Will kinase inhibitors make it as glioblastoma drugs?
Kinase inhibitors have emerged as effective cancer therapeutics in a variety of human cancers. Glioblastoma (GBM), the most common malignant brain tumor in adults, represents a compelling disease for kinase inhibitor therapy because the majority of these tumors harbor genetic alterations that result in aberrant activation of growth factor signaling pathways. Attempts to target the Ras-Phosphatidylinositol 3-kinase (PI3K)-mammalian Target of Rapamycin (mTOR) axis in GBM with first generation receptor tyrosine kinase (RTK) inhibitors and rapalogs have been disappointing. However, there is reason for renewed optimism given the now very detailed knowledge of the cancer genome in GBM and a wealth of novel compounds entering the clinic, including next generation RTK inhibitors, class I PI3K inhibitors, mTOR kinase inhibitors (TORKinibs), and dual PI3(K)/mTOR inhibitors. This chapter reviews common genetic alterations in growth factor signaling pathways in GBM, their validation as therapeutic targets in this disease, and strategies for future clinical development of kinase inhibitors for high grade glioma.
Department and Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. mellingi@mskcc.org
Ingo K
IK
Mellinghoff
Nikolaus
N
Schultz
Paul S
PS
Mischel
Timothy F
TF
Cloughesy
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; C117307:KRAS protein, human; C546842:MTOR protein, human; C512478:EGFR protein, human; C494929:PTEN protein, human