Abstract
The new Cancer Therapeutics Response Portal provides a database that examines the interactions of nearly 250 cancer cell lines with more than 350 small molecules.
Researchers studying the weaknesses of tumor cells have received a major new tool in the Cancer Therapeutics Response Portal (CTRP), a database that records the susceptibilities of nearly 250 cancer cell lines to more than 350 small molecules.
The database joins other resources that have pinpointed vulnerabilities of cancer cell lines as a way to speed drug development. For example, the National Cancer Institute's longstanding NCI-60 program has compiled data on the effects of more than 100,000 compounds on 60 cancer cell lines. Additionally, researchers using data from the Cancer Cell Line Encyclopedia (CCLE) tallied the responses of 479 cell lines to 24 cancer drugs last year.
Presented in a recent paper in Cell, the new CTRP builds on the CCLE, currently incorporating 242 cell lines from the CCLE for which researchers have good genomic information, such as data on gene expression, mutations, and DNA duplications and inversions.
Among the 354 small molecules now in the CTRP are approved drugs, drug candidates, and other compounds. They interact with a wider array of cellular activities than do compounds in the CCLE or other cancer drug studies, says Paul Clemons, PhD, coauthor on the paper and director of computational chemical biology research at the Broad Institute of Harvard and MIT in Cambridge, MA.
To generate the data, the researchers exposed each of the cell lines to eight concentrations of each compound. The team gauged a molecule's impact on a particular cell line by calculating the area under the survival curve, an approach that “gives a single number that simultaneously reports on potency—the concentration at which cell proliferation is inhibited—and efficacy—the extent to which cell proliferation is inhibited,” Clemons says.
Among early examples of the database's ability to point out potential new cancer vulnerabilities, an analysis suggested that the compound navitoclax (ABT-263; AbbVie), which has already undergone phase I/II trials for small cell lung cancer, might also work against colorectal, hepatocellular, gastric, and endometrial cancers that harbor mutations in the gene for the transcription factor beta-catenin. Follow-up in vitro work showed that cancer cell lines with such mutations were among those most sensitive to navitoclax, and suggested that compounds that increase beta-catenin protein levels may render cells more sensitive to navitoclax.
CTRP “is a good resource to have for preliminary data and hypothesis generation,” says Paul Spellman, PhD, an associate professor at Oregon Health and Science University in Portland, who wasn't connected to the study.
“There's nothing like this compound-based database,” comments Michael Roth, PhD, professor at the University of Texas Southwestern Medical Center in Dallas, who also wasn't involved in the work. However, Roth cautions that the paper is highly technical and the database relies on a somewhat esoteric measure of the molecules' effectiveness, so “right now it's a tool only for real experts in the area.”
Clemons and colleagues are working to expand the database's coverage by testing more than 800 cell lines and more than 500 compounds.
