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Published on: November 20, 2012
Akt signaling is required for glioblastoma maintenance in vivo
James P Robinson1, Matthew W Vanbrocklin, Andrea J McKinney
1Nevada Cancer Institute, Las Vegas, NV 89135, USA.
Abstract:
Glioblastoma multiforme (GBM) can be induced in mice through the combined expression of activated forms of KRas and Akt in glial progenitor cells. We have previously demonstrated that KRas is required for the maintenance of these tumors in vivo as inhibition of KRas expression resulted in apoptotic tumor regression and significantly increased survival. To determine the reliance of these tumors on Akt signaling in vivo, we generated a viral vector that allows the expression of Akt to be controlled post-delivery. Survival rates were compared between those animals with continued Akt expression and animals in which expression of Akt was suppressed. Although a fifth of the tumors were refractory to treatment, inhibition of Akt significantly increased the survival of tumor-bearing mice and nearly a fourth of the mice remained in remission four months after the treatment period. These data suggest that Akt is required for glioblastoma maintenance in the context of activated Ras and that loss of Akt expression results in increased survival; therefore, the PI3K/AKT signaling pathway is a viable therapeutic target in this context.
Insights
Inhibition of Akt signaling significantly increased survival in mice with glioblastoma multiforme (GBM). These findings highlight the PI3K/AKT pathway as a potential therapeutic target for GBM treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Glioblastoma multiforme (GBM) is a lethal brain tumor.
- KRas and Akt signaling pathways are implicated in GBM development.
- Previous studies showed KRas is essential for GBM maintenance.
Purpose of the Study:
- To investigate the role of Akt signaling in maintaining established GBM.
- To determine if inhibiting Akt signaling impacts tumor progression and survival in vivo.
- To evaluate the PI3K/AKT pathway as a therapeutic target for GBM.
Main Methods:
- Genetically engineered mice expressing activated KRas and Akt in glial progenitor cells to induce GBM.
- Utilized a viral vector to control Akt expression post-tumor induction.
- Compared survival rates between mice with continuous Akt expression and those with suppressed Akt expression.
Main Results:
- Inhibition of Akt expression significantly increased survival rates in tumor-bearing mice.
- A subset of tumors (approximately 20%) were refractory to Akt inhibition.
- Nearly 25% of mice treated with Akt inhibition remained in remission four months post-treatment.
Conclusions:
- Akt signaling is crucial for the maintenance of KRas-driven GBM.
- Suppression of Akt leads to increased survival and potential long-term remission.
- The PI3K/AKT signaling pathway represents a promising therapeutic target for GBM.
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