c-Met/PTEN Interactions in Gliomas

描述(申请人提供)：在恶性人脑胶质瘤中，酪氨酸激酶受体c-Met及其配体肝细胞生长因子(HGF)经常过度表达，肿瘤抑制基因PTEN经常发生突变。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上的相互作用，并发现c-Met的激活和PTEN的缺失在胶质瘤的恶性程度中具有相加作用。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，重点关注PTEN和c-Met通路之间的新机制相互作用，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。这一发现将揭示HGF诱导恶性转化和PTEN翻译后调控的新机制。在目标2中，我们将检验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过度表达并存的现象，并揭示c-Met表达调控的新机制。在第三个目标中，我们将确定PTEN的表达对抗HGF单抗和一种新的口服生物可用小分子c-Met抑制剂体内治疗效果的影响。我们还将评估联合抗HGF或抗c-Met治疗与mTOR抑制剂的治疗价值，以抵消PTEN突变的异种移植物中PTEN丢失的影响。翻译实验将使用原代胶质瘤细胞来源的异种移植和胶质瘤干细胞来源的异种移植进行。这些实验的成功完成将为PTEN和c-Met的调控提供新的机制洞察力，并揭示它们之间先前未知的分子相互作用。这些发现还将为临床上使用抗HGF和抗c-Met疗法以及与mTOR抑制剂联合使用提供必要和及时的信息。在原代和胶质瘤干细胞动物模型中使用临床适用的药物将赋予所获得的结果高度的有效性和临床前意义。公共卫生相关性：我们先前发现，癌基因c-Met的增加和抑癌基因PTEN的缺失对胶质瘤脑瘤的生长具有相加作用。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在针对c-Met的新的临床有用药物上的效果，并测试治疗胶质瘤的新药和药物组合。这一结果将为开发新的胶质瘤治疗策略提供依据，并为新药在临床上的应用提供重要信息。

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.