Holbeck Susan L, Camalier Richard, Crowell James A, Govindharajulu Jeevan Prasaad, Hollingshead Melinda, Anderson Lawrence W, Polley Eric, Rubinstein Larry, Srivastava Apurva, Wilsker Deborah, Collins Jerry M, Doroshow James H
Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, Maryland.
Clinical Pharmacodynamics Program, Applied/Developmental Research Directorate, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
Cancer Res. 2017 Jul 1;77(13):3564-3576. doi: 10.1158/0008-5472.CAN-17-0489. Epub 2017 Apr 26.
To date, over 100 small-molecule oncology drugs have been approved by the FDA. Because of the inherent heterogeneity of tumors, these small molecules are often administered in combination to prevent emergence of resistant cell subpopulations. Therefore, new combination strategies to overcome drug resistance in patients with advanced cancer are needed. In this study, we performed a systematic evaluation of the therapeutic activity of over 5,000 pairs of FDA-approved cancer drugs against a panel of 60 well-characterized human tumor cell lines (NCI-60) to uncover combinations with greater than additive growth-inhibitory activity. Screening results were compiled into a database, termed the NCI-ALMANAC (A Large Matrix of Anti-Neoplastic Agent Combinations), publicly available at https://dtp.cancer.gov/ncialmanac Subsequent experiments in mouse xenograft models of human cancer confirmed combinations with greater than single-agent efficacy. Concomitant detection of mechanistic biomarkers for these combinations supported the initiation of two phase I clinical trials at the NCI to evaluate clofarabine with bortezomib and nilotinib with paclitaxel in patients with advanced cancer. Consequently, the hypothesis-generating NCI-ALMANAC web-based resource has demonstrated value in identifying promising combinations of approved drugs with potent anticancer activity for further mechanistic study and translation to clinical trials. .
迄今为止，已有100多种小分子肿瘤药物获得美国食品药品监督管理局（FDA）的批准。由于肿瘤固有的异质性，这些小分子药物通常联合使用，以防止耐药细胞亚群的出现。因此，需要新的联合策略来克服晚期癌症患者的耐药性。在本研究中，我们对5000多对FDA批准的癌症药物针对一组60种特征明确的人类肿瘤细胞系（NCI-60）的治疗活性进行了系统评估，以发现具有大于相加生长抑制活性的联合用药方案。筛选结果被汇编成一个数据库，称为NCI-ALMANAC（抗肿瘤药物组合大矩阵），可在https://dtp.cancer.gov/ncialmanac上公开获取。随后在人类癌症小鼠异种移植模型中进行的实验证实了联合用药方案的疗效优于单药治疗。对这些联合用药方案的机制生物标志物进行同步检测，支持了美国国立癌症研究所（NCI）启动两项I期临床试验，以评估氯法拉滨与硼替佐米以及尼洛替尼与紫杉醇联合用于晚期癌症患者的疗效。因此，基于网络的、产生假设的NCI-ALMANAC资源已证明在识别具有强大抗癌活性的已批准药物的有前景联合用药方案方面具有价值，可用于进一步的机制研究并转化为临床试验。
