Control of cell growth by mTOR and BMP in prostate cancer

mTOR 和 BMP 对前列腺癌细胞生长的控制

• 批准号: 7750112
• 负责人: Reema Said Wahdan-Alaswad
• 金额: $ 4.12万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7750112
• 关键词: Affect; Apoptosis; CCI-779; Cell Death; Cell Line; Cessation of life; Clinic; Core Biopsy; Data; Disease-Free Survival; Foundations; Growth; In Vitro; Insulin-Like Growth Factor I; Intercept; Investigation; Laboratories; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Molecular; Pathway interactions; Patients; Phase II Clinical Trials; Prostate; Prostate Adenocarcinoma; Prostate Cancer therapy; Prostatectomy; Reporting; Role; Severity of illness; Signal Transduction; Sirolimus; Staging; Testing; Therapeutic; Tissues; Tumor Suppression; bone morphogenetic protein receptors; cancer cell; cell growth; follow-up; human FRAP1 protein; in vivo; mTOR Inhibitor; mTOR inhibition; receptor function

DESCRIPTION (provided by applicant): Our laboratory was the first to report that IGF-I blocks TGF-(3 induced apoptosis and/or growth arrest by suppressing the activation of Smad3 through an IGF-l/P13K/Akt/mT0R-dependent mechanism. Preliminary data support that the IGF-l/P13K/Akt/mT0R pathway also intercepts BMP signaling. Our data also suggest that rapamycin, a potent mTOR inhibitor currently in phase II clinical trials for prostate cancer, activates Smads 1, 5 or 8. Our plans here are to elucidate the mechanisms by which the above IGF-I pathway affects BMP signaling. This investigation is likely to have therapeutic benefit, by helping to identify patients who may best benefit from mTOR inhibitors, and in optimizing therapeutic strategy. IGF-I pathway has been known to be upregulated during late stage prostate adenocarcinoma, whereas there is a loss of BMP- receptor function observed during late stage prostate cancer. The specific hypothesis to be tested is that the IGF-I suppresses BMP4-induced cell death through the PI3K/Akt/mT0R-dependent mechanism. We also hypothesize that inhibition of mTOR by rapamycin suppresses growth of prostate cancer cells or promotes their death through a mechanism involving Smad activation. Important to cancer therapeutics, our collaborator Dr. Jorge Garcia is conducting a phase II clinical trial at the Cleveland Clinic Foundation (CCF) with a rapamycin analogue, RAD001. Normal and malignant prostate tissue cores from biopsies and prostatectomies of patients treated with RAD001 will be made available for us to analyze immunohistochemically the expression of phospho-Smads and components for the IGF-l/PI3K/Akt/mT0R and BMP pathways. Expression levels of these markers will be correlated to disease severity and followed up by disease-free survival. All in all, these studies will elucidate the role of the TGF-(3 superfamily in the tumor suppression by rapamycin for prostate cancer. The specific Aims of this proposal are: Specific Aim 1: To test the hypothesis that IGF-I suppresses BMP4-induced cell death through a PI3K/Akt/mT0R dependent mechanism. Specific Aim 2: To test the hypothesis that rapamycin reverses mTOR-mediated inhibition of the TGF-p superfamily pathway, thus leading to enhanced Smad activation in PCS cell line both in vitro and in vivo. This study will define the role of IGF-l/PI3K/Akt/mT0R and limiting BMP-induced apoptosis and rapamycin is able to reverse such inhibition. All in all, the study will provide a clear and comprehensive assessment of the molecular mechanisms of rapamycin's action in prostate cancer therapy.

描述（由申请人提供）：我们的实验室是第一个报告IGF-I通过IGF-L/P13K/AKT/MT0R依赖性机制抑制SMAD3的激活，从而阻止TGF- TGF-（3诱导凋亡和/或生长停滞。我们的计划是阐明上述IGF-I途径会影响BMP信号的机制，这可能会通过帮助确定最能从MTOR抑制剂中受益的患者，并在优化治疗策略中受益。众所周知，I途径在晚期前列腺腺癌中被上调，而在晚期前列腺癌期间观察到的BMP受体功能的损失是要测试的特定假设。 PI3K/AKT/MT0R依赖性机制。我们还假设雷帕霉素抑制MTOR会抑制前列腺癌细胞的生长或通过涉及SMAD激活的机制促进其死亡。对于癌症治疗学很重要，我们的合作者Jorge Garcia博士正在克利夫兰诊所基金会（CCF）进行II期临床试验，其中雷帕霉素类似物Rad001。来自活检的正常和恶性前列腺组织核心和接受RAD001治疗的患者的前列腺切除术，可以使我们可以在免疫组织化学上分析IGF-L/PI3K/PI3K/AKT/MT0R和BMP途径的磷酸化和成分的表达。这些标记物的表达水平将与疾病的严重程度相关，并随后无疾病生存。总而言之，这些研究将阐明TGF-（3在雷帕霉素抑制前列腺癌的超家族中。该提议的具体目的是：特定目的1：检验IGF-I抑制BMP4-的假设。通过PI3K/AKT/MT0R依赖机制诱导细胞死亡。本研究将定义IGF-L/PI3K/AKT/MT0R的作用，并限制BMP诱导的细胞凋亡，雷帕霉素能够扭转这种抑制作用。雷帕霉素在前列腺癌疗法中作用的机制。