Evaluation of tyrosine kinase inhibitor combinations for glioblastoma therapy.
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.
Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
Avadhut D
AD
Joshi
Watcharin
W
Loilome
I-Mei
IM
Siu
Betty
B
Tyler
Gary L
GL
Gallia
Gregory J
GJ
Riggins
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D000077156:Gefitinib; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D011916:Rats, Inbred F344; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000077210:Sunitinib; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib; D000077210:Sunitinib