Phenotype-driven precision oncology as a guide for clinical decisions one patient at a time.
Phenotype-driven precision oncology as a guide for clinical decisions one patient at a time.
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DOI：
10.1038/s41467-017-00451-5
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发表时间：
2017-09-05
影响因子：
16.6
通讯作者：
DasGupta R
中科院分区：
文献类型：
--
作者：
Chia S;Low JL;Zhang X;Kwang XL;Chong FT;Sharma A;Bertrand D;Toh SY;Leong HS;Thangavelu MT;Hwang JSG;Lim KH;Skanthakumar T;Tan HK;Su Y;Hui Choo S;Hentze H;Tan IBH;Lezhava A;Tan P;Tan DSW;Periyasamy G;Koh JLY;Gopalakrishna Iyer N;DasGupta R
基因组学驱动的癌症治疗在个性化癌症治疗中占据了重要地位。然而，其在缺乏生物标志物驱动的治疗策略的适应症中的效用仍然有限。在这里，我们提出了一种“表型驱动的精准肿瘤学”方法，该方法基于这样的概念：对化学或遗传扰动的生物反应，体外患者个体化模型可以作为临床治疗反应的预测生物标志物。我们生成了一个用于头颈鳞状细胞癌的“可筛选”患者来源的原代培养物（PDC）库，该库可在匹配的患者来源的异种移植模型中可重复地预测治疗反应。重要的是，在两项 n = 1 的联合临床试验中，PDC 可以指导临床实践并预测肿瘤进展。对源自这些模型之一的 PDC 进行的全面“组学”研究表明，YAP1 是约 24% 口腔鳞状细胞癌治疗反应和生存的假定生物标志物。我们预计，所提出的 PDC 方法的扩展可以发现治疗分层的生物标志物，并指导未来的实时治疗决策。患者衍生模型中的治疗反应可以作为临床反应的生物标志物。在这里，作者使用配对的患者来源的小鼠异种移植物和来自头颈鳞状细胞癌（包括转移瘤）的患者来源的原代培养模型作为抗癌药物高通量筛选的模型。
Genomics-driven cancer therapeutics has gained prominence in personalized cancer treatment. However, its utility in indications lacking biomarker-driven treatment strategies remains limited. Here we present a “phenotype-driven precision-oncology” approach, based on the notion that biological response to perturbations, chemical or genetic, in ex vivo patient-individualized models can serve as predictive biomarkers for therapeutic response in the clinic. We generated a library of “screenable” patient-derived primary cultures (PDCs) for head and neck squamous cell carcinomas that reproducibly predicted treatment response in matched patient-derived-xenograft models. Importantly, PDCs could guide clinical practice and predict tumour progression in two n = 1 co-clinical trials. Comprehensive “-omics” interrogation of PDCs derived from one of these models revealed YAP1 as a putative biomarker for treatment response and survival in ~24% of oral squamous cell carcinoma. We envision that scaling of the proposed PDC approach could uncover biomarkers for therapeutic stratification and guide real-time therapeutic decisions in the future. Treatment response in patient-derived models may serve as a biomarker for response in the clinic. Here, the authors use paired patient-derived mouse xenografts and patient-derived primary culture models from head and neck squamous cell carcinomas, including metastasis, as models for high-throughput screening of anti-cancer drugs.
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影响因子：
82.9
作者：
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通讯作者：
Sellers, William R.
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影响因子：
16
作者：
Hass MR;Liow HH;Chen X;Sharma A;Inoue YU;Inoue T;Reeb A;Martens A;Fulbright M;Raju S;Stevens M;Boyle S;Park JS;Weirauch MT;Brent MR;Kopan R
通讯作者：
Kopan R
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影响因子：
17.1
作者：
Jones S;Anagnostou V;Lytle K;Parpart-Li S;Nesselbush M;Riley DR;Shukla M;Chesnick B;Kadan M;Papp E;Galens KG;Murphy D;Zhang T;Kann L;Sausen M;Angiuoli SV;Diaz LA Jr;Velculescu VE
通讯作者：
Velculescu VE