Avances en el tratamiento del glioblastoma empleando el fármaco rapamicina

Résumé

The principal aim of this study was to enhance rapamycin treatment efficacy in human glioblastoma multiforme, establishing a treatment capable to improve survival. To achieve this proposal we have evaluated the differences in survival and inhibition states of PI3K/Akt/mTOR pathway, when different concentrations and schedules of rapamycin or its analog torisel were used. We demonstrate, in the intracranial U87MG xenograft model, that the increase of the dose concentration do not imply a huge improve on survival. However, when stable levels of rapamycin were kept with intermittent treatment schedules, a significantly improved median survival was observed. No differences were found when the efficacy of rapamycin was compared to its analog torisel. The efficacy of intermittent treatment schedules was associated with prolonged inhibition of PI3K/Akt/mTOR pathway in tumors. The inhibition state of this pathway was studied analyzing the phosphorylation of the ribosomal protein S6. We have characterized the effect of rapamycin upon human glioblastoma cancer stem cells (CSCs). The drug was able to reduce cell proliferation, autoregeneration and the ability of colony formation in vitro; but the intracranial brain tumor xenograft CSCs model was resistant to rapamycin treatment. Combined therapy of rapamycin and nanoliposomal irinotecan (nLs-CPT-11) was used in the treatment of U87MG intracranial brain tumor model resulting in a 6-fold survival improvement in comparison to control animals. We conclude that CED of nLs-CPT-11 and systemic rapamycin may be an effective treatment option for malignant gliomas.