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Perifosine and CCI 779 co-operate to induce cell death and decrease proliferation in PTEN-intact and PTEN-deficient
Kenneth L Pitter1, Craig J Galbán, Stefanie Galbán
1Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
Plos One
|January 27, 2011
Summary
Simultaneously inhibiting Akt and mTOR with perifosine and CCI-779 effectively reduces proliferation and increases cell death in Platelet-Derived Growth Factor Receptor (PDGFR) driven glioblastoma models, regardless of PTEN status.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Deregulation of Platelet-Derived Growth Factor Receptor (PDGFR) signaling, particularly PDGFR-alpha, is implicated in approximately 25-30% of human Glioblastoma Multiforme (GBM).
- This aberrant signaling activates key downstream kinases like phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR), driving tumor growth.
- Understanding the response of PDGFR-driven GBMs to Akt and mTOR inhibition is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the efficacy of inhibiting Akt and mTOR, alone and in combination, in PDGFR-driven GBM mouse models.
- To evaluate the impact of these inhibitors on GBM cell proliferation and survival.
- To determine if the combination therapy's effectiveness is dependent on PTEN status.
Main Methods:
- Utilized genetically engineered PTEN-intact and PTEN-deficient PDGF-driven mouse models of GBM.
- Employed perifosine to inhibit Akt and CCI-779 to inhibit mTOR.
- Conducted in vitro studies on primary glioma cell cultures and in vivo studies involving 5-day treatment of tumor-bearing mice.
- Assessed signaling pathway activity, proliferation, and cell death using immunoblot analysis, histology, and MRI.
Main Results:
- In vitro studies demonstrated that combining perifosine and CCI-779 achieved the most effective inhibition of Akt and mTOR activity in both PTEN-intact and PTEN-null glioma cells.
- In vivo treatment with the combination therapy led to decreased Akt and mTOR signaling.
- This reduction in signaling correlated with decreased tumor cell proliferation and increased cell death, independent of PTEN status.
Conclusions:
- Simultaneous inhibition of Akt and mTOR is essential for significant downregulation of the PI3K pathway in PDGFR-driven GBM.
- The combination of perifosine and CCI-779 shows promise for treating the PDGF-subgroup of GBM.
- These findings support the clinical investigation of this combination therapy in human GBM patients.
