c-Met/PTEN Interactions in Gliomas

描述（由申请人提供）：在恶性人类胶质瘤中，酪氨酸激酶受体c-Met及其配体肝细胞生长因子（HGF）经常过表达，肿瘤抑制因子PTEN经常突变。在之前的资助中，我们发现了PTEN和c-Met通路之间的多种机制和功能相互作用，并发现c-Met激活和PTEN丢失对胶质瘤恶性肿瘤具有叠加效应。在这一竞争性更新中，我们建议继续分析PTEN/c-Met在胶质瘤中的作用，重点是PTEN和c-Met途径之间的新的机制相互作用，以及测试新的临床前治疗药物和策略。在目标1中，我们将研究我们最近发现的HGF对PTEN磷酸化和半衰期的调节。这些发现将揭示hgf诱导恶性肿瘤和PTEN翻译后调控的新机制。在目标#2中，我们将验证PTEN通过涉及p53和microRNA-34a的新途径下调c-Met表达的假设。这一发现可以解释胶质母细胞瘤中PTEN缺失和c-Met过表达并存的现象，揭示c-Met表达调控的新机制。在目标#3中，我们将确定PTEN表达对抗hgf单克隆抗体和一种新的口服生物可用的c-Met小分子抑制剂的体内治疗效率的影响。我们还将评估将抗hgf或抗c- met疗法与mTOR抑制剂联合使用的治疗价值，以抵消PTEN突变异种移植物中PTEN缺失的影响。翻译实验将使用原发胶质瘤细胞衍生和胶质瘤干细胞衍生的异种移植物进行。实验的成功完成将为PTEN和c-Met的调控提供新的机制见解，并揭示它们之间以前未知的分子相互作用。该研究结果还将为临床应用抗hgf和抗c- met治疗以及mTOR抑制剂的临床应用提供必要和及时的信息。在原发性和胶质瘤干细胞动物模型中使用临床适用的药物将使所获得的结果具有高度的有效性和临床前意义。公共卫生相关性：我们之前发现癌基因c-Met的增加和肿瘤抑制因子PTEN的缺失对胶质瘤脑肿瘤的生长具有叠加效应。我们建议研究c-Met和PTEN在胶质瘤中相互调控的新机制。我们还建议测试PTEN对针对c-Met的新的临床有用药物的影响，并测试胶质瘤治疗的新药和药物组合。这一结果将引导胶质瘤治疗新策略的发展，并为新药物的临床应用提供重要信息。

DESCRIPTION (provided by applicant): In malignant human gliomas, the tyrosine kinase receptor c-Met and its ligand hepatocyte growth factor (HGF) are frequently overexpressed and the tumor suppressor PTEN is frequently mutated. In the previous grant, we uncovered multiple mechanistic and functional interactions between PTEN and c-Met pathway and found that c-Met activation and PTEN loss have additive effects on glioma malignancy. In this competitive renewal, we propose a continuation of the analysis of PTEN/c-Met in gliomas with a focus on novel mechanistic interactions between PTEN and c-Met pathway and on testing new preclinical therapeutic agents and strategies. In aim #1, we will study the regulation of PTEN phosphorylation and half-life by HGF that we recently discovered. The findings will uncover a new mechanism of HGF-induced malignancy and of PTEN post-translational regulation. In aim #2, we will test the hypothesis that PTEN downregulates c-Met expression via a new pathway involving p53 and microRNA-34a. The findings could explain the concurrent PTEN loss and c-Met overexpression in glioblastoma and uncover a new mechanism of c-Met expression regulation. In aim #3, we will determine the effects of PTEN expression on the in vivo therapeutic efficiency of anti-HGF monoclonal antibodies and a new orally bioavailable small molecule inhibitor of c-Met. We will also assess the therapeutic value of combining anti-HGF or anti-c-Met therapies with mTOR inhibitors that counteract the effects of PTEN loss in PTEN- mutated xenografts. The translational experiments will be performed using primary glioma cell-derived and glioma stem cell-derived xenografts. Successful completion of the proposed experiments will provide new mechanistic insights into the regulation of PTEN and c-Met and uncover previously unknown molecular interactions between them. The findings will also provide necessary and timely information for the use in a clinical setting of clinically applicable anti-HGF and anti-c-Met therapies also in combination with mTOR inhibitors. The use of clinically applicable agents in primary and glioma stem cell animal models will confer high validity and preclinical significance to the obtained results. PUBLIC HEALTH RELEVANCE: We previously found that increase of the oncogene c-Met and loss of the tumor suppressor PTEN have additive effects on the growth of glioma brain tumors. We propose to study new mechanisms with which c-Met and PTEN regulate each other in gliomas. We also propose to test the effects of PTEN on new clinically useful drugs that target c-Met and also test new drugs and drug combinations for glioma therapies. The results will lead to the development of new glioma therapeutic strategies and provide important information for the use of the new drugs in the clinic.