Combination of CDK4/6 and mTOR Inhibitors Suppressed Doxorubicin-resistant Osteosarcoma in a Patient-derived Orthotopic Xenograft Mouse Model: A Translatable Strategy for Recalcitrant Disease

Abstract

Materials and MethodsMice. Athymic nu/nu nude mice (AntiCancer Inc., San Diego, CA, USA), 4-6 weeks old, were used in the present study. Mouse housing, surgical procedures, imaging and sacrifice were performed as described in previous publications (17)(18)(19)(20). An AntiCancer Institutional Animal Care and Use Committee-approved protocol was used for all of the studies according to the procedures and principles summarized in the National Institutes of Health Guide for the Care and Use of Laboratory Animals, eighth edition, under Public Health Service Approved Animal Welfare Assurance Number A3873-1 (21).

Review: Precise sarcoma patient-derived orthotopic xenograft (PDOX) mouse models enable identification of novel effective combination therapies with the cyclin-dependent kinase inhibitor palbociclib: A strategy for clinical application

“…Monotherapy with palbociclib moderately inhibited the PDOX growth compared to that of the control (38). The combination of palbociclib and everolimus significantly inhibited tumor growth and induced cancer necrosis (38). This was the first report demonstrating the efficacy of the palbociclib-everolimus combination for osteosarcoma, suggesting promising clinical efficacy (38).…”

“…Another osteosarcoma PDOX was treated with palbociclib combined with everolimus, which is an mTOR inhibitor approved for breast and renal cell cancer ( 37 ). The patient tumor used for this osteosarcoma PDOX model was from a fresh surgical sample of femoral osteosarcoma ( 38 ). Monotherapy with palbociclib moderately inhibited the PDOX growth compared to that of the control ( 38 ).…”

“…The patient tumor used for this osteosarcoma PDOX model was from a fresh surgical sample of femoral osteosarcoma ( 38 ). Monotherapy with palbociclib moderately inhibited the PDOX growth compared to that of the control ( 38 ). The combination of palbociclib and everolimus significantly inhibited tumor growth and induced cancer necrosis ( 38 ).…”

“…The combination of palbociclib and everolimus significantly inhibited tumor growth and induced cancer necrosis ( 38 ). This was the first report demonstrating the efficacy of the palbociclib–everolimus combination for osteosarcoma, suggesting promising clinical efficacy ( 38 ). CDK4/6 inhibition was reported to downregulate the downstream mediators of the mTOR pathway in several cancer types, predicting synergy of a CDK4/6 inhibitor combined with an mTOR inhibitor ( 39 ).…”

Chloroquine Combined With Rapamycin Arrests Tumor Growth in a Patient-derived Orthotopic Xenograft (PDOX) Mouse Model of Dedifferentiated Liposarcoma

“…mTOR plays a central role in the regulation of various cellular functions such as survival and proliferation (13). We have previously demonstrated the anticancer effects of mTOR inhibitors in combination with multiple agents in PDOX mouse models of osteosarcoma (14,15). Chloroquine (CQ) is an antimalarial drug developed in Germany in 1934 (16).…”