Project 4: Targeting 4EBP1 in glioblastoma

项目摘要 尽管从磷酸肌醇3-激酶（PI 3 K）到雷帕霉素（mTOR）的机制靶点的信号传导 在胶质母细胞瘤中具有突出的特征，靶向PI 3 K和mTOR的抑制剂在患有 胶质母细胞瘤在本申请中提供的公开和初步数据中，我们鉴定了mTOR靶点p- 4 EBP 1作为治疗反应的稳健生物标志物。我们进一步表明，PI 3 K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， 因为临床上使用的药物不能靶向4 EBP 1。我们现在已经确定并测试了一类新的4 EBP 1 抑制剂（由UCSF合作者Kevan Shokat开发）在体内胶质母细胞瘤中有效阻断4 EBP 1， 导致GBM的临床前原位模型中的存活率的稳健改善。我们的建议发展了这一点 临床使用的药物类别，评估临床4 EBP 1抑制剂，并提供精确的药物路径 在胶质母细胞瘤患者中进行临床试验。该临床药物Rev 1可通过协作获得 与Shokat博士共同创立的Revolution Medicines公司合作虽然胶质母细胞瘤最初不是 Revolution Medicine的临床项目，这个孢子激励神经胶质瘤中Rev 1的测试。我们将测试Rev 1， 在第4年之前完成该SPORE的早期临床试验。因此，SPORE机制提供了一种独特的 有机会检验从RapaLink-1衍生的临床药物代表有效的临床 4 EBP 1的抑制剂，并将在GBM的相关亚群中具有高度活性。我们的具体目标是： 目标1。确定使用4 EBP 1抑制剂进行临床试验的最佳胶质瘤亚群 目标2.优化4种EBP 1抑制剂的临床开发效果。 目标3。设计并实施一项在通路激活的复发性 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.