Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer.
Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer.
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DOI：
10.1158/2159-8290.cd-18-0349
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发表时间：
2018-09
期刊：
影响因子：
28.2
通讯作者：
Tuveson DA
中科院分区：
文献类型：
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作者：
Tiriac H;Belleau P;Engle DD;Plenker D;Deschênes A;Somerville TDD;Froeling FEM;Burkhart RA;Denroche RE;Jang GH;Miyabayashi K;Young CM;Patel H;Ma M;LaComb JF;Palmaira RLD;Javed AA;Huynh JC;Johnson M;Arora K;Robine N;Shah M;Sanghvi R;Goetz AB;Lowder CY;Martello L;Driehuis E;LeComte N;Askan G;Iacobuzio-Donahue CA;Clevers H;Wood LD;Hruban RH;Thompson E;Aguirre AJ;Wolpin BM;Sasson A;Kim J;Wu M;Bucobo JC;Allen P;Sejpal DV;Nealon W;Sullivan JD;Winter JM;Gimotty PA;Grem JL;DiMaio DJ;Buscaglia JM;Grandgenett PM;Brody JR;Hollingsworth MA;O'Kane GM;Notta F;Kim E;Crawford JM;Devoe C;Ocean A;Wolfgang CL;Yu KH;Li E;Vakoc CR;Hubert B;Fischer SE;Wilson JM;Moffitt R;Knox J;Krasnitz A;Gallinger S;Tuveson DA
胰腺癌是最常见的致死性实体恶性肿瘤。全身治疗通常无效，迫切需要指导治疗的预测性生物标志物。我们生成了一个胰腺癌患者源性类器官（PDO）库，该库概括了原发性胰腺癌的突变谱和转录亚型。新的驱动癌基因被提名，转录组学分析揭示了独特的集群。PDO对标准化疗药物和研究药物的反应不均匀。在一个案例研究的方式，我们发现，PDO的治疗概况，患者的结果和PDO使纵向评估化疗敏感性和同步转移的评价。我们推导出了基于类器官的化学敏感性基因表达特征，这些特征预测了许多患者在辅助和晚期疾病环境中对化疗的反应改善。最后，我们使用靶向药物治疗谱提名了化学难治性PDO的替代治疗策略。我们建议，结合分子和治疗概况的PDO可以预测临床反应，使前瞻性的治疗选择。
Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we find that PDO therapeutic profiles paralleled patient outcomes and that PDOs enable longitudinal assessment of chemo-sensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemo-sensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemo-refractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.