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Published on: July 25, 2020
Combination of CDK4/6 and mTOR Inhibitors Suppressed Doxorubicin-resistant Osteosarcoma in a Patient-derived
Hiromichi Oshiro1,2,3, Yasunori Tome3, Kentaro Miyake1,2
1AntiCancer Inc., San Diego, CA, U.S.A.
Background:
Osteosarcoma is the most frequent malignant bone neoplasm. The efficacy of combination therapy of a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and a mammalian-target-of-rapamycin (mTOR) inhibitor was previously reported in several cancer types. In the present study, we evaluated the efficacy of a combination of palbociclib (CDK 4/6 inhibitor) and everolimus (mTOR inhibitor) on an osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model.
Materials And Methods:
osteosarcoma PDOX mouse models were randomized into five treatment groups of seven mice each: Group 1, untreated control; group 2, doxorubicin treatment; group 3, palbociclib treatment; group 4, everolimus treatment; group 5, palbociclib-everolimus combination treatment. Treatment duration was 2 weeks.
Results:
The palbociclib-everolimus combination reduced the tumor-volume ratio in the osteosarcoma PDOX mouse model compared with the control and doxorubicin (p=0.018). Everolimus alone also inhibited osteosarcoma PDOX growth compared to the control (p=0.04), but less than the combination. Palbociclib alone and doxorubicin were ineffective. There were no significant body-weight losses in any group. Only the palbociclib-everolimus combination induced extensive tumor necrosis observed histopathologically.
Conclusion:
The present study demonstrated that the combination of CDK4/6 and mTOR inhibitors can be a translatable approach for doxorubicin-resistant osteosarcoma in the clinic.
Insights
The combination of palbociclib (a CDK4/6 inhibitor) and everolimus (an mTOR inhibitor) effectively reduced osteosarcoma tumor growth in a mouse model. This combination therapy shows promise for treating doxorubicin-resistant osteosarcoma.
Area of Science:
- Oncology
- Pharmacology
- Preclinical Cancer Research
Background:
- Osteosarcoma is the most common primary malignant bone tumor.
- Combination therapy with CDK4/6 and mTOR inhibitors has shown efficacy in other cancers.
- The study investigates palbociclib (CDK4/6 inhibitor) and everolimus (mTOR inhibitor) for osteosarcoma.
Purpose of the Study:
- To evaluate the efficacy of combining palbociclib and everolimus in an osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model.
- To compare the combination therapy against individual agents and doxorubicin treatment.
Main Methods:
- Osteosarcoma PDOX mouse models were established.
- Mice were randomized into five groups: control, doxorubicin, palbociclib, everolimus, and palbociclib-everolimus combination.
- Treatments were administered for two weeks.
Main Results:
- The palbociclib-everolimus combination significantly reduced tumor volume compared to control and doxorubicin (p=0.018).
- Everolimus alone showed some inhibition, while palbociclib and doxorubicin were ineffective.
- Extensive tumor necrosis was observed only in the combination treatment group, with no significant weight loss.
Conclusions:
- The combination of CDK4/6 and mTOR inhibitors is a potential therapeutic strategy for doxorubicin-resistant osteosarcoma.
- This preclinical finding suggests a translatable approach for clinical application.
