Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Antineoplastic Agents / pharmacology*
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Clinical Trials as Topic
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Drug Resistance, Neoplasm
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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Glioblastoma / drug therapy*
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Glioblastoma / enzymology
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Glioblastoma / genetics
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Humans
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Mutation*
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PTEN Phosphohydrolase / antagonists & inhibitors
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Platelet-Derived Growth Factor / genetics
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Platelet-Derived Growth Factor / metabolism
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins p21(ras)
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Signal Transduction
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism
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ras Proteins / antagonists & inhibitors
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ras Proteins / genetics
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ras Proteins / metabolism
Substances
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Antineoplastic Agents
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KRAS protein, human
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Phosphoinositide-3 Kinase Inhibitors
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Platelet-Derived Growth Factor
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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MTOR protein, human
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EGFR protein, human
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ErbB Receptors
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TOR Serine-Threonine Kinases
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PTEN Phosphohydrolase
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PTEN protein, human
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Proto-Oncogene Proteins p21(ras)
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ras Proteins
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Sirolimus