TY - JOUR
T1 - The National Cancer Institute ALMANAC
T2 - A comprehensive screening resource for the detection of anticancer drug pairs with enhanced therapeutic activity
AU - Holbeck, Susan L.
AU - Camalier, Richard
AU - Crowell, James A.
AU - Govindharajulu, Jeevan Prasaad
AU - Hollingshead, Melinda
AU - Anderson, Lawrence W.
AU - Polley, Eric
AU - Rubinstein, Larry
AU - Srivastava, Apurva
AU - Wilsker, Deborah
AU - Collins, Jerry M.
AU - Doroshow, James H.
N1 - Funding Information:
The authors wish to thank the University of Pittsburgh and SRI International for acquisition of in vitro data, SRI for performing follow-up xenograft experiments, Dr. Karen Schweikart for excellent project management, Dr. Robert Kinders for helpful discussion regarding the biomarker analyses, Dr. Daniel Zaharevitz for construction of the NCI-ALMANAC website, and Drs. Mariam Konate and Sarah Miller, Kelly Services, for editorial assistance in the preparation of this manuscript. This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. This research was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and in part by American Recovery and Reinvestment Act funds. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2017 AACR.
PY - 2017/7/1
Y1 - 2017/7/1
N2 - 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/ncial manac. 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.
AB - 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/ncial manac. 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.
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U2 - 10.1158/0008-5472.CAN-17-0489
DO - 10.1158/0008-5472.CAN-17-0489
M3 - Article
C2 - 28446463
AN - SCOPUS:85023780563
SN - 0008-5472
VL - 77
SP - 3564
EP - 3576
JO - Cancer research
JF - Cancer research
IS - 13
ER -