Dual mTORC1/2 Blockade Inhibits Glioblastoma Brain Tumor Initiating Cells In Vitro and In Vivo and Synergizes with Temozolomide to Increase Orthotopic Xenograft Survival

Oct 16, 2014Clinical cancer research : an official journal of the American Association for Cancer Research

Blocking mTORC1 and mTORC2 slows glioblastoma tumor-starting cells in lab and animals and works with temozolomide to improve survival in brain tumor models

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Abstract

AZD8055 was highly effective at reducing the viability of brain tumor-initiating cells (BTICs) regardless of their EGFR and PTEN mutational status.

Gefitinib and rapamycin showed modest effects in most BTIC lines.
Systemic administration of AZD8055 effectively inhibited tumor growth in subcutaneous BTIC xenografts.
AZD8055 dramatically reduced Akt/mTORC2 activity in BTICs.
AZD8055 was synergistic with temozolomide (TMZ), leading to significantly prolonged survival in animal models.
Dual inhibition of mTORC1/2 may benefit glioblastoma, including TMZ-resistant subgroups.

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PURPOSE: The EGFR and PI3K/mTORC1/2 pathways are frequently altered in glioblastoma (GBM), but pharmacologic targeting of EGFR and PI3K signaling has failed to demonstrate efficacy in clinical trials. Lack of relevant models has rendered it difficult to assess whether targeting these pathways might be effective in molecularly defined subgroups of GBMs. Here, human brain tumor-initiating cell (BTIC) lines with different combinations of endogenous EGFR wild-type, EGFRvIII, and PTEN mutations were used to investigate response to the EGFR inhibitor gefitinib, mTORC1 inhibitor rapamycin, and dual mTORC1/2 inhibitor AZD8055 alone and in combination with temozolomide (TMZ) EXPERIMENTAL DESIGN: In vitro growth inhibition and cell death induced by gefitinib, rapamycin, AZD8055, and TMZ or combinations in human BTICs were assessed by alamarBlue, neurosphere, and Western blotting assays. The in vivo efficacy of AZD8055 was assessed in subcutaneous and intracranial BTIC xenografts. Kaplan-Meier survival studies were performed with AZD8055 and in combination with TMZ.

RESULTS: We confirm that gefitinib and rapamycin have modest effects in most BTIC lines, but AZD8055 was highly effective at inhibiting Akt/mTORC2 activity and dramatically reduced the viability of BTICs regardless of their EGFR and PTEN mutational status. Systemic administration of AZD8055 effectively inhibited tumor growth in subcutaneous BTIC xenografts and mTORC1/2 signaling in orthotopic BTIC xenografts. AZD8055 was synergistic with the alkylating agent TMZ and significantly prolonged animal survival.

CONCLUSION: These data suggest that dual inhibition of mTORC1/2 may be of benefit in GBM, including the subset of TMZ-resistant GBMs.

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Dual mTORC1/2 Blockade Inhibits Glioblastoma Brain Tumor Initiating Cells In Vitro and In Vivo and Synergizes with Temozolomide to Increase Orthotopic Xenograft Survival

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