Research Project 2: Combined inhibition of AR and PI3K signaling in metastatic prostate cancer: Exploiting reciprocal feedback

研究项目 2：转移性前列腺癌中 AR 和 PI3K 信号传导的联合抑制：利用相互反馈

• 批准号: 9148032
• 负责人: NEAL ROSEN
• 金额: $ 17.18万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-14 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9148032
• 关键词: Aftercare; Androgen Receptor; Apoptosis; Basic Science; Biological; Biological Assay; Biopsy; Castration; Catalytic Domain; Clinic; Clinical Sciences; Clinical Trials; Clinical Trials Design; Complex; DNA Sequence Alteration; Data; Dependency; Development; Disease; Doctor of Philosophy; Dose; Event; Feedback; Future; Generations; Genetic; Genetically Engineered Mouse; Genomics; Genotype; Goals; Human; Knowledge; Lead; Malignant neoplasm of prostate; Metabolism; Metastatic Prostate Cancer; Modeling; Mutation; Oncogenic; Organoids; Output; PIK3CA gene; PIK3CB gene; PSA level; PTEN gene; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Play; Pre-Clinical Model; Prostatic Neoplasms; Protein Isoforms; Receptor Activation; Receptor Inhibition; Receptor Signaling; Regimen; Reporting; Research Project Grants; Resistance; Role; Schedule; Signal Pathway; Signal Transduction; Therapeutic; Therapeutic Effect; Toxic effect; Translating; Treatment Efficacy; Tumor Suppressor Genes; Work; abiraterone; base; castration resistant prostate cancer; genomic profiles; inhibitor/antagonist; men; migration; mouse model; novel; serum PSA; therapy resistant; tumor

PROJECT SUMMARY/ABSTRACT The androgen receptor (AR) signaling pathway is the key driver of human prostate cancer. Prostate cancers are almost always sensitive to blockade of the androgen receptor, and tumors with acquired resistance to these therapies are often sensitive to second-generation inhibitors of the pathway. However, the vast majority of men with progressive prostate cancer will ultimately succumb to the disease. Activation of the PI3K signaling pathway is the second most prevalent oncogenic event in prostate cancer, occurring in the majority of advanced castration-resistant tumors. The PTEN tumor suppressor gene is lost or inactivated in 40% of these tumors, and genetic events that activate PI3K are also found in a significant number of patients. While PTEN loss is the most commonly altered regulator of PI3K signaling in prostate cancer, recent genomic profiling studies of metastatic castration-resistant prostate cancer (CRPC) have reported activating alterations in the subunits of the PI3K complex (PIK3CA, PIK3CB, PIK3R1) in approximately 10% to 20% of cases. Our previous work revealed that activation of AR-signaling or PI3K signaling each cause feedback inhibition of the other in a reciprocal fashion. As predicted from this finding, inhibition of androgen receptor signaling activates PI3K signaling in these tumors and correspondingly, inhibitors of PI3K signaling activate AR signaling. It is likely that relief of feedback inhibition of the other pathway reduces the benefit of therapy with single agent AR or PI3K inhibitors. In support of this hypothesis, we showed that combined inhibition of both pathways has profound therapeutic effects in preclinical models of advanced prostate cancer. The major goal of this proposal is to optimize such therapies, tailoring the therapeutic strategy to specific tumor genotypes. We will do this by determining the biologic consequences of different mechanisms of PI3K activation in prostate cancer, determining the best means of pharmacologically inhibiting PI3K and AR signaling in prostate tumors with PTEN loss and/or PI3K activation, and optimizing the dose and schedule of these combinations in novel organoid and genetically engineered mouse models of prostate cancer. The aims of this proposal are to explore the biologic consequences of PI3K pathway activation in AR-driven prostate cancer and to determine the optimal combination regimens with which to treat these tumors.

项目概要/摘要 雄激素受体（AR）信号通路是人类前列腺癌的关键驱动因素。前列腺 癌症几乎总是对雄激素受体的阻断敏感，并且具有获得性的肿瘤 对这些疗法的耐药性通常对该途径的第二代抑制剂敏感。 然而，绝大多数患有进展性前列腺癌的男性最终都会死于癌症。 疾病。 PI3K 信号通路的激活是第二个最常见的致癌事件 前列腺癌，发生在大多数晚期去势抵抗性肿瘤中。 PTEN肿瘤 40% 的肿瘤中抑制基因丢失或失活，激活 PI3K 的基因事件 在相当数量的患者中也发现了这种情况。虽然 PTEN 丢失是最常改变的调节因子 PI3K 信号在前列腺癌中的作用，最近转移性去势抵抗的基因组分析研究 前列腺癌 (CRPC) 已报道 PI3K 复合物亚基发生激活性改变 （PIK3CA、PIK3CB、PIK3R1）约占 10% 至 20% 的病例。我们之前的工作表明 AR 信号或 PI3K 信号的激活各自导致对方的反馈抑制 时尚。正如这一发现所预测的，雄激素受体信号传导的抑制会激活 PI3K 这些肿瘤中的信号传导，相应地，PI3K 信号传导的抑制剂会激活 AR 信号传导。这是 缓解其他途径的反馈抑制可能会降低单一治疗的益处 AR或PI3K抑制剂。为了支持这一假设，我们证明了两者的联合抑制 途径在晚期前列腺癌的临床前模型中具有深远的治疗作用。这 该提案的主要目标是优化此类疗法，根据具体情况定制治疗策略 肿瘤基因型。我们将通过确定不同机制的生物学后果来做到这一点 前列腺癌中 PI3K 的激活，确定药理学抑制 PI3K 的最佳方法 具有 PTEN 缺失和/或 PI3K 激活的前列腺肿瘤中的 AR 信号转导，以及优化剂量和 这些组合在新型类器官和基因工程小鼠模型中的时间表 前列腺癌。该提案的目的是探索 PI3K 通路的生物学后果 AR 驱动的前列腺癌中的激活并确定最佳组合方案 来治疗这些肿瘤。