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-?1is 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.

Public Health Relevance

We describe a novel mTOR inhibitor, RapaLink-1, that is 1-2 logs more potent that existing mTOR inhibitors, is blood brain barrier permeable, accumulates in glioblastoma tumor cells and shows efficacy in-vivo. We propose a detailed characterization, including analysis of efficacy, identification of response biomarkers, and development and characterization of existing and novel agents that enhance efficacy in combination. Successful completion provides the preclinical rational to initiate a clinical trial of RapaLink-1 in patients with glioblastoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA221969-01
Application #
9421529
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
2018-02-01
Project End
2023-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
An, Zhenyi; Knobbe-Thomsen, Christiane B; Wan, Xiaohua et al. (2018) EGFR Cooperates with EGFRvIII to Recruit Macrophages in Glioblastoma. Cancer Res 78:6785-6794
Griveau, Amelie; Seano, Giorgio; Shelton, Samuel J et al. (2018) A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment. Cancer Cell 33:874-889.e7
Zheng, Tina; Ménard, Marie; Weiss, William A (2017) Neuroblastoma Metastases: Leveraging the Avian Neural Crest. Cancer Cell 32:395-397