Abstract B55: Glioblastoma xenografts obtained from patient derived cancer stem cells preserve the heterogeneous response to targeted therapy
Authors: deCarvalho Ana C. , Hasselbach Laura , Nelson Kevin , Mikkelsen Tom 
Published: June 2012

Abstract
Molecular and signaling pathway heterogeneity contributes to the poor prognosis and high recurrence rate after therapy prevalent for glioblastoma (GBM) patients. Our goal was to test response to pharmacological agents targeting signaling pathways deregulated in glioblastomas: mTOR, RAF/MEK/ERK, VEGFR-2/PDGFRbeta, in preclinical models that use cancer stem cells to preserve the molecular signatures and heterogeneity characteristic of GBMs. Response to the DNA alkylating agent temozolomide (TMZ), used in the standard of care of GBMs, was assessed and correlated with the 06-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, a known predictive biomarker. The efficacy of targeting the base-excision DNA repair protein poly (ADP-ribose) polymerase (PARP) in potentiating TMZ therapy was tested. Neurosphere cultures enriched in cancer stem cells were obtained from four GBM tumors resected at our institution, three from first surgery and one from a post-treatment recurrence. Neurosphere cells were orthotopically implanted in nude mice. TMZ (Schering-Plough), the PI3K/mT0R dual inhibitor BEZ-235 (Novartis), the PARP inhibitor ABT-888 (Abbott Laboratories), and the multi-kinase inhibitor Sorafenib Tosylate (BAY43-9006, Nexavar), which blocks RAF kinase and the VEGFR-2/PDGFRbeta signaling cascade, were tested as part of the Ivy Genomics-Based Medicine Consortium. For the chemoprofiling studies, mice were implanted with each GBM neurosphere line, and divided into treatment cohorts. Drugs were administered 5 days/week intragastrically, for 4 weeks (BEZ-235, Sorafenib and control), or 2 cycles of 1 week each (TMZ and TMZ/ABT-888). Animals were sacrificed when moribund and brain tissue was harvested for molecular profiling and immunohistochemistry. Kaplan-Meier survival curves were compared by log-rank test to evaluate response to treatment. TMZ monotherapy significantly increased survival of xenografts derived from treatment naïve tumors with methylated MGMT promoter. The PARP inhibitor in combination to TMZ did not further improve survival for this cohort. TMZ treatment had no significant effect in survival for the xenografts obtained from the glioblastoma with unmethylated MGMT promoter, but the PARP inhibitor significantly potentiated TMZ for this line. As monotherapy, both the multi-kinase inhibitor Sorafenib and the pan-PI3K/mTOR inhibitor BEZ-235 were effective for one of the four lines. Xenografts derived from the recurrent, previously treated tumor, did not exhibited a significant response to the regimens tested. Improved design of pre-clinical studies using patient derived cancer stem cells will accelerate the pace of translational research, allowing for biomarker identification and testing of targeted agents currently under clinical investigation in animal models that preserve the molecular signatures and heterogeneity of GBMs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B55.