Servei d'Oncologia Medica, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Oncology (V.H.I.O), Passatge Vall d'Hebron 119, 08035 Barcelona, Spain.
Oncologist. 2010;15(1):37-50. doi: 10.1634/theoncologist.2009-0117. Epub 2010 Jan 15.
Numerous practical issues must be considered when combining targeted therapies in early clinical drug development. These include tumor resistance mechanisms, the existence of multiple, redundant signaling pathways, and the failure of single-agent therapies to achieve cures. The strategies adopted to examine combinatorial therapy include the goal of hitting more than one target by specifically inhibiting signal transduction cascades and suppressing specific mechanisms of action with the use of multitargeted kinase inhibitors made possible by high-throughput screening techniques, combinatorial chemistry, and chemoinformatics. Two complex considerations are: which agents to combine given the heterogeneity of tumors and their various underlying perturbations, including secondary mutations and feedback loops, and how to translate findings from the bench to the bedside or directly from the bedside. Another consideration is: When is there enough information to provide a rationale for instituting a phase I trial? Various strategies have been used in combining molecules, including targeting diverse pathways, inhibiting upstream and downstream signals, and adopting a synthetic lethality paradigm. Other issues are: determining appropriate target populations for treatment, how to combine therapeutics with diagnostics, and the frequency of targets in patients referred to clinical trials. Here, we review these issues and we propose various novel trial designs that are logical for determining the efficacy of a drug or drug combination for personalized treatment. A difficult issue that must be answered is how many and which drugs to combine. Recent technologies, such as multiplexed assay platforms and bioinformatics, will shape the future of clinical trials and help answer these questions surrounding combinatorial treatment.
在早期临床药物开发中结合靶向治疗时，必须考虑许多实际问题。这些问题包括肿瘤耐药机制、多个冗余信号通路的存在，以及单药治疗无法治愈疾病的问题。为了检验联合治疗策略，我们采用了以下方法：通过特异性抑制信号转导级联反应，同时利用高通量筛选技术、组合化学和化学信息学来实现多靶点激酶抑制剂，从而达到靶向多个目标的目的；联合使用靶向药物，抑制特定作用机制。需要考虑两个复杂的问题：考虑到肿瘤及其各种潜在扰动（包括继发突变和反馈回路）的异质性，应该选择哪些药物进行联合；以及如何将实验室的研究结果转化为临床应用，或者直接从临床转化为实际应用。另一个需要考虑的问题是：何时有足够的信息为启动 I 期临床试验提供依据？目前已经采用了多种联合分子的策略，包括靶向不同的通路、抑制上下游信号，以及采用合成致死性的方法。还有一些其他的问题需要考虑：确定治疗的合适目标人群，如何将治疗药物与诊断技术相结合，以及临床试验中患者的靶点数。在这里，我们将对这些问题进行综述，并提出各种新颖的临床试验设计，以便为个性化治疗确定药物或药物组合的疗效。必须回答的一个难题是要联合多少种药物，以及应该选择哪些药物。最近的技术，如多重检测平台和生物信息学，将塑造临床试验的未来，并有助于回答这些关于联合治疗的问题。
