解并提供 使用 PTEN 和 TP53 缺陷作为分子生物标志物来预测反应的令人信服的理由 针对 CRPC 患者的 B7-H3 靶向治疗。拟议的研究还将首次建立 B7-H3 信号在 TME 中骨髓细胞重编程中的作用并开发有效的组合 针对 B7-H3 的免疫疗法。