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Improving the efficacy of mTOR inhibition

提高 mTOR 抑制的功效

基本信息

批准号：
10083195
负责人：
Qi Wen Fan
金额：
$ 59.03万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10083195
关键词：
1-Phosphatidylinositol 3-Kinase Active Sites Apoptosis Automobile Driving Autophagocytosis Back Binding Binding Sites Blood - brain barrier anatomy Brain Brain Neoplasms Cell Line Cells Clinical Clinical Trials Combined Modality Therapy Data Development Diarrhea Drug Kinetics Eukaryotic Initiation Factor-4E Exanthema FRAP1 gene Feedback Generations Glioblastoma Glioma Goals Growth Harvest Ligands Link MAP Kinase Gene Malignant Neoplasms Manuscripts Medicine Molecular Molecular Chaperones Mucositis Mus Neuraxis Pathway interactions Patient Care Patients Pharmacology Phosphotransferases Pre-Clinical Model Primary Brain Neoplasms Proteins Proto-Oncogene Proteins c-akt Radiation Recovery Resistance Signal Pathway Signal Transduction Sirolimus Survival Analysis Tacrolimus Binding Proteins Testing Time Toxic effect Tumor Markers Work Xenograft procedure base bevacizumab biomarker development blood-brain barrier permeabilization cancer cell cytotoxicity efficacy evaluation feeding improved in vivo inhibitor/antagonist mTOR Inhibitor mTOR inhibition neoplastic cell novel pre-clinical preclinical efficacy response response biomarker senescence standard of care synergism temozolomide therapy resistant transcriptome sequencing tumor

项目摘要

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.

胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，也是最具侵袭性的癌症之一，磷脂酰肌醇3-激酶（PI 3 K）、AKT和mTOR（雷帕霉素的机制靶标）信号传导。抑制剂靶向PI 3 K-AKT-mTOR通路在临床应用中或在开发中，然而，我们先前已经证明， PI 3 K/AKT的抑制不阻断GBM中的下游mTOR信号传导，从而限制PI 3 K/AKT的功效抑制剂的第一代mTOR抑制剂（雷帕霉素和雷帕霉素类似物）选择性地仅抑制一种mTOR效应子。 mTORC 1蛋白复合物1（S6 K1），抑制反馈激活PI 3 K/AKT信号。二代 mTORC 1/2的ATP活性位点抑制剂（MLN 0128和其他）可抑制mTORC 1的两种效应物（S6 K1和EIF 4 E）还能阻止AKT我们发现，在体内胶质瘤的临床前模型中，这些药物不如雷帕霉素有效，追踪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，我们表明， RapaLink-1具有与雷帕霉素相似的mTORC 1特异性结合和血脑屏障通透性，使用mTORC 1 选择性既能有效阻断mTORC 1内mTOR的催化ATP结合位点，又能在脑中蓄积肿瘤细胞因此，Rapalink-β-1比雷帕霉素更有效，药代动力学优于MLN 0128。 Revolution Medicine正在开发这样的第三代mTORC抑制剂，我们正在与他们合作，开发治疗GBM的药物我们假设第三代mTOR抑制剂在神经胶质瘤中具有高度活性，阐明作用机制，确定反应的生物标志物，优化递送，并确定合作，以驱动细胞毒性，提供了临床前的基本原理，以测试这些药物在患者与GBM。我们的目标是： 1.阐明肿瘤在体内初始消退后如何恢复，并确定反应的生物标志物。 2.合成和测试驱动雷帕霉素和RapaLink-1进入大脑的药物。 3.鉴定协同化疗的药物，以提高RapaLink-1在胶质母细胞瘤中的疗效。