A new kinase inhibitor for glioblastoma

摘要： 肿瘤抑制因子 PTEN 抵消膜中 1 类 PI3 激酶的功能，导致 目前正在进行大规模激酶抑制剂开发工作，试图抵消 PTEN 的损失 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，即 与 1 类 PI3 激酶完全解耦。 “脱钩”对于抗癌药物很重要 设计的原因是，如果肿瘤因核 PTEN（1 类 PI3 激酶抑制剂）缺失而生长 对这些肿瘤无效。事实上，PI3 激酶抑制剂常常无法挽救 PTEN 在临床试验中发挥作用，原因尚不完全清楚。此外，这个新的PTEN 该途径从未在任何癌症模型中进行过研究，正如我们在研究过程中偶然发现的那样 检查内分泌失调。核途径中对抗 PTEN 的激酶是一种很差的激酶。 肌醇激酶超家族的特征成员，称为“肌醇多磷酸多激酶” （IPMK）。 IPMK 是一种核 PIP2 激酶，在所有人体组织中普遍表达，结构上 与 1 类 PI3 激酶无关。 Alfred Yung 发现某些胶质母细胞瘤细胞系停止生长 当与核而非细胞质 PTEN2 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。确实， 初步数据显示 IPMK 表型的 CRSIPR 敲除可导致核 PTEN 互补 这些细胞。野生型而非激酶死亡的 IPMK 拯救了表型，表明 IPMK 抑制剂可能是一种有效的治疗方法。这笔赠款开发了 IPMK 的化学基因突变体 确定 IPMK 抑制剂是否对胶质母细胞瘤有效。未来的项目将使用 生理相关的小鼠模型，将 IPMK 建立为全面验证的目标 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.