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

基本信息

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
项目类别：
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

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

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项目摘要

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.

抽象的超过60％的转移性cast割前列腺癌（CRPC）包含PTEN和TP53基因删除和突变。迄今为止，该分子亚型的治疗选择有限。总体该应用的目的是阐明B7-H3信号在前列腺癌（PCA）中的复杂作用作为生物标志物驱动的B7-H3针对CRPC的靶向疗法。我们的初步研究表明 PTEN/TP53缺陷诱导B7-H3的过表达和B7-H3在癌细胞中的耗竭 PTEN/p53缺陷PCA在体内的进展受损。质量细胞仪分析表明B7-H3信号传导参与PCA肿瘤微环境（TME）中的免疫抑制性髓样细胞。这里，中心假设是B7-H3信号传导有助于含有PTEN/p53的PCA的进展缺陷和在PCA TME中重编程免疫抑制髓样细胞中起关键作用。这中央假设将通过追求以下特定目标来检验。目标1。阐明B7-H3对含有PTEN/TP53损失的晚期PCA的进展。这个目的的假设是B7-H3扮演关键在PCA的进展和对ADT的抗性中的作用，PTEN/TP53缺陷使CRPC更响应于 B7-H3靶向治疗。为此，我们产生了一个新颖的宝石 PTEN/TRP53/CD276。这种最先进的赞助宝石提供了一种独特的工具来剖析B7-H3的作用 PCA发育和治疗性抗性中的信号传导。机械研究将阐明PTEN和P53的方式途径控制B7-H3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含有PTEN/TP53损失的转移性CRPC的临床前模型。目标2。了解B7-H3信号如何调节CRPC中的免疫抑制髓样细胞。假设是B7-H3信号传导有助于 PCA TME中髓样细胞的重编程。单细胞转录组学分析将在上述宝石。功能研究将解决B7-H3信号传导如何介导癌细胞和免疫抑制髓样细胞。 B7-H3受体（S）和髓样细胞中的下游信号通路也将被描述。最后，共同靶向B7-H3和免疫抑制的治疗潜力将在CRPC的临床前模型中评估髓样细胞。这些研究预计将具有重要的积极的影响，包括促进对B7-H3生物学的理解，并提供使用PTEN和TP53缺陷作为分子生物标志物来预测对响应的反应针对CRPC患者的B7-H3靶向疗法。拟议的研究还将首次确定 B7-H3信号在重编程TME中重编程并发展有效组合中的作用靶向B7-H3的免疫疗法。