Combine and conquer: challenges for targeted therapy combinations in early phase trials.
Combine and conquer: challenges for targeted therapy combinations in early phase trials.
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DOI：
10.1038/nrclinonc.2016.96
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发表时间：
2017-01
期刊：
影响因子：
--
通讯作者：
Banerji U
中科院分区：
文献类型：
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作者：
Lopez JS;Banerji U
对癌症生物学的更好理解导致了靶向抗癌药物的发展。然而，由于存在新生耐药，这些药物的全部潜力尚未实现，新生耐药通常是由代偿性信号通路或在治疗的选择压力下经历克隆进化的癌细胞中获得性耐药的发展引起的。联合靶向治疗可以规避一些耐药机制，产生临床效益。我们探索如何确定最佳药物组合，最佳组合策略以及将这些药物交付给患者的复杂性的挑战。认识到治疗引起的毒性和无法使用许多靶向治疗的连续药效学有效剂量，需要创造性的间歇性计划。连续肿瘤分析和平行联合临床试验的使用有助于理解耐药机制，并将指导适应性临床试验设计的发展，以适应假设检验，从而充分发挥联合治疗的潜力。
A better understanding of cancer biology has led to the development of targeted anticancer drugs. However, the full potential of these agents has not been realised due to the presence of de novo resistance, often resulting from compensatory signalling pathways or the development of acquired resistance in cancer cells that undergo clonal evolution under selective pressures of treatment. Combinations of targeted treatments can circumvent some mechanisms of resistance yielding clinical benefit. We explore the challenges of how to identify the best drug combinations, the best combination strategies, and the complexities of delivering these to patients. Recognizing treatment-induced toxicity and the inability to use continuous pharmacodynamically effective doses of many targeted treatments needs creative intermittent scheduling. Serial tumour profiling and the use of parallel co-clinical trials contribute to understanding mechanisms of resistance, and will guide the development of adaptive clinical trial designs that can accommodate hypothesis testing, to enable the full potential of combination therapies.
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影响因子：
16.6
作者：
Domcke, Silvia;Sinha, Rileen;Levine, Douglas A.;Sander, Chris;Schultz, Nikolaus
通讯作者：
Schultz, Nikolaus
影响因子：
11.5
作者：
Bedard, Philippe L.;Tabernero, Josep;Sessa, Cristiana
通讯作者：
Sessa, Cristiana
影响因子：
28.2
作者：
Deuker, Marian M.;Durban, Victoria Marsh;McMahon, Martin
通讯作者：
McMahon, Martin
DOI：
10.1126/science.1254721
发表时间：
2014-12-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Crystal AS;Shaw AT;Sequist LV;Friboulet L;Niederst MJ;Lockerman EL;Frias RL;Gainor JF;Amzallag A;Greninger P;Lee D;Kalsy A;Gomez-Caraballo M;Elamine L;Howe E;Hur W;Lifshits E;Robinson HE;Katayama R;Faber AC;Awad MM;Ramaswamy S;Mino-Kenudson M;Iafrate AJ;Benes CH;Engelman JA
通讯作者：
Engelman JA
影响因子：
82.9
作者：
通讯作者：
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