Novel targeted agents for platelet-derived growth factor receptor and c-KIT in malignant gliomas.
Malignant gliomas are a heterogeneous group of tumors with a varying natural history and response to treatment. Despite current therapeutic strategies, these tumors almost universally recur after excision and are associated with a poor survival. Increasingly, the true heterogeneity of these tumors is being correlated with distinct molecular subgroups. Platelet-derived growth factor receptor (PDGFR) alpha is almost universally expressed on glioma cells; expression of the proto-oncogene c-KIT has also been reported. These findings have led to the clinical investigation of inhibitors of this pathway, such as imatinib and dasatinib, for the treatment of recurrent malignant glioma. To date, this approach in unselected patients has been disappointing. However, isolated responses have been seen, which may correlate with constitutive activation of one or more of the corresponding tyrosine kinases. In the future, it is hoped that an increasing knowledge of glioma biology will translate into the more judicious use of these and other targeted therapies, resulting in improvements in patient outcomes. This review describes the preclinical science behind PDGFR and c-KIT, the clinical importance of these molecular pathways and the available data from translational clinical trials.
Morris
Patrick G
PG
Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. morrisp1@mskcc.org
Abrey
Lauren E
LE
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002986:Clinical Trials as Topic; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction
D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor