Therapeutic vulnerabilities associated with PTEN missense mutations

项目总结/摘要 磷酸酶和张力蛋白同源物（PTEN）基因内的遗传丢失或错义突变的获得是 多形性胶质母细胞瘤（GBM）中的常见事件。PTEN活性的丧失导致PI 3 K的稳健活化 由于其作为脂质磷酸酶的既定作用以及MAPK途径的活化，因此其在信号传导中起作用。 在GBM中，PTEN内保留磷酸酶催化活性的错义突变是常见的， 证明了它们在体外驱动胶质瘤生成的能力。这些分子机制 突变消除PTEN的肿瘤抑制功能是未知的，代表了一个重要的研究领域 在癌症中。我们假设磷酸酶活性保留错义突变不是同义的 完全丧失PTEN或磷酸酶活性死亡的错义突变体的机制， 肿瘤抑制，并代表不同类别的PTEN驱动的癌症， 与以PI 3 K和MEK为中心的治疗方案不同。在此基础上，我们建议：1）开发新的 PTEN基因工程错义突变体的小鼠模型，并利用这些模型优化 针对PI 3 K和MEK的靶向疗法，和2）产生同基因PTEN错义突变体人GBM PDX 线，以揭示新的PI 3 K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转化使用， 人类疾病，以指导研究开发新的治疗方法。

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.