c-Met/PTEN Interactions in Gliomas

描述（由申请人提供）：在恶性人类神经胶质瘤中，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。在之前的研究中，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缺失对胶质瘤恶性程度具有累加效应。在这一竞争性更新中，我们建议继续分析胶质瘤中的PTEN/c-Met，重点关注PTEN和c-Met通路之间的新型机制相互作用，并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翻译后调节的新机制。在目标#2中，我们将测试PTEN通过涉及p53和microRNA-34 a的新途径下调c-Met表达的假设。这一发现可能解释了胶质母细胞瘤中PTEN缺失和c-Met过表达的同时发生，并揭示了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单克隆抗体和新的口服生物可利用的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抑制剂组合的治疗价值，所述mTOR抑制剂抵消PTEN突变的异种移植物中的PTEN损失的作用。将使用原代胶质瘤细胞衍生的和胶质瘤干细胞衍生的异种移植物进行转化实验。这些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。这些发现还将为在临床环境中使用临床适用的抗HGF和抗c-Met疗法以及与mTOR抑制剂组合提供必要和及时的信息。在原代和神经胶质瘤干细胞动物模型中使用临床适用的药物将为所获得的结果提供高有效性和临床前意义。公共卫生相关性：我们以前发现，癌基因c-Met的增加和肿瘤抑制基因PTEN的缺失对胶质瘤脑肿瘤的生长具有累加效应。我们建议研究c-Met和PTEN在胶质瘤中相互调节的新机制。我们还建议测试PTEN对靶向c-Met的新的临床有用药物的影响，并测试用于神经胶质瘤治疗的新药和药物组合。本研究结果将为脑胶质瘤治疗新策略的开发和新药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.