Supplementary Information from The National Cancer Institute ALMANAC: A Comprehensive Screening Resource for the Detection of Anticancer Drug Pairs with Enhanced Therapeutic Activity
This file contains: Supplementary Methods for pharmacodynamic biomarker analyses, clinicaltrials.gov searches, and molecular correlation analyses; Supplementary Figures S1 (overview of the NCI-ALMANAC web resource), S2 (apoptotic biomarker response to bortezomib-clofarabine), and S3 (associations between ABC transporter activity and nilotinib-paclitaxel combination activity); and Supplementary Tables S1 (FDA-approved agents used in the NCI-ALMANAC screen), S2 (tumor doubling time analysis of xenograft experiments with clinically tested NCI-ALMANAC-derived combinations), S3 (in vitro, in vivo, and clinical activity of NCI-ALMANAC-derived combinations), and S4 (tumor doubling time analysis of xenograft experiments with novel NCI-ALMANAC-derived combinations).
Funding
National Cancer Institute
NIH
History
ARTICLE ABSTRACT
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 in vivo experiments in mouse xenograft models of human cancer confirmed combinations with greater than single-agent efficacy. Concomitant detection of mechanistic biomarkers for these combinations in vivo 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. Cancer Res; 77(13); 3564–76. ©2017 AACR.Usage metrics
