Drug repurposing is an attractive strategy for extending the therapeutic portfolio in oncology. Screening of a large collection of existing non-oncology compounds against a panel of cancer cell lines now identifies several drugs capable of selectively inhibiting the growth of cancer cells.
Todd Golub and colleagues tested thousands of drugs not originally developed for cancer treatment across 578 human cancer cell lines, revealing growth-inhibitory effects and providing a resource to identify drugs with the potential to be repurposed for cancer management according to an article published in February 2020 issue of the Nature Cancer.
The rationale for repurposing existing drugs for new clinical indications is that rapid clinical translation can occur for drugs already proven safe in humans. In principle, existing drugs can also establish starting points for drug development when new targets of old drugs are discovered. To date, most oncology repurposing discoveries have been serendipitous. However, systematic, at-scale screening of the entire pharmacopoeia has not been feasible and the extent to which non-oncology drugs have potential as future cancer therapeutics is unknown, the authors wrote in the study background.
Recent efforts have demonstrated the power of large-scale cancer cell line screening, like testing either many compounds across a limited number of cell lines in case of the NCI-60 panel or a modest number of oncology compounds across many cell lines, like in case of the Genomics of Drug Sensitivity in Cancer project at the Sanger Institute and the Cancer Target Discovery and Development project at the Broad Institute.
The ideal study would involve screening of many drugs, most of which are non-oncology drugs, across a large panel of genomically characterised cell lines to capture the molecular diversity of human cancer.
In their article, the investigators report the feasibility of using the PRISM (profiling relative inhibition simultaneously in mixtures) molecular barcoding and multiplexed screening method to test 4,518 existing drugs against 578 cancer cell lines. They find that non-oncology drugs have an unexpectedly high rate of anticancer activity. The sensitivity of cancer cell lines to many of these compounds can be predicted from the genomic features of the cell lines, thereby suggesting potentially relevant patient populations.
In particular, the investigators sought to create a public resource and found an unexpectedly large number of non-oncology drugs that selectively inhibited subsets of cancer cell lines in a manner predictable from the molecular features of the cell lines. Their findings include compounds that killed by inducing phosphodiesterase 3A-Schlafen 12 complex formation, vanadium-containing compounds whose killing depended on the sulfate transporter SLC26A2, the alcohol dependence drug disulfiram, which killed cells with low expression of metallothioneins, and the anti-inflammatory drug tepoxalin, which killed via the multidrug resistance protein ATP-binding cassette subfamily B member 1.
The authors concluded that the PRISM drug repurposing resource is a starting point to develop new oncology therapeutics, and more rarely, for potential direct clinical translation. Given the large number of unexpected findings that emerged from the initial screen, the study team believe that expansion of the PRISM resource in both the dimension of drugs and cancer models is warranted. Such data will provide an important pharmacological component of the Cancer Dependency Map, which in turn will form a preclinical foundation for cancer precision medicine.
The study was supported in part by the Carlos Slim Foundation (Slim Initiative in Genomic Medicine for the Americas), the Next Generation Fund at the Broad Institute of MIT and Harvard, the Conquer Cancer Foundation of ASCO Young Investigator Award and US National Institutes of Health grants.
Reference
Corsello SM, Nagari RT, Spangler RD, et al. Discovering the anticancer potential of non-oncology drugs by systematic viability profiling. Nature Cancer 2020; 1: 235–248. https://doi.org/10.1038/s43018-019-0018-6