The National Cancer Institute ALMANAC: A Comprehensive Screening Resource for the Detection of Anticancer Drug Pairs with Enhanced Therapeutic Activity

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13), p.3564-3576
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antitumor activity; Bortezomib; Cancer; Cell Line, Tumor; Clinical trials; Drug resistance; Drug Screening Assays, Antitumor; Drugs; Humans; Mice; National Cancer Institute (U.S.); Paclitaxel; Small Molecule Libraries - pharmacology; Subpopulations; Translation; Tumor cell lines; Tumors; United States; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-17-0489

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. .