1. PI3K/AKT/mTOR inhibition in combination with doxorubicin is an effective therapy for leiomyosarcoma
- Author
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Babichev, Yael, Kabaroff, Leah, Datti, Alessandro, Uehling, David, Isaac, Methvin, Al-awar, Rima, Prakesch, Michael, Sun, Ren X, Boutros, Paul C, Venier, Rosemarie, Dickson, Brendan C, and Gladdy, Rebecca A
- Subjects
Biomedical and Clinical Sciences ,Health Sciences ,Rare Diseases ,Orphan Drug ,Biotechnology ,Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Aminopyridines ,Animals ,Antineoplastic Combined Chemotherapy Protocols ,Apoptosis ,Cell Line ,Tumor ,Cell Proliferation ,Doxorubicin ,Drug Evaluation ,Preclinical ,Drug Synergism ,Female ,Humans ,Imidazoles ,Leiomyosarcoma ,Mice ,Inbred NOD ,Morpholines ,Phosphatidylinositol 3-Kinases ,Phosphoinositide-3 Kinase Inhibitors ,Protein Kinase Inhibitors ,Proto-Oncogene Proteins c-akt ,Quinolines ,Reproducibility of Results ,TOR Serine-Threonine Kinases ,PI3K ,mTOR ,Drug discovery ,Sarcoma ,Medical and Health Sciences ,Immunology ,Biomedical and clinical sciences ,Health sciences - Abstract
BackgroundLeiomyosarcoma (LMS) is a common type of soft tissue sarcoma that responds poorly to standard chemotherapy. Thus the goal of this study was to identify novel selective therapies that may be effective in leiomyosarcoma by screening cell lines with a small molecule library comprised of 480 kinase inhibitors to functionally determine which signalling pathways may be critical for LMS growth.MethodsLMS cell lines were screened with the OICR kinase library and a cell viability assay was used to identify potentially effective compounds. The top 10 % of hits underwent secondary validation to determine their EC50 and immunoblots were performed to confirm selective drug action. The efficacy of combination drug therapy with doxorubicin (Dox) in vitro was analyzed using the Calcusyn program after treatment with one of three dosing schedules: concurrent treatment, initial treatment with a selective compound followed by Dox, or initial treatment with Dox followed by the selective compound. Single and combination drug therapy were then validated in vivo using LMS xenografts.ResultsCompounds that targeted PI3K/AKT/mTOR pathways (52 %) were most effective. EC50s were determined to validate these initial hits, and of the 11 confirmed hits, 10 targeted PI3K and/or mTOR pathways with EC50 values
- Published
- 2016