Background: Glioblastoma (GBM) is the most common and aggressive form of brain tumor characterized by poor prognosis and high recurrence rate. Several new targeted agents are being considered for the adjuvant treatment of GBMs. Cabozantinib, a multi-kinase currently in clinical trials for several malignancies, including glioblastoma, targets c-Met and VEGFR2 receptors, as well as Ret, Kit, Flt-1/3/4, Tie2, and AXL. Our goal is to first evaluate sensitivity and molecular response of patient-derived GBM cancer stem cells (CSCs) to XL184 in vitro. Anti-tumor efficacy of cabozantinib as a single agent and in combination with the DNA-alkylating agent temozolomide (TMZ) in orthotopic xenografts was then evaluated.
Methods: Neurospheres enriched in CSCs were cultured from resected GBM tumors. Sensitivity to cabozantinib was determined in vitro. Cells were treated (IC40) in triplicate, and cell lysates were analyzed by reverse phase protein microarrays. GBM CSCs were implanted intracranially into nude mice. Cabozantinib was administered by oral gavage at a dose of 60mg/kg for 4 weeks (5 days/week) as a single agent or in combination with 40mg/kg TMZ. Tumor growth and response to treatment were monitored by non-invasive in vivo biolumiescent imaging (BLI) using the Xenogen IVIS System (Caliper Life Sciences), and overall survival.
Results: Sensitivity to cabozantinib treatment varied for the different GBM CSCs. From 70 proteins and phosphoproteins measured, 29 distributed among several signaling pathways were significantly altered after treatment in both resistant and sensitive GBM CSCs. Cabozantinib single agent treatment reduced GBM tumor growth and increased mouse survival in two xenograft lines. Cabozantinib monotherapy reduced tumor size, as measured by BLI, but had no significant effect on overall survival for another xenograft line, however, the combination treatment resulted in sensitization of these xenografts to TMZ treatment.
Conclusion: The use of multi-kinase inhibitors is a promising strategy for GBMs, and given the range of responses, identifying predictive biomarkers, though challenging, will be invaluable for patient stratification.
Citation Format: Ana C. deCarvalho, Kimberly Arnold, Claudius Mueller, Emanuel F. Petricoin, Laila M. Poisson, Tom Mikkelsen. Cabozantinib affects multiple signaling pathways in glioblastoma and is effective in a subset of xenograft tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3795. doi:10.1158/1538-7445.AM2014-3795