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最常见的癌症，2007年将杀死大约27,050名男性。雄激素消融疗法和多西他赛延长生存率并改善了患者的生活质量，但转移性前列腺癌继续造成重大痛苦和死亡和死亡和新治疗。 PTEN/PI3K/AKT途径的放松管制在晚期前列腺癌中很常见，并且是治疗的有吸引力的靶标。由于前列腺靶向PTEN或AKT激活，抑制MTOR是Akt信号传导的效应组，足以逆转转基因小鼠的肿瘤前列腺表型。但是，来自临床试验的新兴数据表明，尽管MTOR抑制作用导致40％的男性稳定疾病，但客观反应并不常见，并且对未选择的晚期前列腺癌男性人群的生存影响仍然不清楚。该提案将确定我们既定的免疫组织化学方法和表达分析是否可以鉴定具有MTOR活性的肿瘤，预测接受MTOR抑制治疗的个体患者的稳定疾病，并测试替代途径或化学疗法反应特征之间的关联以及对MTOR抑制的抵抗力。在AIM 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“特征”，以确定细胞和遗传环境如何影响MTOR特征与MTOR活性相关的能力。在AIM 2中，将测试与AIM 1的MTOR活性相关的免疫组织化学测量和与MTOR活性相关的最佳MTOR响应特征，以预测从II期试验中对MTOR抑制对MTOR抑制的反应的准确性，在该试验中，患者将用RAD001治疗患者（mTOR抑制剂）。在AIM 3中，通过在RAD001之前和之后对转移性疾病的CT引导的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/或预测特征的测量的变化与临床抵抗相关。使用遗传定义的前列腺上皮细胞随着PTEN/PI3K/AKT途径的激活而转化的遗传定义的前列腺上皮细胞，将测试候选途径对MTOR抑制的影响。至于许多有针对性的疗法，尽管该疾病中这种途径具有确定的生物学重要性，但未选择的转移性前列腺癌男性中，单药MTOR抑制的临床结果显得谦虚。这里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组合疗法来改善前列腺癌男性的护理。虽然专注于转移性前列腺癌中的MTOR反应，但可以广泛应用在该提案中开发和测试的方法。