Glioblastoma multiforme (GBM) is the most common intracranial
cancer but despite recent advances in
therapy the overall survival remains about 20 months. Whole genome exon sequencing studies implicate mutations in the
receptor tyrosine kinase pathways (RTK) for driving
tumor growth in over 80% of GBMs. In spite of various RTKs being mutated or altered in the majority of GBMs, clinical studies have not been able to demonstrate efficacy of
molecular targeted therapies using
tyrosine kinase inhibitors in GBMs. Activation of multiple downstream signaling pathways has been implicated as a possible means by which inhibition of a single RTK has been ineffective in GBM. In this study, we sought a combination of approved drugs that would inhibit in vitro and in vivo growth of GBM oncospheres. A combination consisting of
gefitinib and
sunitinib acted synergistically in inhibiting growth of GBM oncospheres in vitro.
Sunitinib was the only RTK inhibitor that could induce apoptosis in GBM cells. However, the in vivo efficacy testing of the
gefitinib and
sunitinib combination in an EGFR amplified/PTEN wild type GBM xenograft model revealed that
gefitinib alone could significantly improve survival in animals whereas
sunitinib did not show any survival benefit. Subsequent testing of the same
drug combination in a different syngeneic
glioma model that lacked EGFR amplification but was more susceptible to
sunitinib in vitro demonstrated no survival benefit when treated with
gefitinib or
sunitinib or the
gefitinib and
sunitinib combination. Although a modest survival benefit was obtained in one of two animal models with EGFR amplification due to
gefitinib alone, the addition of
sunitinib, to test our best in vitro combination
therapy, did not translate to any additional in vivo benefit. Improved targeted
therapies, with
drug properties favorable to intracranial
tumors, are likely required to form effective
drug combinations for GBM.