title: Identification of repurposed small molecule drugs for chordoma therapy.
abstract: Chordoma is a rare, slow growing malignant tumor arising from remnants of the fetal notochord. Surgery is the first choice for chordoma treatment, followed by radiotherapy, although postoperative complications remain significant. Recurrence of the disease occurs frequently due to the anatomy of the tumor location and violation of the tumor margins at the initial surgery. Currently, there are no effective drugs available for patients with chordoma. Due to the rarity of the disease, there is limited opportunity to test agents in clinical trials and no concerted effort to develop agents for chordoma in the pharmaceutical industry. To rapidly and efficiently identify small molecules that inhibit chordoma cell growth, we screened the NCGC Pharmaceutical Collection (NPC) containing approximately 2800 clinically approved and investigational drugs at 15 different concentrations in chordoma cell lines, U-CH1 and U-CH2. We identified a group of drugs including bortezomib, 17-AAG, digitoxin, staurosporine, digoxin, rubitecan, and trimetrexate that inhibited chordoma cell growth, with potencies from 10 to 370 nM in U-CH1 cells, but less potently in U-CH2 cells. Most of these drugs also induced caspase 3/7 activity with a similar rank order as the cytotoxic effect on U-CH1 cells. Cantharidin, digoxin, digitoxin, staurosporine, and bortezomib showed similar inhibitory effect on cell lines and 3 primary chordoma cell cultures. The combination treatment of bortezomib with topoisomerase I and II inhibitors increased the therapeutic potency in U-CH2 and patient-derived primary cultures. Our results provide information useful for repurposing currently approved drugs for chordoma and potential approach of combination therapy.
authors.affiliation: NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA. mxia@mail.nih.gov
authors.forename: Menghang
authors.initials: M
authors.lastname: Xia
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.forename: Srilatha
authors.initials: S
authors.lastname: Sakamuru
authors.forename: David
authors.initials: D
authors.lastname: Alcorta
authors.forename: Ming-Hsuang
authors.initials: MH
authors.lastname: Cho
authors.forename: Dae-Hee
authors.initials: DH
authors.lastname: Lee
authors.forename: Deric M
authors.initials: DM
authors.lastname: Park
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kelley
authors.forename: Josh
authors.initials: J
authors.lastname: Sommer
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002817:Chordoma / Q000188:drug therapy* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D054852:Small Molecule Libraries
chemical_list: D000970:Antineoplastic Agents; D054852:Small Molecule Libraries
keywords: NCGC Pharmaceutical Collection; U-CH1; U-CH2; caspase 3/7; cell viability; chordoma; qHTS