Molecularly targeted therapies are transforming the care of patients with malignant gliomas, including glioblastoma, the most common malignant primary brain tumor of adults. With an arsenal of small molecule inhibitors and antibodies that target key components of the signal transduction machinery that are commonly activated in gliomas, neurooncologists and neurosurgeons are poised to transform the care of these patients. Nonetheless, successful application of targeted therapies remains a challenge. Strategies are lacking for directing kinase inhibitor or other pathway-specific therapies to individual patients most likely to benefit. In addition, response to targeted agents is determined not only by the presence of the key mutant kinases, but also by other critical changes in the molecular circuitry of cancer cells, such as loss of key tumor suppressor proteins, the selection for kinase-resistant mutants, and the deregulation of feedback loops. Understanding these signaling networks, and studying them in patients, will be critical for developing rational combination therapies to suppress resistance for malignant glioma patients. Here we review the current status of molecular targeted therapies for malignant gliomas. We focus initially on identifying some of the insights gained to date from targeting the EGFR/PI3K/Akt/mTOR signaling pathway in patients and on how this has led toward a reconceptualization of some of the challenges and directions for targeted treatment. We describe how advances from the world of genomics have the potential to transform our approaches toward targeted therapy, and describe how a deeper understanding of the complex nature of cancer, and its adeptness at rewiring molecular circuitry to evade targeted agents, has raised new challenges and identified new leads.

中文翻译：

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恶性胶质瘤患者的靶向治疗：经验教训和未来之路。

分子靶向治疗正在改变恶性胶质瘤患者的护理，包括胶质母细胞瘤，这是成人最常见的恶性原发性脑肿瘤。凭借一系列针对通常在神经胶质瘤中激活的信号转导机制的关键组件的小分子抑制剂和抗体，神经肿瘤学家和神经外科医生准备改变这些患者的护理。尽管如此，靶向治疗的成功应用仍然是一个挑战。缺乏将激酶抑制剂或其他途径特异性疗法引导至最有可能受益的个体患者的策略。此外，对靶向药物的反应不仅取决于关键突变激酶的存在，还取决于癌细胞分子回路的其他关键变化，例如关键肿瘤抑制蛋白的丢失、激酶抗性突变体的选择以及反馈回路的失调。了解这些信号网络并在患者身上进行研究，对于开发合理的联合疗法以抑制恶性胶质瘤患者的耐药性至关重要。在这里，我们回顾了恶性胶质瘤分子靶向治疗的现状。我们最初专注于确定迄今为止从靶向患者的 EGFR/PI3K/Akt/mTOR 信号通路中获得的一些见解，以及这如何导致对靶向治疗的一些挑战和方向的重新概念化。我们描述了基因组学领域的进步如何有可能将我们的方法转变为靶向治疗，