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.

摘要 超过60%的转移性去势耐受前列腺癌(CRPC)含有PTEN和TP53基因 缺失和突变。到目前为止，对这种分子亚型的治疗选择有限。整体而言 本应用的目的是阐明B7-H3信号在前列腺癌(PCa)中的复杂作用 AS开发生物标记物驱动的B7-H3靶向治疗CRPC。我们的初步研究表明 PTEN/TP53缺陷显著诱导癌细胞B7-H3过度表达和缺失 抑制体内PTEN/P53缺陷性前列腺癌的进展。质量细胞学分析显示B7-H3信号 参与调节前列腺癌肿瘤微环境(TME)中的免疫抑制髓系细胞。这里, 中心假说是B7-H3信号参与了含有PTEN/P53的前列腺癌的进展 在PCATME中免疫抑制髓系细胞的重新编程中起着关键作用。这个 中心假说将通过追求以下具体目标来检验。目的1.阐明B7-H3病毒对S的影响 含PTEN/TP53缺失的晚期PCa的研究进展这一目标的假设是B7-H3起关键作用 PTEN/TP53缺陷在前列腺癌进展和ADT耐药性中的作用及使CRPC对 B7-H3靶向治疗。为此，我们已经产生了一种新型的GEMM，它带有前列腺特异性的共缺失的 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 前列腺癌发生和治疗耐药中的信号转导。机制研究将阐明PTEN和P53如何 途径控制B7-H3的表达。B7-H3表达、PTEN/TP53状态和 疾病进展将在人类CRPC中进行评估。B7-H3靶向疗法也将在各种不同的 含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 调节CRPC中免疫抑制的髓系细胞。假设是B7-H3信号参与了 前列腺癌TME中髓系细胞的重新编程。单细胞转录组分析将在上面进行 GEMM。功能研究将解决B7-H3信号如何介导癌细胞和 免疫抑制的髓系细胞。髓系细胞中的B7-H3受体(S)及其下游信号通路(S) 也将被描述为。最后，联合靶向B7-H3和免疫抑制的治疗潜力 髓系细胞将在CRPC的临床前模型中进行评估。这些研究预计将具有重要的 积极影响，包括促进对B7-H3生物学在癌症中的理解，并提供 使用PTEN和TP53缺陷作为预测疗效的分子生物标记物的可信理由 B7-H3-CRPC患者的靶向治疗。拟议的研究还将首次确立 B7-H3信号在TME髓系细胞重编程中的作用及发展有效的组合 针对B7-H3的免疫治疗。