Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, UK.
Clinical Trials and Statistical Unit, The Institute of Cancer Research, UK.
Cancer Treat Rev. 2023 Jul;118:102583. doi: 10.1016/j.ctrv.2023.102583. Epub 2023 May 24.
The evolution of drug-resistant cell subpopulations causes cancer treatment failure. Current preclinical evidence shows that it is possible to model herding of clonal evolution and collateral sensitivity where an initial treatment could favourably influence the response to a subsequent one. Novel therapy strategies exploiting this understanding are being considered, and clinical trial designs for steering cancer evolution are needed. Furthermore, preclinical evidence suggests that different subsets of drug-sensitive and resistant clones could compete between themselves for nutrients/blood supply, and clones that populate a tumour do so at the expense of other clones. Treatment paradigms based on this clinical application of exploiting cell-cell competition include intermittent dosing regimens or cycling different treatments before progression. This will require clinical trial designs different from the conventional practice of evaluating responses to individual therapy regimens. Next-generation sequencing to assess clonal dynamics longitudinally will improve current radiological assessment of clinical response/resistance and be incorporated into trials exploiting evolution. Furthermore, if understood, clonal evolution can be used to therapeutic advantage, improving patient outcomes based on a new generation of clinical trials.
耐药细胞亚群的进化导致癌症治疗失败。目前的临床前证据表明，有可能对克隆进化的趋同和附带敏感性进行建模，其中初始治疗可能有利于对后续治疗的反应。正在考虑利用这种理解的新治疗策略，并且需要针对癌症进化的临床试验设计。此外，临床前证据表明，药物敏感和耐药克隆的不同亚群可能会为营养/血液供应而相互竞争，并且在肿瘤中定植的克隆是以牺牲其他克隆为代价的。基于这种细胞-细胞竞争的临床应用的治疗方案包括间歇性给药方案或在进展前循环使用不同的治疗方法。这将需要不同于评估个体治疗方案反应的传统实践的临床试验设计。用于评估克隆动力学的下一代测序将改善目前对临床反应/耐药性的放射学评估，并纳入利用进化的试验。此外，如果能够理解，克隆进化可以被用于治疗优势，根据新一代临床试验改善患者的预后。
