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Discovering the anti-cancer potential of non-oncology drugs by systematic viability profiling.

ABSTRACT: Anti-cancer uses of non-oncology drugs have occasionally been found, but such discoveries have been serendipitous. We sought to create a public resource containing the growth inhibitory activity of 4,518 drugs tested across 578 human cancer cell lines. We used PRISM, a molecular barcoding method, to screen drugs against cell lines in pools. An unexpectedly large number of non-oncology drugs selectively inhibited subsets of cancer cell lines in a manner predictable from the cell lines' molecular features. Our findings include compounds that killed by inducing PDE3A-SLFN12 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 multi-drug resistance protein ABCB1. The PRISM drug repurposing resource (https://depmap.org/repurposing) is a starting point to develop new oncology therapeutics, and more rarely, for potential direct clinical translation.

SUBMITTER: Corsello SM

PROVIDER: S-EPMC7328899 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cancer cachexia (CC) is a multifactorial syndrome driven by inflammation, defined by ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support. CC leads to progressive functional impairment, with its clinical management complicated and limited therapeutic options available. The objective of this review was to assess the efficacy and safety of non-steroidal anti-inflammatory drugs (NSAIDs) on patient-centred outcomes in patients with CC. In 2013, two systematic reviews concluded that there was insufficient evidence to recommend NSAIDs for clinical management of CC outside of clinical trials. However, clinical trials of multi-component CC interventions have included NSAIDs as an intervention component, so an up-to-date assessment of the evidence for NSAIDs in the treatment of CC is warranted. Four databases (MEDLINE, EMBASE, CENTRAL and CINAHL) and three trial registers (clinicaltrials.gov, WHO ICTRP and ISRCTN) were searched on 16 December 2022. Randomized controlled trials (RCTs) comparing any NSAID (any dose or duration) with a control arm, in adult patients with CC, reporting measures of body weight, body composition, nutrition impact symptoms, inflammation, physical function or fatigue, were eligible for inclusion. Primary outcomes (determined with patient involvement) were survival, changes in muscle strength, body composition, body weight and quality of life. Included studies were assessed for risk of bias using the Revised Cochrane risk-of-bias tool for randomized trials. Five studies were included, which investigated Indomethacin (n = 1), Ibuprofen (n = 1) and Celecoxib (n = 3). Four studies were judged to be at high risk of bias for all outcomes, with one study raising concerns for most outcomes. Considerable clinical and methodological heterogeneity amongst the studies meant that meta-analysis was not appropriate. There was insufficient evidence to determine whether Indomethacin or Ibuprofen is effective or safe for use in patients with CC; RCTs with lower risk of bias are needed. Celecoxib studies indicated it was safe for use in this population at the doses tested (200-400 mg/day) but found contrasting results regarding efficacy, potentially reflecting heterogeneity amongst the studies. There is inadequate evidence to recommend any NSAID for CC. While current clinical trials for CC treatments are shifting towards multi-component interventions, further research to determine the efficacy and safety of NSAIDs alone is necessary if they are to be included in such multi-component interventions. Furthermore, the lack of data on patient-determined primary outcomes in this review highlights the need for patient involvement in clinical trials for CC.

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Discovering the anti-cancer potential of non-oncology drugs by systematic viability profiling.

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