Therapeutic vulnerabilities associated with PTEN missense mutations

项目摘要/摘要 磷酸酶和张力蛋白同源基因(PTEN)内错义突变的遗传丢失或获得 多形性胶质母细胞瘤(GBM)的常见事件。PTEN活性的丧失导致PI3K的强劲激活 这不仅是由于其作为脂质磷酸酶的既定作用，而且也是由于MAPK通路的激活。 保留磷酸酶催化活性的PTEN错义突变在GBM和WE中很常见 展示它们在体外驱动神经胶质瘤形成的能力。这些基因的分子机制 PTEN抑制肿瘤功能的突变是未知的，并且代表了一个重要的研究领域 在癌症中。我们假设保留磷酸酶活性的错义突变不是同义的 PTEN或磷酸酶活性完全丧失死亡错义突变体在其机制中 肿瘤抑制，代表不同类别的PTEN驱动的癌症将会有反应 不同于以PI3K和MEK为中心的治疗方案。在此基础上，我们建议1)开发新的 PTEN基因工程小鼠错义突变模型并利用这些模型优化 针对PI3K和MEK的靶向治疗，以及2)创建同基因PTEN错义突变的人GBM PDX 以发现新的PI3K和MEK抑制策略。拟议研究的总体目标是 提供对GBM基因尖端模型的有效翻译使用，准确概括 将人类疾病的研究引向开发新的治疗方法。

Project Summary/Abstract Genetic loss or acquisition of missense mutations within the phosphatase and tensin homolog (PTEN) gene is a frequent event in glioblastoma multiforme (GBM). Loss of PTEN activity leads to a robust activation of PI3K signaling due to its established role as a lipid phosphatase but also to an activation of the MAPK pathway. Missense mutations within PTEN that retain phosphatase catalytic activity are common in GBM and we demonstrate their capacity to drive gliomagenesis in vitro. The molecular mechanisms by which these mutations abrogate PTEN's tumor suppressive function are unknown and represent a crucial area of research in cancer. We hypothesize that phosphatase activity-retaining missense mutations are not synonymous to complete loss of PTEN or phosphatase activity dead missense mutants in their mechanisms of tumor suppression and represent distinct categories of PTEN driven cancers that will respond differently to PI3K- and MEK-centric treatment regimens. On this basis, we propose to 1) develop new PTEN genetically engineered mouse models of missense mutants and utilize these models to optimize targeted therapies against PI3K and MEK, and 2) create isogenic PTEN missense mutant human GBM PDX lines to uncover new PI3K and MEK inhibition strategies. The overall goal of the proposed research is to deliver on an effective translational use of genetically cutting edge models of GBM that accurately recapitulate human disease to direct research toward the development of new treatments.