Rowinsky Eric K
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas, USA.
Clin Cancer Res. 2004 Jun 15;10(12 Pt 2):4220s-4226s. doi: 10.1158/1078-0432.CCR-040013.
A greater understanding of the pathogenesis and biology of cancer coupled with major advances in biotechnology has resulted in the identification of rationally designed, target-based (RDTB) anticancer therapeutics, ushering in new therapeutic opportunities and high expectations for the future as well as developmental challenges. Because these agents appear to principally target malignant cells, it is expected that they will produce less toxicity at clinically effective doses than nonspecific cytotoxic agents, but their target requirements are likely to be much more stringent. The innate complexity of the networks that contain elements targeted by these agents also decreases the probability that any single therapeutic manipulation will result in robust clinical activity and success when used alone, particularly in patients with solid malignancies that have multiple relevant signaling aberrations. In contrast, proof of principle and robust antitumor activity may be most efficiently demonstrated in nonrandomized evaluations involving tumors that are principally driven by aberrations of the specific target. The predominant therapeutic manifestation of RDTB agents in preclinical studies is due to decreased tumor growth rates and will likely be similar in the clinic; however, such manifestations are not readily detectable and quantifiable using nonrandomized clinical evaluations. To curtail the increasing rate of late-stage attrition of RDTB agents, which, if maintained, will stymie progress in cancer therapy, the design of initial nonrandomized evaluations, particularly the selection of tumors and patients, must be guided by the principal biological features of the agents. Next, evaluations, some of which must be randomized, can be performed in a wide range of tumor types, depending on the presence and relevance of the target. To validate the concept of RDTB therapeutics and to realize their full potential, radically different development, evaluation, and regulatory paradigms must be adopted.
对癌症发病机制和生物学的更深入理解，再加上生物技术的重大进展，已促成了合理设计的、基于靶点的（RDTB）抗癌疗法的识别，带来了新的治疗机遇以及对未来的高度期望，同时也带来了发展挑战。由于这些药物似乎主要靶向恶性细胞，预计它们在临床有效剂量下产生的毒性将低于非特异性细胞毒性药物，但它们对靶点的要求可能更为严格。包含这些药物所靶向元素的网络固有的复杂性也降低了任何单一治疗操作单独使用时产生强大临床活性和成功的可能性，尤其是在患有多种相关信号异常的实体恶性肿瘤患者中。相比之下，在涉及主要由特定靶点异常驱动的肿瘤的非随机评估中，可能最有效地证明原理验证和强大的抗肿瘤活性。RDTB药物在临床前研究中的主要治疗表现是肿瘤生长速率降低，在临床中可能也类似；然而，使用非随机临床评估不容易检测和量化这种表现。为了降低RDTB药物后期淘汰率的上升，如果这种情况持续下去，将阻碍癌症治疗的进展，初始非随机评估的设计，特别是肿瘤和患者的选择，必须以药物的主要生物学特征为指导。接下来，可以根据靶点的存在和相关性，在广泛的肿瘤类型中进行评估，其中一些评估必须是随机的。为了验证RDTB疗法的概念并实现其全部潜力，必须采用截然不同的开发、评估和监管模式。
