Evolutionary dynamics of cancer in response to targeted combination therapy.
Evolutionary dynamics of cancer in response to targeted combination therapy.
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DOI：
10.7554/elife.00747
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发表时间：
2013-06-25
期刊：
影响因子：
7.7
通讯作者：
Nowak MA
中科院分区：
文献类型：
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作者：
Bozic I;Reiter JG;Allen B;Antal T;Chatterjee K;Shah P;Moon YS;Yaqubie A;Kelly N;Le DT;Lipson EJ;Chapman PB;Diaz LA Jr;Vogelstein B;Nowak MA
在实体瘤中，靶向治疗可以导致显著的消退，但由于耐药癌细胞的出现，反应往往是短暂的。为克服耐药性提出的主要策略是联合治疗。我们提出了一个数学模型，描述病变的治疗反应的演变动力学。我们首先研究了20例接受维罗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胰腺癌、结直肠癌和黑色素瘤转移性疾病患者。我们发现，如果没有导致对两种药物交叉耐药的单一突变，双重治疗对大多数患者都能实现长期疾病控制;在疾病负担较大的患者中，需要三联治疗。我们还发现，同时使用两种药物治疗比序贯治疗更有效。我们的研究结果为新药物组合的疗效提供了现实的预期，并为新癌症疗法的试验设计提供了信息。DOI：http://dx.doi.org/10.7554/eLife.00747.001随着医学变得越来越个性化，越来越多的重点放在针对特定致癌突变的治疗方法的开发上。但是，尽管这些药物中的许多在短期内有效，并确实延长了患者的生命，但肿瘤往往会在几个月内对它们产生耐药性。关键问题是大肿瘤在遗传上是多样的。这意味着对于任何给定的治疗，肿瘤内可能有一小群细胞对药物的作用具有抗性。当药物被给予患者时，这些细胞将存活并繁殖，最终导致治疗失败。鉴于单一药物因此极不可能根除肿瘤，两种或多种药物的组合可能提供更高的治愈机会。这种方法在治疗艾滋病毒以及某些形式的白血病方面是有效的。在这里，Bozic等人提出了一个数学模型，旨在预测联合靶向治疗对肿瘤的影响，基于从20名黑色素瘤（皮肤癌）患者获得的数据。他们的模型显示，即使人类二倍体细胞中存在的66亿个DNA碱基对中有1个发生了突变，使其对两种药物中的每一种都产生了耐药性，那么用这些药物治疗也不会导致大多数患者的持续改善。这证实了需要开发针对不同途径的药物。该模型还表明，同时给予两种药物的联合治疗远比一个接一个地使用药物的序贯治疗有效。事实上，Bozic等人的模型表明，即使不存在交叉耐药突变，序贯治疗也没有治愈的机会，而联合治疗即使存在交叉耐药突变，也有治愈的希望。通过强调需要开发针对不同途径的药物，并将其组合而不是顺序给药，Bozic等人的研究为药物开发和临床试验设计以及临床实践提供了宝贵的建议。DOI：http://dx.doi.org/10.7554/eLife.00747.002网站
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 As medicine becomes increasingly personalized, more and more emphasis is being placed on the development of therapies that target specific cancer-causing mutations. But while many of these drugs are effective in the short term, and do extend patient lives, tumors tend to evolve resistance to them within a few months. The key problem is that large tumors are genetically diverse. This means that for any given treatment, there is likely to be a small population of cells within the tumor that is resistant to the effects of the drug. When the drug is given to a patient, these cells will survive and multiply and this will lead ultimately to treatment failure. Given that a single drug is therefore highly unlikely to eradicate a tumor, combinations of two or more drugs may offer a higher chance of cure. This approach has been effective in the treatment of HIV as well as certain forms of leukemia. Here, Bozic et al. present a mathematical model designed to predict the effects of combination targeted therapies on tumors, based on the data obtained from 20 melanoma (skin cancer) patients. Their model revealed that if even 1 of the 6.6 billion base pairs of DNA present in a human diploid cell has undergone a mutation that confers resistance to each of two drugs, treatment with those drugs will not lead to sustained improvement for the majority of patients. This confirms the need to develop drugs that target distinct pathways. The model also reveals that combination therapy with two drugs given simultaneously is far more effective than sequential therapy where the drugs are used one after the other. Indeed, the model of Bozic et al. indicates that sequential treatment offers no chance of a cure, even when there are no cross-resistance mutations present, whereas combination therapy offers some hope of a cure, even in the presence of cross-resistance mutations. By emphasizing the need to develop drugs that target distinct pathways, and to administer them in combination rather than sequentially, the study by Bozic et al. offers valuable advice for drug development and the design of clinical trials, as well as for clinical practice. DOI: http://dx.doi.org/10.7554/eLife.00747.002