title: Repurposing and Rescuing of Mibefradil, an Antihypertensive, for Cancer: A Case Study.
abstract: The expanding "valley of death" in drug development is leaving potentially life-saving new chemical entities and molecular targets fallow. This situation is forcing early-stage companies to think creatively about moving their technologies forward, especially as institutional investors show more interest in later stages of development. Drug repurposing, a strategy to examine existing drugs for therapeutic value against different diseases, is an emerging method to bring an off-market drug back onto the market. Tau Therapeutics LLC identified the role of T-type calcium channel blockers (Cav3) in cancer proliferation, but the company was unable to attract funding while having both a nonvalidated drug target and new chemical entities. To change the risk profile of the company, Tau set out to repurpose the known Cav3 drug mibefradil as a proof of concept for the treatment of cancer. Mibefradil was launched for hypertension in the 1990s but withdrawn because of drug-drug interactions. A new sequential combination treatment, termed Interlaced Therapy™, uses short-term administration of mibefradil to enhance the overall therapeutic potential of conventional anticancer agents. Mibefradil is currently in a phase Ib clinical trial with the National Cancer Institute (NCI) Adult Brain Tumor Consortium. Mibefradil has been repurposed from an abandoned antihypertensive to a targeted solid tumor treatment, and it has been rescued from drug-drug interactions by using short-term dose exposure. Tau is using the early success of mibefradil as a proof of concept to build a platform technology of Cav3 blockers for broad antitumor applications in combination with new targeted cancer therapies, well-established chemotherapies, and radiation.
authors.affiliation: Tau Therapeutics LLC , Charlottesville, Virginia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Krouse
authors.affiliation: Tau Therapeutics LLC , Charlottesville, Virginia.
authors.forename: Lloyd
authors.initials: L
authors.lastname: Gray
authors.affiliation: Tau Therapeutics LLC , Charlottesville, Virginia.
authors.forename: Timothy
authors.initials: T
authors.lastname: Macdonald
authors.affiliation: Tau Therapeutics LLC , Charlottesville, Virginia.
authors.forename: John
authors.initials: J
authors.lastname: McCray
mesh_terms: D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000378:metabolism; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D058492:Drug Repositioning / Q000379:methods*; D004357:Drug Synergism; D006801:Humans; D020748:Mibefradil / Q000494:pharmacology / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000959:Antihypertensive Agents; C479952:CACNA1H protein, human; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D020748:Mibefradil