Molecular interactions and restoration strategies of PTEN and p53 in gliomas

描述（由申请人提供）：PTEN和p53是人类癌症（包括神经胶质瘤）中最常见的突变肿瘤抑制因子。最近的证据表明野生型PTEN和野生型p53（wt-p53）增强彼此的肿瘤抑制功能。Wt-p53诱导PTEN基因转录，wt-PTEN保护wt-p53蛋白免于降解。我们最近首次发现，PTEN在一些神经胶质瘤细胞和肿瘤异种移植物中具有意想不到的肿瘤促进特性。我们有初步证据表明，PTEN获得这些意想不到的肿瘤促进性能，通过提高半衰期和致癌作用的功能获得性p53突变体（mut-p53）。基于这些发现，我们提出了以下新的假设：PTEN肿瘤抑制因子在功能获得性mut-p53基因的调控下可以表现出肿瘤促进作用。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影响，这取决于p53的突变状态。为了检验这一假设及其预后、机制、功能和治疗意义，我们提出了以下研究：在目标#1中，我们将使用大量库存的人类胶质母细胞瘤标本来确定组合的PTEN/p53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，我们将评估恢复PTEN对具有不同p53突变状态的神经胶质瘤肿瘤的体内作用。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细胞和肿瘤中的肿瘤促进作用。将评估所有目标的结果与假设的一致性。成功完成本申请中建议的研究将：1）建立组合的PTEN/p53状态作为预后参数（目的1），2）揭示以前未知的PTEN和mut-p53之间的机制和功能相互作用（目的2），3）确定成功治疗性恢复PTEN的条件和策略（目的3），和4）通过鉴定对p53的小分子调节剂更敏感的肿瘤亚组并提供它们与PTEN恢复的组合的基本原理，对p53的小分子调节剂的使用具有重要的临床意义（目的4）。

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).