权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Improving the efficacy of mTOR inhibition

提高 mTOR 抑制的功效

基本信息

批准号：
10328880
负责人：
Qi Wen Fan
金额：
$ 57.85万
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328880
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 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

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

IFITM proteins assist cellular uptake of diverse linked chemotypes.

IFITM蛋白有助于细胞摄取各种连接的化学型。

DOI：
10.1126/science.abl5829
发表时间：
2022-12-09
期刊：
Science (New York, N.Y.)
影响因子：
0
作者：
通讯作者：

Brain-restricted mTOR inhibition with binary pharmacology.

DOI：
10.1038/s41586-022-05213-y
发表时间：
2022-09
期刊：
NATURE
影响因子：
64.8
作者：
Zhang, Ziyang;Fan, Qiwen;Luo, Xujun;Lou, Kevin;Weiss, William A.;Shokat, Kevan M.
通讯作者：
Shokat, Kevan M.

All eyes on a phosphatase in glioma stem cells.

DOI：
10.1084/jem.20211605
发表时间：
2021-11-01
期刊：
The Journal of experimental medicine
影响因子：
0
作者：
Lindquist RA;Weiss WA
通讯作者：
Weiss WA

Dissecting the biology of mTORC1 beyond rapamycin.

DOI：
10.1126/scisignal.abe0161
发表时间：
2021-09-21
期刊：
Science signaling
影响因子：
7.3
作者：
Yang G;Francis D;Krycer JR;Larance M;Zhang Z;Novotny CJ;Diaz-Vegas A;Shokat KM;James DE
通讯作者：
James DE

Tissue-restricted inhibition of mTOR using chemical genetics.