title: A synergetic screening approach with companion effector for combination therapy: application to retinoblastoma.
abstract: For many cancers, the lack of potency and the toxicity of current drugs limits the dose achievable in patients and the efficacy of treatment. Among them, retinoblastoma is a rare cancer of the eye for which better chemotherapeutic options are needed. Combination therapy is a compelling approach to enhance the efficacy of current treatment, however clinical trials to test rationally designed combinations of approved drugs are slow and expensive, and limited by our lack of in-depth knowledge of drug specificity. Since many patients already turn to nutraceuticals in hopes of improving their condition, we hypothesized that certain approved drugs could potentially synergize with widely consumed supplements. Following this hypothesis, we devised an alternative screening strategy aimed at taking advantage of a bait compound such as a nutraceutical with potential therapeutic benefits but low potency, by screening chemical libraries for approved drugs that synergize with this companion effector. As a proof of concept, we sought to identify approved drugs with synergetic therapeutic effects toward retinoblastoma cells in combination with the antioxidant resveratrol, popular as a supplement. We systematically tested FDA-approved drugs and known bioactives seeking to identify such pairs, which led to uncovering only a few additive combinations; but to our surprise, we identified a class of anticancer drugs widely used in the clinic whose therapeutic effect is antagonized with resveratrol. Our observations could explain in part why some patients do not respond well to treatment. Our results validate this alternative approach, and we expect that our companion effector strategy could significantly impact both drug discovery and the nutraceutical industry.
authors.affiliation: HTS Core Facility, Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Jeni P
authors.initials: JP
authors.lastname: Mahida
authors.forename: Christophe
authors.initials: C
authors.lastname: Antczak
authors.forename: Daniel
authors.initials: D
authors.lastname: Decarlo
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Champ
authors.forename: Jasmine H
authors.initials: JH
authors.lastname: Francis
authors.forename: Brian
authors.initials: B
authors.lastname: Marr
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Polans
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Albert
authors.forename: David H
authors.initials: DH
authors.lastname: Abramson
authors.forename: Hakim
authors.initials: H
authors.lastname: Djaballah
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004357:Drug Synergism; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D015203:Reproducibility of Results; D000077185:Resveratrol; D019572:Retinal Neoplasms / Q000188:drug therapy; D012175:Retinoblastoma / Q000188:drug therapy; D054852:Small Molecule Libraries; D013267:Stilbenes / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D054852:Small Molecule Libraries; D013267:Stilbenes; D000077185:Resveratrol