Hait William N, Hambley Trevor W
Division of Johnson and Johnson, Ortho Biotech Oncology Research and Development, Raritan, New Jersey 08869, USA.
Cancer Res. 2009 Feb 15;69(4):1263-7; discussion 1267. doi: 10.1158/0008-5472.CAN-08-3836. Epub 2009 Feb 10.
Targeted therapies can be defined as drugs developed against a specific target based on its important biological function in cancer. In contrast, nontargeted therapies are drugs identified by phenotypic screening of natural products or chemical libraries against established cancer cell lines or preclinical animal models without a priori knowledge of the target. Targeted therapies are designed to selectively inhibit a target that is abnormal in malignant compared with normal tissues; these drugs often affect proximal events in signaling pathways that drive abnormal growth and have relatively low toxicity. In contrast, nontargeted therapies affect proteins or nucleic acids that may or may not be abnormal in malignant compared with normal tissues; these drugs often target the downstream consequences of activated signaling pathways, e.g., DNA synthesis and microtubule assembly, and are toxic. Whereas targeted therapies are highly effective in selected hematopoietic malignancies, most have shown limited efficacy against complex solid tumors. In contrast, nontargeted drugs include some of the most effective yet most toxic drugs in the oncology pharmacopoeia. In the future, advances in genomics, proteomics, biology, biomarkers, chemistry, and protein engineering will coalesce to accelerate the development of increasingly selective and effective targeted therapies. Understanding the target in context will help identify biomarkers predictive of response. Finally, a detailed understanding of the target's structure and function will help anticipate and identify mechanism of drug resistance and help design drugs and combinations of drugs that retain activity.
靶向疗法可定义为基于其在癌症中重要的生物学功能针对特定靶点研发的药物。相比之下，非靶向疗法是通过对天然产物或化学文库针对已建立的癌细胞系或临床前动物模型进行表型筛选而鉴定出的药物，事先并不了解靶点。靶向疗法旨在选择性抑制与正常组织相比在恶性肿瘤中异常的靶点；这些药物通常影响驱动异常生长的信号通路中的近端事件，且毒性相对较低。相比之下，非靶向疗法影响与正常组织相比在恶性肿瘤中可能异常也可能不异常的蛋白质或核酸；这些药物通常靶向激活的信号通路的下游后果，例如DNA合成和微管组装，并且具有毒性。虽然靶向疗法在某些血液系统恶性肿瘤中非常有效，但大多数对复杂实体瘤的疗效有限。相比之下，非靶向药物包括肿瘤学药典中一些最有效但毒性也最大的药物。未来，基因组学、蛋白质组学、生物学、生物标志物、化学和蛋白质工程等领域的进展将汇聚在一起，加速研发出越来越具选择性和有效性的靶向疗法。了解靶点的背景情况将有助于识别预测反应的生物标志物。最后，对靶点结构和功能的详细了解将有助于预测和识别耐药机制，并有助于设计保持活性的药物和药物组合。
