Project 4: Targeting 4EBP1 in glioblastoma

项目总结 尽管从磷脂酰肌醇3-激酶(PI3K)到雷帕霉素(MTOR)机制靶点的信号转导 胶质母细胞瘤的显著特征，靶向PI3K和mTOR的抑制剂在 胶质母细胞瘤。在本申请中公布的初步数据中，我们确定了mTOR目标p- 4EBP1作为治疗反应的可靠生物标志物。我们进一步证明了PI3K和mTOR的失败 在胶质母细胞瘤患者中测试抑制剂并不是因为这些靶点和途径不重要，而是 因为临床上使用的药物不能靶向4EBP1。我们现在已经确定并测试了一类新的4EBP1 抑制剂(由加州大学旧金山分校的合作者Kevin an Shokat开发)在体内有效地阻断胶质母细胞瘤中的4EBP1， 导致GBM临床前原位模型存活率的显著提高。我们的建议发展了这一点 临床用药类别，评价临床4EBP1抑制剂，提供精准用药路径 期待在胶质母细胞瘤患者中进行临床试验。这种名为Rev1的临床药物可通过合作方式获得 与由肖卡特博士共同创立的革命药品公司合作。虽然胶质母细胞瘤最初不是 革命医学的临床项目，这种孢子激励对胶质瘤的Rev1进行测试。我们将在中测试Rev1 该孢子的早期临床试验将于第四年进行。因此，孢子机制提供了一种独特的 检验假设的机会，即从RapaLink-1衍生的临床药物代表强大的临床 4EBP1的抑制剂，并将在GBM的相关亚群中高度活跃。我们的具体目标是： 目的1.确定使用4EBP1抑制剂进行临床试验的最佳胶质瘤亚群 目的2.优化4EBP1抑制剂的临床疗效。 目的3.设计并进行一项使用Rev1治疗通路激活的复发的IB期临床试验 胶质母细胞瘤。

PROJECT SUMMARY Although signaling from phosphoinositide 3-kinase (PI3K) to the mechanistic target of rapamycin (mTOR) features prominently in glioblastoma, inhibitors that target PI3K and mTOR have failed in patients with glioblastoma. In published and preliminary data presented in this application, we identified the mTOR target p- 4EBP1 as a robust biomarker for therapeutic response. We further show that the failure of PI3K and mTOR inhibitors tested in glioblastoma patients is not because these targets and pathways are unimportant, but because agents used clinically fail to target 4EBP1. We have now identified and tested a new class of 4EBP1 inhibitors (developed by UCSF collaborator Kevan Shokat) that potently block 4EBP1 in glioblastoma in-vivo, leading to robust improvement in survival in preclinical orthotopic models of GBM. Our proposal develops this class of drugs for clinical use, evaluating a clinical 4EBP1 inhibitor, and providing a precision medicine path forward for a clinical trial in patients with glioblastoma. This clinical agent, Rev1, is available collaboratively with Revolution Medicines, a company co-founded by Dr. Shokat. While glioblastoma was not initially part of Revolution Medicine's clinical program, this SPORE incentivizes testing of Rev1 in glioma. We will test Rev1 in an early phase clinical trial by year 4 for this SPORE. The SPORE mechanism therefore provides a unique opportunity to test the hypothesis that clinical agents derivatized from RapaLink-1 represent potent clinical inhibitors of 4EBP1, and will be highly active in relevant subpopulations of GBM. Our specific aims are: Aim 1. To define the optimal glioma sub-population for clinical trials using inhibitors of 4EBP1 Aim 2. To optimize the efficacy of 4EBP1 inhibitors for clinical development. Aim 3. To design and conduct a phase IB clinical trial with Rev1 in pathway-activated recurrent glioblastoma.