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|Ref Type||Journal Article|
|Authors||Babichev Y, Kabaroff L, Datti A, Uehling D, Isaac M, Al-Awar R, Prakesch M, Sun RX, Boutros PC, Venier R, Dickson BC, Gladdy RA|
|Title||PI3K/AKT/mTOR inhibition in combination with doxorubicin is an effective therapy for leiomyosarcoma.|
|Journal||Journal of translational medicine|
|Date||2016 Mar 08|
|Abstract Text||Leiomyosarcoma (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.LMS 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.Compounds 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 <1 μM. We therefore examined if BEZ235 and BKM120, two selective compounds in these pathways, would inhibit leiomyosarcoma growth in vitro. Immunoblots confirmed on-target effects of these compounds in the PI3K and/or mTOR pathways. We next investigated if there was synergy with these agents and first line chemotherapy doxorubicin (Dox), which would allow for earlier introduction into patient care. Only combined treatment of BEZ235 and Dox was synergistic in vitro. To validate these findings in pre-clinical models, leiomyosarcoma xenografts were treated with single agent and combination therapy. BEZ235 treated xenografts (n = 8) demonstrated a decrease in tumor volume of 42 % whereas combining BEZ235 with Dox (n = 8) decreased tumor volume 68 % compared to vehicle alone.In summary, this study supports further investigation into the use of PI3K and mTOR inhibitors alone and in combination with standard treatment in leiomyosarcoma patients.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||leiomyosarcoma||not applicable||Dactolisib||Preclinical||Actionable||In a preclinical study, leiomyosarcoma cells treated with BEZ235 in culture and in mouse models demonstrated increased levels of apoptosis and a 42% reduction in tumor volume (PMID: 26952093).||26952093|
|Unknown unknown||leiomyosarcoma||not applicable||Aldoxorubicin + Buparlisib||Preclinical||Actionable||In a preclinical study, the combination of BKM120 and doxorubicin produced an additive effect when treating leiomyosarcoma cells (PMID: 26952093).||26952093|
|Unknown unknown||leiomyosarcoma||not applicable||Aldoxorubicin + Dactolisib||Preclinical||Actionable||In a preclinical study, the combination of doxorubicin and BEZ235 produced a synergistic effect in leiomyosarcoma cells both in culture and in mouse models, resulting in apoptotic induction and a 68% reduction in tumor volume (PMID: 26952093).||26952093|