Dual targeting of mTOR and Aurora-A kinase for the treatment of uterine leiomyosarcoma
Clinical Cancer Research, 07/24/2012
Savannah KB et al. – mTOR and Aurk-A pathways are commonly deregulated in ULMS. Preclinical data support further exploration of dual mTOR and Aurk-A therapeutic blockade for human ULMS.Methods
- Immunohistochemical staining was used to evaluate expression of activated mTOR componentry in a large (greater than 200 samples) ULMS tissue microarray.
- Effects of mTOR blockade (using rapamycin) and Aurk-A inhibition (using MLN8237) alone and in combination on human ULMS cell growth, cell-cycle progression, and apoptosis were assessed in cellular assays.
- Drug interactions were determined via combination index (CI) analyses.
- The anti-tumor effects of inhibitors alone or in combination were evaluated in vivo.
- Enhanced mTOR activation was seen in human ULMS samples.
- Increased pS6RP and p4EBP1 expression correlated with disease progression; p4EBP1 was found to be an independent prognosticator of patient outcome.
- Rapamycin inhibited growth and cell cycle progression of ULMS cell strains/lines in culture.
- However, only a cytostatic effect on tumor growth was found in vivo.
- Combining rapamycin with MLN8237 profoundly (and synergistically) abrogated ULMS cells' growth in culture; interestingly, these effects were seen only when MLN8237 was pre-administered.
- This novel therapeutic combination and scheduling regimen resulted in marked tumor growth inhibition in vivo.