Penas-Prado Marta, Gilbert Mark R
The UT MD Anderson Cancer Center, Department of Neuro-Oncology, Houston, 77030 TX, USA.
Expert Rev Anticancer Ther. 2007 May;7(5):641-61. doi: 10.1586/14737140.7.5.641.
The identification of molecular markers associated with tumor but not with normal tissue has allowed the development of highly specific, targeted therapies for the treatment of cancer. Over the last several years, tremendous advances in our understanding of the genetic and molecular changes involved in the progression of malignant gliomas have triggered a large effort in the development of targeted therapies to treat these tumors. However, to date only a modest clinical benefit, limited to subsets of patients, has been demonstrated. Furthermore, despite a high degree of target selectivity, the use of targeted therapies often has systemic toxicity. The reasons behind this limited clinical success are complex and include the intricacy of the signaling pathways in gliomas and the heterogeneity of the disease process, compounded by existing limitations in assessing the efficacy of these novel agents when conventional end points and clinical trial designs are utilized. However, despite these difficulties targeted therapies remain a very attractive avenue of treatment for malignant gliomas. Three basic approaches are needed to overcome the hurdles associated with targeted therapies: first, further development of genetic profiling techniques will help to better determine the genetic changes and molecular pathways involved in gliomas and will potentially allow the design of individualized therapies based on the genetic and molecular signature of each tumor. Second, there is a need for the development of better combination strategies (complementary targeted agents or targeted agents with chemotherapy drugs) directed towards disease heterogeneity. Third, we need to optimize the design of preclinical and clinical trials to obtain the maximum amount of information in the shortest period of time.
与肿瘤而非正常组织相关的分子标志物的鉴定，使得针对癌症治疗的高度特异性靶向疗法得以发展。在过去几年中，我们对恶性胶质瘤进展过程中涉及的基因和分子变化的理解取得了巨大进展，这引发了在开发治疗这些肿瘤的靶向疗法方面的大量努力。然而，迄今为止，仅证明了对部分患者有适度的临床益处。此外，尽管靶向疗法具有高度的靶点选择性，但使用时往往具有全身毒性。这种有限的临床成功背后的原因很复杂，包括胶质瘤信号通路的复杂性和疾病过程的异质性，当使用传统终点和临床试验设计来评估这些新型药物的疗效时，现有局限性又使情况变得更加复杂。然而，尽管存在这些困难，靶向疗法仍然是治疗恶性胶质瘤非常有吸引力的途径。需要三种基本方法来克服与靶向疗法相关的障碍：第一，进一步发展基因分析技术将有助于更好地确定胶质瘤中涉及的基因变化和分子途径，并有可能根据每个肿瘤的基因和分子特征设计个性化疗法。第二，需要开发针对疾病异质性的更好的联合策略（互补靶向药物或靶向药物与化疗药物联合）。第三，我们需要优化临床前和临床试验的设计，以便在最短时间内获得最大量的信息。
