Bozic Ivana, Reiter Johannes G, Allen Benjamin, Antal Tibor, Chatterjee Krishnendu, Shah Preya, Moon Yo Sup, Yaqubie Amin, Kelly Nicole, Le Dung T, Lipson Evan J, Chapman Paul B, Diaz Luis A, Vogelstein Bert, Nowak Martin A
Program for Evolutionary Dynamics , Harvard University , Cambridge , United States ; Department of Mathematics , Harvard University , Cambridge , United States.
Elife. 2013 Jun 25;2:e00747. doi: 10.7554/eLife.00747.
In solid tumors, targeted treatments can lead to dramatic regressions, but responses are often short-lived because resistant cancer cells arise. The major strategy proposed for overcoming resistance is combination therapy. We present a mathematical model describing the evolutionary dynamics of lesions in response to treatment. We first studied 20 melanoma patients receiving vemurafenib. We then applied our model to an independent set of pancreatic, colorectal, and melanoma cancer patients with metastatic disease. We find that dual therapy results in long-term disease control for most patients, if there are no single mutations that cause cross-resistance to both drugs; in patients with large disease burden, triple therapy is needed. We also find that simultaneous therapy with two drugs is much more effective than sequential therapy. Our results provide realistic expectations for the efficacy of new drug combinations and inform the design of trials for new cancer therapeutics. DOI:http://dx.doi.org/10.7554/eLife.00747.001.
在实体瘤中，靶向治疗可导致肿瘤显著消退，但由于耐药癌细胞的出现，疗效往往是短暂的。为克服耐药性而提出的主要策略是联合治疗。我们提出了一个数学模型，用于描述肿瘤病灶对治疗的进化动力学。我们首先研究了20名接受维莫非尼治疗的黑色素瘤患者。然后，我们将我们的模型应用于一组独立的患有转移性疾病的胰腺癌、结直肠癌和黑色素瘤患者。我们发现，如果不存在对两种药物都产生交叉耐药性的单一突变，双重治疗可使大多数患者实现长期疾病控制；对于疾病负担较大的患者，则需要三联治疗。我们还发现，两种药物同时治疗比序贯治疗有效得多。我们的结果为新药联合治疗的疗效提供了现实的预期，并为新的癌症治疗试验设计提供了参考。DOI:http://dx.doi.org/10.7554/eLife.00747.001 。
