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

项目 3：确定靶向激酶信号传导与雄激素受体阻断相结合的适当背景，以增强转移性前列腺癌的治疗反应

• 批准号: 10005212
• 负责人: Brett Stewart Carver
• 金额: $ 48.75万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005212
• 关键词: AKT inhibition; Acetates; Androgen Receptor; Androgens; Back; Biological Markers; Biology; Breast; Cancer Therapy Evaluation Program; Characteristics; Clinical Trials; Combined Modality Therapy; Development; Disease; Disease Resistance; ERBB2 gene; Event; FGF8 gene; Feedback; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Formularies; Future; Generations; Hormonal; Impairment; Ligands; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Memorial Sloan-Kettering Cancer Center; Metastatic Prostate Cancer; Modeling; Molecular; Neurosecretory Systems; Nuclear Hormone Receptors; Oncogenic; PTEN gene; Pathway interactions; Patient Selection; Patient-Focused Outcomes; Patients; Pertuzumab; Phosphotransferases; Pre-Clinical Model; Prostate; Proto-Oncogene Proteins c-akt; Regulation; Reporting; Resistance; Resistance development; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Therapeutic Effect; Thyroid Gland; Translations; Trastuzumab; Up-Regulation; Work; abiraterone; advanced prostate cancer; base; bench to bedside; cancer drug resistance; castration resistant prostate cancer; design; drug sensitivity; genetic signature; genomic profiles; improved; improved outcome; in vivo; inhibitor/antagonist; men; novel; overexpression; pre-clinical; preclinical trial; prevent; prostate cancer model; resistance mechanism; response; targeted treatment; therapy resistant; treatment response; tumor

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.

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。