Improving the efficacy of mTOR inhibition

胶质母细胞瘤(GBM)是最常见的原发脑肿瘤，也是最具侵袭性的癌症之一，由 磷脂酰肌醇3-激酶(PI3K)、AKT和mTOR(雷帕霉素的机制靶点)信号转导。抑制剂 靶向PI3K-AKT-mTOR通路正在临床使用或正在开发中，但我们之前已经证明 抑制PI3K/AKT不会阻断GBM中下游的mTOR信号，从而限制PI3K/AKT的疗效 抑制剂。第一代mTOR抑制剂(雷帕霉素和雷帕洛格)仅选择性地抑制 MTORC1蛋白复合体1(S6K1)，通过抑制反馈激活PI3K/AKT信号。第二代 MTORC1/2的ATP活性位点抑制剂(MLN0128等)抑制mTORC1(S6K1和eIF4E)的两个效应器 并且还阻止了AKT。我们发现，在体内的胶质瘤临床前模型中，这些药物不如雷帕霉素有效， 可追溯到不良的药代动力学。我们测试了第三代mTOR抑制剂(Rapalink-1)。在内部，我们展示了 RapaLink-1具有mTORC1特异性结合和血脑屏障通透性，类似于雷帕霉素，使用mTORC1 选择性地有效地阻断mTORC1内mTOR的催化ATP结合部位，并在大脑中积聚 肿瘤细胞。因此，Rapalink--1比雷帕霉素更有效，比MLN0128表现出更好的药代动力学。 革命医学正在开发这种第三代mTORC抑制剂，我们正在与他们合作帮助 开发这些用于GBM的试剂。我们假设第三代mTOR抑制剂在胶质瘤中高度活跃，并且 阐明作用机制，确定反应的生物标志物，优化给药，并确定 合作驱动细胞毒性，为在GBM患者中测试这些药物提供了临床前理论基础。我们的目标是： 1.阐明肿瘤在体内最初消退后如何恢复，并确定反应的生物标志物。 2.合成并测试将雷帕霉素和RapaLink-1推向大脑的药物。 3.寻找药物协同作用的药物，提高RapaLink-1治疗胶质母细胞瘤的疗效。

Glioblastoma (GBM), the most common primary brain tumor and among the most aggressive of cancers, is driven by phosphatidylinositide 3-kinase (PI3K), AKT, and mTOR (mechanistic target of rapamycin) signaling. Inhibitors that target PI3K-AKT-mTOR pathways are in clinical use or in development, however we have demonstrated previously that inhibition of PI3K/AKT does not block downstream mTOR signaling in GBM, thereby limiting efficacy of PI3K/AKT inhibitors. First generation mTOR inhibitors (rapamycin and rapalogs) selectively inhibit only one effector of the mTORC1 protein complex1 (S6K1), with inhibition feeding back to activate PI3K/AKT signaling. Second generation ATP-active site inhibitors of mTORC1/2 (MLN0128 and others) inhibit both effectors of mTORC1 (S6K1 and EIF4E) and also block AKT. We show within that these are less effective than rapamycin in preclinical models of glioma in-vivo, traced to poor pharmacokinetics. We tested a third generation mTOR inhibitor (Rapalink-1). Within, we show that RapaLink-1 has mTORC1-specific binding and blood brain barrier permeability similar to rapamycin, uses mTORC1 selectivity both to potently block the catalytic ATP-binding site of mTOR within mTORC1, and to accumulate in brain tumor cells. Consequently, Rapalink-­‐1 is more potent than rapamycin and shows better pharmacokinetics than MLN0128. Revolution Medicine is developing such third generation mTORC inhibitors, and we are working with them to help develop these agents for GBM. We hypothesize that third generation mTOR inhibitors will be highly active in glioma, and that clarifying mechanism of action, identifying biomarkers of response, optimizing delivery, and identifying agents that cooperate to drive cytotoxicity, provides a preclinical rationale to test these agents in patients with GBM. Our aims are: 1. To clarify how tumors recover after initial regression in vivo, and to identify biomarkers of response. 2. Synthesize and test agents that drive rapamycin and RapaLink-1 into the brain. 3. To identify agents that cooperate pharmacologically, to improve the efficacy of RapaLink-1 in glioblastoma.