Molecular interactions and restoration strategies of PTEN and p53 in gliomas

描述(申请人提供)：PTEN和P53是人类癌症中最常见的突变肿瘤抑制基因，包括胶质瘤。最近的证据表明，野生型PTEN和野生型P53(wt-P53)相互增强肿瘤抑制功能。Wt-p53诱导PTEN基因转录，wt-PTEN保护wt-p53蛋白不降解。我们最近首次发现，PTEN在一些胶质瘤细胞和肿瘤移植瘤中具有意想不到的促肿瘤特性。我们有初步证据表明，PTEN通过增强功能获得的p53突变体(mut-p53)的半衰期和致癌效应，获得了这些意想不到的促癌特性。基于这些发现，我们提出了以下新的假设：PTEN肿瘤抑制因子可以在功能获得型mut-p53的背景下表现出促肿瘤特性。因此，旨在恢复PTEN表达或功能的治疗策略可能会导致不同的效果，这取决于p53的突变状态。为了验证这一假设及其预后、机制、功能和治疗意义，我们提出了以下研究：在目标1中，我们将使用大量的人脑胶质母细胞瘤样本来确定PTEN/P53联合突变状态与临床结果之间的关联。在目标2中，我们将研究PTEN调节mut-p53蛋白水平和功能的机制。在目标3中，我们将评估修复PTEN对具有不同P53突变状态的胶质瘤的体内效果。在目标4中，我们将确定P53的小分子调节剂是否可以逆转PTEN在mut-P53细胞和肿瘤中的促肿瘤作用。所有AIMS的结果都将被评估其与假设的一致性。本申请中建议的研究的成功完成将：1)确定PTEN/P53的联合状态作为预后参数(目标1)，2)揭示先前未知的PTEN和MUT-P53之间的机制和功能相互作用(目标2)，3)确定成功修复PTEN的条件和策略(目标3)，以及4)通过确定对这些药物更敏感的一组肿瘤并为其与PTEN修复结合使用(目标4)，对于使用小分子调节剂P53具有重要的临床意义。

DESCRIPTION (provided by applicant): PTEN and p53 are the most frequently mutated tumor suppressors in human cancer, including gliomas. Recent evidence shows that wild-type PTEN and wild-type p53 (wt-p53) enhance each other's tumor suppressive functions. Wt-p53 induces PTEN gene transcription and wt-PTEN protects wt-p53 protein from degradation. We recently found, for the first time, that PTEN has unexpected tumor promoting properties in some glioma cells and tumor xenografts. We have preliminary evidence that PTEN acquires these unexpected tumor promoting properties by enhancing the half-life and oncogenic effects of gain-of-function p53 mutants (mut-p53). Based on these findings, we formulate the following novel hypothesis: PTEN tumor suppressor can exhibit tumor promoting properties in the setting of gain-of-function mut-p53. Therefore, therapeutic strategies that aim at restoring PTEN expression or function could lead to varying effects that depend on the mutational status of p53. To test this hypothesis and its prognostic, mechanistic, functional and therapeutic implications, we propose the following studies: In aim #1, we will use a large number of banked human glioblastoma specimens to determine the association between the combined PTEN/p53 mutational status and clinical outcome. In aim #2, we will investigate the mechanism through which PTEN regulates mut-p53 protein levels and function. In aim #3, we will assess the in vivo effects of restoring PTEN to glioma tumors with varying p53 mutational status. In aim #4, we will determine if small molecule modulators of p53 can reverse the tumor promoting effects of PTEN in mut-p53 cells and tumors. The results from all aims will be assessed for their consistency with the hypothesis. Successful completion of the studies proposed in this application would: 1) establish the combined PTEN/p53 status as a prognostic parameter (aim 1), 2) uncover previously unknown mechanistic and functional interactions between PTEN and mut-p53 (aim 2), 3) determine conditions and strategies for a successful therapeutic restoration of PTEN (aim 3), and 4) have important clinical implications for the use of small molecule modulators of p53 by identifying a subset of tumors that are more sensitive to these drugs and providing a rationale for their combination with PTEN restoration (aim 4).