Background: Glioblastomas (GBMs) are highly malignant brain tumours with a poor prognosis, and current\ncytotoxic regimens provide only a limited survival benefit. The PI3K/Akt/mTOR pathway has been an attractive\ntarget for therapy due to its high activation in GBMs as well as other cancers. The dual pan-PI3K/mTOR kinase\ninhibitor dactolisib (NVP-BEZ235) is an anti-neoplastic compound currently under investigation. However, little\nis known about its efficacy in human GBMs. We aimed at evaluating the efficacy of dactolisib in human\nglioblastoma cells, as well as in murine models carrying human GBM xenografts.\nMethods: To assess the effect of dactolisib in vitro, MTS assay, manual cell count, BrdU incorporation and Annexin V\nstaining experiments were used to observe growth and apoptosis. Furthermore, Akt phosphorylation (S473), a\ndownstream target of PI3K, was explored by western blotting. Animal studies utilizing orthotopic xenograft models of\nglioblastoma were performed in nude rats and NOD/SCID mice to monitor survival benefit or inhibition of tumor growth.\nResults: We found that dactolisib in vitro shows excellent dose dependent anti-growth properties and\nincrease in apoptosis. Moreover, dose dependent inhibition of Akt phosphorylation (S473), a downstream\neffect of PI3K, was observed by western blotting. However, in two independent animal studies utilizing nude\nrats and NOD/SCID mice in orthotopic xenograft models of glioblastoma, we observed no survival benefit or\ninhibition of tumour growth. Severe side effects were observed, such as elevated levels of blood glucose and\nthe liver enzyme alanine transaminase (ALT), in addition to diarrhoea, hair loss (alopecia), skin rash and\naccumulation of saliva in the oral cavity.\nConclusion: Taken together, our results suggest that despite the anti-neoplastic efficacy of dactolisib in\nglioma treatment in vitro, its utility in vivo is questionable due to toxicity.
Loading....