Project 3: Defining the appropriate context for targeting kinase signaling in combination with androgen receptor blockade to enhance therapeutic response in metastatic prostate cancer

摘要 通过从凳子到床边的翻译，我们发现PI3K和AR通路在一种 通过反馈的相互作用和抑制方式，解释了PI3K途径抑制剂的有限疗效 转移性前列腺癌患者的单一疗法临床试验。基于我们的工作，第一个临床 PI3K和AR途径联合抑制的试验最近被报道显示对 PTEN缺失的肿瘤患者的联合治疗。我们的提案旨在将这些令人兴奋的 回到临床前空间，1)定义内在敏感性和抵抗力的生物标记物 选择合适的患者进行联合治疗；2)确定获得性耐药的机制；3) 制定克服耐药性的治疗策略；4)在PI3K的背景下优化AR通路靶向 抑制通路以最大限度地提高肿瘤反应以及5)探索FGFR在新亚群中的治疗作用 AR阴性前列腺癌。

ABSTRACT Through bench to bedside translation, we discovered that the PI3K and AR pathways regulate one another in a reciprocal and inhibitory fashion through feedback, explaining the limited efficacy of PI3K pathway inhibitors as monotherapy in clinical trials of patients with metastatic prostate cancer. Based on our work, the first clinical trial of combined PI3K and AR pathway inhibition was recently reported demonstrating a significant benefit for combination therapy in patients with tumors harboring loss of PTEN. Our proposal aims to take these exciting finding back to the pre-clinical space to 1) define biomarkers of intrinsic sensitivity and resistance to inform appropriate patient selection for combination therapy; 2) define the mechanisms of acquired resistance; 3) devise therapeutic strategies to overcome resistance; 4) optimize AR pathway targeting in the setting of PI3K pathway inhibition to maximize tumor response and 5) explore the therapeutic role of FGFR in a novel subset of AR negative prostate cancers.