Background.
Glioblastoma multiforme (GBM) is a devastating disease showing a very poor prognosis. New therapeutic approaches are needed to improve survival and quality of life. GBM is a highly vascularized
tumor and as such,
chemotherapy and
anti-angiogenic drugs have been combined for treatment. However, as treatment-induced resistance often develops, our goal was to identify and treat pathways involved in resistance to treatment to optimize the treatment strategies. Anti-angiogenetic compounds tested in preclinical and clinical settings demonstrated recurrence associated to secondary activation of the
phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway. Aims. Here, we determined the sensitizing effects of the small molecule and oral available dual
TORC1/
TORC2 dissociative inhibitor, RES529, alone or in combination with the anti-
VEGF blocking antibody,
bevacizumab, or the
tyrosine kinase inhibitor,
sunitinib, in human GBM models. Results. We observed that RES529 effectively inhibited dose-dependently the growth of GBM cells in vitro counteracting the insurgence of recurrence after
bevacizumab or
sunitinib administration in vivo. Combination strategies were associated with reduced
tumor progression as indicated by the analysis of Time to
Tumor Progression (
TTP) and disease-free survival (DSF) as well as increased overall survival (OS) of
tumor bearing mice. RES529 was able to reduce the in vitro migration of
tumor cells and tubule formation from both brain-derived endothelial cells (angiogenesis) and
tumor cells (vasculogenic mimicry). Conclusions. In summary, RES529, the first dual
TORC1/
TORC2 dissociative inhibitor, lacking affinity for ABCB1/ABCG2 and having good brain penetration, was active in GBM preclinical/murine models giving credence to its use in clinical trial for patients with GBM treated in association with anti-angiogenetic compounds.