Medium-throughput Drug Screening of Patient-derived Organoids from Colorectal Peritoneal Metastases to Direct Personalized Therapy.
Medium-throughput Drug Screening of Patient-derived Organoids from Colorectal Peritoneal Metastases to Direct Personalized Therapy.
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DOI：
10.1158/1078-0432.ccr-20-0073
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发表时间：
2020-07-15
期刊：
影响因子：
--
通讯作者：
Woods SL
中科院分区：
文献类型：
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作者：
Narasimhan V;Wright JA;Churchill M;Wang T;Rosati R;Lannagan TRM;Vrbanac L;Richardson AB;Kobayashi H;Price T;Tye GXY;Marker J;Hewett PJ;Flood MP;Pereira S;Whitney GA;Michael M;Tie J;Mukherjee S;Grandori C;Heriot AG;Worthley DL;Ramsay RG;Woods SL
结直肠癌（CRC）腹膜转移（CRPM）患者的治疗选择有限，CRC生存率最低。我们的目的是确定类器官检测是否可以帮助指导CRPM患者的精确治疗，因为包括非标准药物在内的前瞻性功能性药物筛选的临床应用尚不清楚。从患者身上分离的CRPM类器官（腹膜）进行平行下一代测序和中通量药物小组体外测试，以确定每个患者的特异性药物敏感性。我们测量了这种服务的效用，包括：腹膜生成的成功，培养腹膜的时间，中等通量药物测试的可重复性，以及测试结果对临床治疗的记录变化。68%（19/28）接受标准治疗的患者成功生成并验证了腹膜样体。基因组和药物分析在8周内完成，并在标准护理治疗失败后向肿瘤医学小组提供药物敏感性排名的正式报告。这导致了2名患者的治疗改变，其中一名患者尽管先前在多轮标准治疗化疗中取得进展，但仍有部分反应。在澳大利亚实施这项技术的障碍是药物获取和标签外适应症的资金需求。我们的方法是可行的，可重复的，并且可以指导这种预后不良人群的新治疗选择，在这些人群中迫切需要新的治疗选择。这个平台与许多实体器官恶性肿瘤有关。
Colorectal cancer (CRC) patients with peritoneal metastases (CRPM) have limited treatment options and the lowest CRC survival rates. We aimed to determine whether organoid testing could help guide precision treatment for CRPM patients, as the clinical utility of prospective, functional drug screening including non-standard agents is unknown. CRPM organoids (peritonoids) isolated from patients underwent parallel next-generation sequencing and medium-throughput drug panel testing ex vivo to identify specific drug sensitivities for each patient. We measured the utility of such a service including: success of peritonoid generation, time to cultivate peritonoids, reproducibility of the medium-throughput drug testing, and documented changes to clinical therapy as a result of the testing. Peritonoids were successfully generated and validated from 68% (19/28) of patients undergoing standard care. Genomic and drug profiling was completed within 8 weeks and a formal report ranking drug sensitivities was provided to the medical oncology team upon failure of standard care treatment. This resulted in a treatment change for 2 patients, one of whom had a partial response despite previously progressing on multiple rounds of standard care chemotherapy. The barrier to implementing this technology in Australia is the need for drug access and funding for off-label indications. Our approach is feasible, reproducible and can guide novel therapeutic choices in this poor prognosis cohort, where new treatment options are urgently needed. This platform is relevant to many solid organ malignancies.