mTOR Therapy in Prostate Cancer: Signatures of Response and Biology of Resistance

前列腺癌的 mTOR 疗法：反应特征和耐药生物学

• 批准号: 7665071
• 负责人: PHILLIP G FEBBO
• 金额: $ 30.88万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-25 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7665071
• 关键词: AKT1 gene; Aftercare; American; Androgens; Biological; Biology; Biopsy; Cancer Model; Cancer cell line; Caring; Cessation of life; Clinical; Clinical Data; Clinical Trials; Combined Modality Therapy; Data; Disease; Epithelial Cells; Gene Expression; Genetic; Goals; Grant; Human; Individual; Malignant neoplasm of prostate; Measures; Metastatic Prostate Cancer; Methods; Molecular; Molecular Profiling; Oncogenic; PI3K/AKT; PTEN gene; Pathway interactions; Patient Care; Patients; Phase II Clinical Trials; Phenotype; Population; Prostate; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Quality of life; RNA; Resistance; Sampling; Signal Transduction; Stable Disease; Testing; Therapeutic; Transgenic Mice; Upper arm; Work; base; cancer diagnosis; cancer therapy; chemotherapy; docetaxel; human FRAP1 protein; improved; killings; mTOR Inhibitor; mTOR inhibition; men; molecular phenotype; neoplastic; novel; patient population; resistance mechanism; response; response marker; tumor

DESCRIPTION (provided by applicant): Prostate cancer is the most commonly diagnosed cancer in American men and will kill approximately 27,050 men in 2007. Androgen ablative therapy and docetaxel prolong survival and improve patients' quality of life but metastatic prostate cancer continues to cause significant suffering and death and novel treatments are required. Deregulation of the PTEN/PI3K/AKT pathway is common in advanced prostate cancer and an attractive target for therapy. Inhibition of mTOR, an effector arm of AKT signaling, is sufficient to reverse neoplastic prostate phenotypes in transgenic mice due to prostate-targeted loss of PTEN or AKT activation. However, emerging data from clinical trials suggest that while mTOR inhibition results in stable disease for 40% of men, objective responses are uncommon and the impact on survival in an unselected population of men with advanced prostate cancer remains unclear. This proposal will determine if our established methods of immunohistochemical and expression analysis can identify tumors with mTOR activity, predict stable disease in individual patients treated with mTOR inhibition, and test for associations between alternative pathway or chemotherapy response signatures and resistance to mTOR inhibition. In Aim 1, expression "signatures" of mTOR activity will be developed across a range of prostate cancer models and human tumors to determine how cellular and genetic context impact the ability of mTOR signatures to correlate with mTOR activity. In Aim 2, the immunohistochemical measures and the best mTOR response signatures correlating with mTOR activity from in Aim 1 will be tested for their accuracy in predicting response to mTOR inhibition on prostate cancer samples from a phase II trial during which patients will be treated with RAD001 (an mTOR inhibitor). In Aim 3, by performing immunohistochemical and expression analysis on CT-guided biopsies of metastatic disease prior to and following RAD001 we will determine how changes in measures of mTOR activity and alternative pathways and/or predictive signatures correlate with clinical resistance. Candidate pathways will be tested for their impact on mTOR inhibition using genetically- defined, prostate epithelial cells transformed with activation of the PTEN/PI3K/AKT pathway. As for many targeted therapies, the clinical results of single agent mTOR inhibition in an unselected population of men with metastatic prostate cancers appear modest despite the established biological importance of this pathway in the disease. The overall goal of the work herein proposed is to improve the care of men with prostate cancer by providing predictive markers and identify potentially synergistic combination therapy. While focused on mTOR response in metastatic prostate cancer, the methods developed and tested in this proposal can be broadly applied.

描述（由申请人提供）：前列腺癌是美国男性中最常诊断出的癌症，2007 年将导致约 27,050 名男性死亡。雄激素消融疗法和多西紫杉醇可延长患者的生存期并改善患者的生活质量，但转移性前列腺癌仍会造成严重的痛苦需要死亡和新的治疗方法。 PTEN/PI3K/AKT 通路失调在晚期前列腺癌中很常见，也是一个有吸引力的治疗靶点。 mTOR（AKT 信号传导的效应臂）的抑制足以逆转转基因小鼠中由于前列腺定向丧失 PTEN 或 AKT 激活而导致的前列腺肿瘤表型。然而，临床试验的新数据表明，虽然 mTOR 抑制可使 40% 的男性病情稳定，但客观反应并不常见，而且对未经选择的晚期前列腺癌男性群体的生存影响仍不清楚。该提案将确定我们建立的免疫组织化学和表达分析方法是否可以识别具有 mTOR 活性的肿瘤，预测接受 mTOR 抑制治疗的个体患者疾病稳定，并测试替代途径或化疗反应特征与 mTOR 抑制耐药性之间的关联。在目标 1 中，将在一系列前列腺癌模型和人类肿瘤中开发 mTOR 活性的表达“特征”，以确定细胞和遗传背景如何影响 mTOR 特征与 mTOR 活性相关的能力。在目标 2 中，将测试与目标 1 中的 mTOR 活性相关的免疫组织化学测量和最佳 mTOR 反应特征，以检验其预测 II 期试验中前列腺癌样本 mTOR 抑制反应的准确性，在此期间患者将接受 RAD001 治疗（一种 mTOR 抑制剂）。在目标 3 中，通过在 RAD001 之前和之后对 CT 引导的转移性疾病活检进行免疫组织化学和表达分析，我们将确定 mTOR 活性和替代途径和/或预测特征的测量变化如何与临床耐药相关。将使用通过激活 PTEN/PI3K/AKT 途径转化的基因定义的前列腺上皮细胞来测试候选途径对 mTOR 抑制的影响。对于许多靶向治疗而言，尽管该通路在该疾病中的生物学重要性已被证实，但在未经选择的转移性前列腺癌男性人群中，单药 mTOR 抑制的临床结果似乎并不显着。本文提出的工作的总体目标是通过提供预测标记并确定潜在的协同联合疗法来改善男性前列腺癌的护理。虽然重点关注转移性前列腺癌中的 mTOR 反应，但本提案中开发和测试的方法可以广泛应用。