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Abstract
BackgroundGlioblastomas (GBMs) are highly malignant brain tumours with a poor prognosis, and current cytotoxic regimens provide only a limited survival benefit. The PI3K/Akt/mTOR pathway has been an attractive target for therapy due to its high activation in GBMs as well as other cancers. The dual pan-PI3K/mTOR kinase inhibitor dactolisib (NVP-BEZ235) is an anti-neoplastic compound currently under investigation. However, little is known about its efficacy in human GBMs. We aimed at evaluating the efficacy of dactolisib in human glioblastoma cells, as well as in murine models carrying human GBM xenografts.MethodsTo assess the effect of dactolisib in vitro, MTS assay, manual cell count, BrdU incorporation and Annexin V staining experiments were used to observe growth and apoptosis. Furthermore, Akt phosphorylation (S473), a downstream target of PI3K, was explored by western blotting. Animal studies utilizing orthotopic xenograft models of glioblastoma were performed in nude rats and NOD/SCID mice to monitor survival benefit or inhibition of tumor growth.ResultsWe found that dactolisib in vitro shows excellent dose dependent anti-growth properties and increase in apoptosis. Moreover, dose dependent inhibition of Akt phosphorylation (S473), a downstream effect of PI3K, was observed by western blotting. However, in two independent animal studies utilizing nude rats and NOD/SCID mice in orthotopic xenograft models of glioblastoma, we observed no survival benefit or inhibition of tumour growth. Severe side effects were observed, such as elevated levels of blood glucose and the liver enzyme alanine transaminase (ALT), in addition to diarrhoea, hair loss (alopecia), skin rash and accumulation of saliva in the oral cavity.ConclusionTaken together, our results suggest that despite the anti-neoplastic efficacy of dactolisib in glioma treatment in vitro, its utility in vivo is questionable due to toxicity.
Highlights
Glioblastomas (GBMs) are highly malignant brain tumours with a poor prognosis, and current cytotoxic regimens provide only a limited survival benefit
Cells were pulsed with BrdU after dactolisib exposure, and the subsequent quantification of BrdU positive cells demonstrated a clear dose dependent reduction in cell proliferation (Fig. 1c)
Annexin-Propidium Iodide (PI) Apoptosis assay post dactolisib-exposure showed a dose-dependent increase of apoptosis (Fig. 1d)
Summary
Glioblastomas (GBMs) are highly malignant brain tumours with a poor prognosis, and current cytotoxic regimens provide only a limited survival benefit. The PI3K/Akt/mTOR pathway has been an attractive target for therapy due to its high activation in GBMs as well as other cancers. The PI3K/Akt/mTOR pathway is frequently deregulated in GBM [7], and represents an attractive target for molecular therapies. Clinical trials of tyrosine kinase inhibitors (TKIs) in glioblastoma have, Netland et al BMC Cancer (2016) 16:657 despite good tolerability, generally showed limited efficacy [8]. This may be due to several factors, such as genetic instability and escape mechanisms, as well as inefficient drug delivery and effects, pharmacokinetic properties and unacceptable side effects [8]. Combination therapy with several inhibitors is associated with increased risk of dose limiting toxicity due to drug interactions and risk of accumulated toxicity [10]
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