A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response.
A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response.
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DOI：
10.1038/nature10937
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发表时间：
2012-03-18
期刊：
影响因子：
64.8
通讯作者：
Wong, Kwok-Kin
中科院分区：
文献类型：
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作者：
Chen, Zhao;Cheng, Katherine;Walton, Zandra;Wang, Yuchuan;Ebi, Hiromichi;Shimamura, Takeshi;Liu, Yan;Tupper, Tanya;Ouyang, Jing;Li, Jie;Gao, Peng;Woo, Michele S.;Xu, Chunxiao;Yanagita, Masahiko;Altabef, Abigail;Wang, Shumei;Lee, Charles;Nakada, Yuji;Pena, Christopher G.;Sun, Yanping;Franchetti, Yoko;Yao, Catherine;Saur, Amy;Cameron, Michael D.;Nishino, Mizuki;Hayes, D. Neil;Wilkerson, Matthew D.;Roberts, Patrick J.;Lee, Carrie B.;Bardeesy, Nabeel;Butaney, Mohit;Chirieac, Lucian R.;Costa, Daniel B.;Jackman, David;Sharpless, Norman E.;Castrillon, Diego H.;Demetri, George D.;Jaenne, Pasi A.;Pandolfi, Pier Paolo;Cantley, Lewis C.;Kung, Andrew L.;Engelman, Jeffrey A.;Wong, Kwok-Kin
靶向治疗已证明对分子定义的癌症的特定子集有效。尽管大多数肺癌患者根据单一致癌驱动因素进行分层，但携带相同激活基因突变的癌症对相同靶向治疗的反应显示出很大差异。这种异质性背后的生物学尚未得到很好的理解，共存的基因突变的影响，特别是肿瘤抑制因子的丢失，尚未得到充分的探讨。在这里，我们使用基因工程小鼠模型进行“共同临床”试验，反映了正在进行的KRAS突变肺癌患者的人类临床试验。本试验旨在确定MEK抑制剂selumetinib（AZD 6244）是否增加多西他赛（一种标准化疗）的疗效。我们的研究表明，p53（也称为Tp53）或Lkb1（也称为Stk11）（两种临床相关的肿瘤抑制因子）的伴随丢失显著损害了Kras突变型癌症对多西他赛单药治疗的反应。我们观察到，添加司美替尼为Kras和Kras和p53突变引起的肺癌小鼠提供了实质性益处，但Kras和Lkb1突变小鼠对这种联合治疗具有原发性抗性。药效学研究，包括正电子发射断层扫描（PET）和计算机断层扫描（CT），确定了小鼠和患者的生物标志物，为这些疗法在不同基因型中的差异疗效提供了依据。这些共同临床结果确定了预测性遗传生物标志物，这些生物标志物应通过询问同期临床试验中招募的患者的样本进行验证。这些研究还强调了同步联合临床试验的基本原理，不仅可以预测正在进行的人体临床试验的结果，还可以产生临床相关的假设，为人体研究的分析和设计提供信息。
Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a ‘co-clinical’ trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.
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DOI：
10.1158/1078-0432.ccr-10-0125
发表时间：
2010-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Zhao B;Oxnard GR;Moskowitz CS;Kris MG;Pao W;Guo P;Rusch VM;Ladanyi M;Rizvi NA;Schwartz LH
通讯作者：
Schwartz LH
影响因子：
50.3
作者：
Carretero J;Shimamura T;Rikova K;Jackson AL;Wilkerson MD;Borgman CL;Buttarazzi MS;Sanofsky BA;McNamara KL;Brandstetter KA;Walton ZE;Gu TL;Silva JC;Crosby K;Shapiro GI;Maira SM;Ji H;Castrillon DH;Kim CF;García-Echeverría C;Bardeesy N;Sharpless NE;Hayes ND;Kim WY;Engelman JA;Wong KK
通讯作者：
Wong KK
影响因子：
8
作者：
Gill RK;Yang SH;Meerzaman D;Mechanic LE;Bowman ED;Jeon HS;Roy Chowdhuri S;Shakoori A;Dracheva T;Hong KM;Fukuoka J;Zhang JH;Harris CC;Jen J
通讯作者：
Jen J
有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
45.3
作者：
Politi, Katerina;Pao, William
通讯作者：
Pao, William