First Systematic Characterization of Approved Oncology Drugs Shows Benefit of Combinations
“A total of 300,000 combination experiments were required to evaluate 5,000 pairs of combinations in each of the NCI-60 cell lines,” noted Susan Holbeck, PhD, a biologist in the Division of Cancer Treatment and Diagnosis at the NCI.
The NCI-60 panel of human cancer cell lines—derived from nine different types of cancer—has been extensively molecularly characterized, including molecular profiling for many analytes, such as mRNA, microRNA, DNA sequence, protein expression, NDA methylation, and metabolites. “This provides a framework in which to investigate why a particular drug pair is active in one cell line, but not in another,” she said.
“Many groups are focusing on ‘rational' combinations; i.e., making scientific inferences about which pathways it might make sense to block simultaneously with different drugs. We took a step back, and took an approach that tests all possible drug pairs. This allowed us to test not only the rational combinations, but also to explore drug pairs that otherwise would likely never be tested together,” including determining whether toxicity of specific combinations would require lower doses, which in turn “may not fully engage the targets,” she noted.
Results of xenograft testing identified some novel combinations that had improved activity over the most active dose of the single agents. “These results are promising, but we need to repeat and confirm them. There will be many more leads than we can possibly follow through on,” Dr. Holbeck said. “Once these data are published, the dataset, and tools to analyze it, will be made available on our web site for all to utilize as they wish.”
Prof. Stefan Sleijfer, scientific chair of the EORTC-NCI-AACR Symposium, from Erasmus University Medical Centre, The Netherlands, commented: “This study is interesting because of the use of combinations of drugs already approved and on the market, which were tested in cell lines that have been well characterized in terms of genetic profiles. If confirmed, this study will form a basis for future clinical trials on such combinations in well-defined patient groups.”
All data generated from the project is freely available at http://dtp.cancer.gov.
Abstract (select abstract #27):