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

项目总结/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 癌症几乎总是对雄激素受体的阻断敏感，并且具有获得性雄激素受体的肿瘤几乎总是敏感的。 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会屈服于前列腺癌。 疾病PI 3 K信号通路的激活是癌症中第二大最普遍的致癌事件。 前列腺癌，发生在大多数晚期去势抵抗性肿瘤中。PTEN肿瘤 在这些肿瘤中，40%的抑制基因丢失或失活，激活PI 3 K的遗传事件 在很多病人身上也发现了这种现象。虽然PTEN缺失是最常见的改变调节器， PI 3 K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）已经报道了PI 3 K复合物亚基的活化改变 （PIK 3CA，PIK 3CB，PIK 3R 1），约10%至20%的病例。我们之前的工作表明， AR信号传导或PI 3 K信号传导的激活各自以相互作用的方式引起另一个的反馈抑制。 时尚.正如从这一发现预测的那样，雄激素受体信号传导的抑制激活PI 3 K 在这些肿瘤中，PI 3 K信号传导的抑制剂激活AR信号传导。是 可能的是，另一途径的反馈抑制的缓解降低了单用 试剂AR或PI 3 K抑制剂。为了支持这一假设，我们发现， pathways在晚期前列腺癌的临床前模型中具有深远的治疗效果。的 该提案的主要目标是优化这些疗法，使治疗策略适应特定的 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。 前列腺癌中的PI 3 K活化，确定前列腺癌抑制PI 3 K的最佳方法， 前列腺肿瘤中的AR信号传导与PTEN丢失和/或PI 3 K激活，并优化剂量和 这些组合在新的类器官和遗传工程小鼠模型中的时间表 前列腺癌该提案的目的是探索PI 3 K通路的生物学后果， 在AR驱动的前列腺癌中激活，并确定最佳组合方案， 来治疗这些肿瘤

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.