Alternative Dosing Schedule Could Delay Resistance to Targeted Melanoma Therapy
针对黑色素瘤的另一给药方案可能延缓耐药
Treatment with vemurafenib, a drug in the BRAF inhibitor family, results in rapid tumor shrinkage in metastatic melanoma patients with the V600E BRAF mutation. The response lasts for months, but unfortunately, tumors ultimately become resistant to the treatment. Currently, vemurafenib is given as an oral dose on a daily basis. But a new study published in Nature (doi:10.1038/nature11814) suggests that a 4-weeks-on, 2-weeks-off dosing schedule may help to stave off resistance.
方案采用Vemurafenib（一种BRAF家族的抑制剂），使具有V600 BRAF突变的转移性黑色素瘤患者肿瘤迅速缩小。反应持续在几个月后，最终还是由于肿瘤的耐药结束。现在，Vemurafenib每天以口服的形式给药。然而Nature(doi:10.1038/nature11814)上刊登了一种吃四周停两周的新方案，这种方案或可躲避耐药现象。
The study was performed in a mouse model of metastatic melanoma by Darrin Stuart, a senior investigator at the Novartis Institutes for Biomedical Research in California and Martin McMahon, a professor of cancer biology at the Helen Diller Family Comprehensive Cancer Center at the University of California in San Francisco. These investigators and colleagues used mice that had received xenografts (transplants of human tissue) of BRAF-mutated melanoma. The researchers created vemurafenib-resistant tumors in these mice by giving them a daily, continuous dose of vemurafenib.
实验在有转移性黑色素瘤的小鼠模型展开，诺华的研究员使用了已获得BRAF突变的黑色素瘤异种移植小鼠（人体组织移植）作为实验对象，持续每天饲以Vemurafenib，以使小鼠获得对Vemurafenib耐药的肿瘤。
Culturing of vemurafenib-resistant tumor cells taken from the mouse models led to an interesting observation. The resistant cells had difficulty growing unless the media was spiked with vemurafenib. “The fitness benefit given to resistant cells by elevated BRAF (V600E) in the presence of vemurafenib becomes a fitness deficit when the drug is removed,” state the authors in the paper.
在小鼠模型上得到的耐药肿瘤使我们看到一个有趣的现象。除非媒介（？）中渗入vemurafenib，否则耐药细胞的增长也会遇到阻碍。作者在其报告中指出：“如果vemurafenib被撤掉，由上升的BRAF(V600E)带给耐药细胞的益处会对健康造成损害。”（大意是说如果停药，Braf除了自己本身对肿瘤的影响，还会刺激原本由于服药新产生的耐药细胞增长）
McMahon and colleagues then compared a continuous vemurafenib treatment schedule with a 4-weeks-on, 2-weeks-off schedule in the BRAF-mutant mouse model. While the mice that were continuously dosed developed vemurafenib-resistant melanoma within 100 days of starting the treatment, mice given vemurafenib on an on-off schedule did not have drug-resistant melanoma as many as 200 days after their initial therapy.
随后研究人员在Braf突变的小鼠模型比较了4周给药2周停药的方案。与100天持续给药的小鼠相比，断断续续的给药方案使小鼠在最初治疗的200天后仍未产生耐药黑色素瘤。
These results suggest that constant exposure to vemurafenib leads to resistance and that an intermittent dosing schedule could delay—if not prevent—resistance. Whether the same results will be observed in patients needs to be tested. The perfect dosing schedule would balance between allowing tumors to regress and stalling resistance
这些结果表明，经常接触到vemurafenib会导致耐药，而间歇给药方案即使不能防止耐药，也可能会延迟耐药的到来。在患者中是否会获得相同的结果仍将进行测试。完美的给药方案将是在肿瘤减小和不产生抗药性取得平衡。
More basic research in mouse models is needed, but the concept could be tested in a metastatic melanoma clinical trial soon. This study also has implications for other targeted therapies. Hopefully, testing various dosing schedules of targeted agents to find an optimal balance between response and rate of resistance will now be a high priority for not just melanoma researchers, but for all cancer researchers. For example, it is possible that continuous dosing contributes to the rate of resistance to other targeted agents, such as imatinib (Gleevec) prescribed for chronic myeloid leukemia. This could be relatively easily tested in experimental models and then in clinical trials.
我们需要在小鼠模型中进行更多的基础研究，但这个理论可以马上就能在转移性黑素瘤进行临床试验。这项研究同样也对其他靶向治疗药物有意义。希望各种不同服药方案的实验能在响应率和耐药率之间找到最佳平衡，不仅针对黑色素瘤并且能在所有类型的癌症中进行研究。
Effects of Pharmacokinetic Processes and Varied Dosing Schedules on the Dynamics of Acquired Resistance to Erlotinib in EGFR-Mutant Lung Cancer
EGFR突变肺癌患者对厄罗替尼获得性耐药细胞在药代动力学和不同给药方案的的影响
Introduction—Erlotinib (Tarceva) is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, which effectively targets EGFR-mutant driven non–small-cell lung cancer. However, the evolution of acquired resistance because of a second-site mutation (T790M) within EGFR remains an obstacle to successful treatment.
厄洛替尼（特罗凯）是表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，它有效地靶向EGFR突变驱动的非小细胞肺癌。然而，由于EGFR二次突变（T790M）所进化产生而来的获得性耐药因子，仍是成功的治疗的障碍。
Methods—We used mathematical modeling and available clinical trial data to predict how different pharmacokinetic parameters (fast versus slow metabolism) and dosing schedules (low dose versus high dose; missed doses with and without make-up doses) might affect the evolution of T790M-mediated resistance in mixed populations of tumor cells.
我们使用数学模型和现有的临床试验数据来预测不同的药代动力学参数（快与慢代谢）和给药方案（低剂量和高剂量;错过给药后补充和不补充），分析T790M突变导致耐药在不同肿瘤细胞人群中的影响。
Results—We found that high-dose pulses with low-dose continuous therapy impede the development of resistance to the maximum extent, both pre- and post-emergence of resistance. The probability of resistance is greater in fast versus slow drug metabolizers, suggesting a potential mechanism, unappreciated to date, influencing acquired resistance in patients. In case of required dose modifications because of toxicity, little difference is observed in terms of efficacy and resistance dynamics between the standard daily dose (150 mg/d) and 150 mg/d alternating with 100 mg/d. Missed doses are expected to lead to resistance faster, even if make-up doses are attempted.
我们发现，无论是在耐药产生前还是开始产生耐药时，高剂量脉冲合并低剂量持续疗法在最大程度上阻止抗药性的发展。耐药性在很大概率上是受药物代谢速度快慢的影响。考虑到药物毒性，采用了小差异交替给药——比较组：标准每日剂量（150毫克/ d）；实验组：100毫克/天&150毫克/天之间交替。实验观察疗效和耐药动力学方面观察。即使补充给药，预计错过给药会导致耐药更快到达。
Conclusions—For existing and new kinase inhibitors, this novel framework can be used to rationally and rapidly design optimal dosing strategies to minimize the development of acquired resistance.
对于现有的和新的激酶抑制剂，这种新给药结构可用于设计最佳给药方案，以减少获得性耐药。
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