A new kinase inhibitor for glioblastoma

摘要： 肿瘤抑制因子PTEN抵消膜中的1类PI 3激酶功能，导致 目前，大规模的激酶抑制剂开发工作试图抵消在 人类肿瘤然而，我们在细胞核中发现了一条新的PTEN信号通路， 与1类PI 3激酶完全解耦。“脱钩”对抗癌药物很重要 设计是因为如果肿瘤由于核PTEN的丢失而生长，则1类PI 3激酶抑制剂 对这些肿瘤无效事实上，PI 3-激酶抑制剂通常不能挽救 在临床试验中，由于不完全理解的原因，PTEN功能。此外，这种新的PTEN 这条通路从未在任何癌症模型中进行过研究，因为我们偶然发现了它， 检查内分泌失调在核途径中，与PTEN相反的激酶是一种不良的 被称为“肌醇多磷酸多激酶”的肌醇激酶超家族的特征成员 （IPMK）。IPMK是一种核PIP 2激酶，在所有人体组织中普遍表达，结构上 与1类PI 3激酶无关。Alfred Yung表明某些胶质母细胞瘤细胞系停止生长 当与细胞核而不是细胞质的PTEN 2互补时。基于核途径，我们 假设IPMK敲除可能模拟这些细胞中的核PTEN互补。的确， 初步数据显示CRSIPR敲除IPMK表型与核PTEN互补相关， 这些细胞。野生型但非激酶死亡的IPMK挽救了表型，表明IPMK 抑制剂可能是一种有效疗法。这项资助开发了IPMK的化学遗传突变体， 确定IPMK抑制剂是否对胶质母细胞瘤有效。未来项目将使用 生理学相关的小鼠模型，以建立IPMK作为全规模验证的目标 工业激酶抑制剂的努力。

Abstract: The tumor suppressor PTEN counteracts Class 1 PI3-kinase functions in membranes, leading to the massive kinase inhibitor development efforts currently attempting to counteract loss of PTEN in human tumors. However, we discovered a new PTEN signaling pathway in the nucleus that is completely decoupled from Class 1 PI3-kinases. The “decoupling” is important for anti-cancer drug design because if a tumor is growing due to loss of nuclear PTEN, Class 1 PI3-kinase inhibitors would be ineffective against those tumors. Indeed, PI3-kinase inhibitors often fail to rescue loss of PTEN function in clinical trials, for incompletely understood reasons. Further, this new PTEN pathway has never been studied in any model of cancer, as we discovered it fortuitously while examining endocrine disorders. The kinase opposing PTEN in the nuclear pathway is a poorly characterized member of the inositol kinase superfamily called “Inositol Polyphosphate Multikinase” (IPMK). IPMK is a nuclear PIP2-kinase with ubiquitous expression in all human tissues, structurally unrelated to Class 1 PI3-kinases. Alfred Yung showed certain glioblastoma cell lines halted growth when complemented with nuclear, not cytoplasmic PTEN2. Based on the nuclear pathway, we hypothesized IPMK knockout might mimic nuclear PTEN complementation in these cells. Indeed, preliminary data show CRSIPR knockout of IPMK phenocopies nuclear PTEN complementation in these cells. Wild type but not kinase-dead IPMK rescues the phenotype, suggesting an IPMK inhibitor could be an effective therapy. This grant develops a chemical genetic mutant of IPMK to determine if IPMK inhibitors would be effective in glioblastoma. Future projects will use physiologically relevant mouse models to establish IPMK as a validated target for full scale industrial kinase inhibitor efforts.