Department and Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Curr Top Microbiol Immunol. 2012;355:135-69. doi: 10.1007/82_2011_178.
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.
激酶抑制剂已成为多种人类癌症的有效癌症治疗方法。胶质母细胞瘤（GBM）是成人中最常见的恶性脑肿瘤，代表了激酶抑制剂治疗的一个引人注目的疾病，因为这些肿瘤中的大多数都存在遗传改变，导致生长因子信号通路的异常激活。使用第一代受体酪氨酸激酶（RTK）抑制剂和雷帕霉素类似物靶向 Ras-Phosphatidylinositol 3-kinase（PI3K）-哺乳动物雷帕霉素靶蛋白（mTOR）轴治疗 GBM 的尝试令人失望。然而，鉴于 GBM 中癌症基因组的现有非常详细的知识和大量新型化合物进入临床，包括下一代 RTK 抑制剂、I 类 PI3K 抑制剂、mTOR 激酶抑制剂（TORKinibs）和双重 PI3（K）/mTOR 抑制剂，现在有理由重新感到乐观。本章回顾了 GBM 中生长因子信号通路的常见遗传改变，以及它们在该疾病中作为治疗靶点的验证，并讨论了用于高级别神经胶质瘤的激酶抑制剂的未来临床开发策略。
