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Dactolisib (NVP-BEZ235) toxicity in murine brain tumour models
I A Netland1, H E Førde1, L Sleire1
1Oncomatrix research lab, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway.
Background:
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 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.
Methods:
To 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.
Results:
We 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.
Conclusion:
Taken 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.
Insights
Dactolisib effectively reduced glioblastoma growth and increased apoptosis in lab studies. However, this dual PI3K/mTOR inhibitor showed no survival benefit in animal models and caused significant toxicity, questioning its in vivo utility.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Glioblastomas (GBMs) are aggressive brain tumors with limited treatment options.
- The PI3K/Akt/mTOR pathway is frequently activated in GBMs, making it a therapeutic target.
- Dactolisib (NVP-BEZ235) is a dual PI3K/mTOR inhibitor under investigation for cancer therapy.
Purpose of the Study:
- To evaluate the efficacy of dactolisib in human glioblastoma cells and xenograft models.
- To assess the drug's impact on tumor growth, apoptosis, and key signaling pathways.
- To determine the in vivo safety and therapeutic potential of dactolisib in glioblastoma.
Main Methods:
- In vitro studies included MTS assays, cell counting, BrdU incorporation, and Annexin V staining.
- Western blotting was used to analyze Akt phosphorylation (S473) as a downstream marker.
- In vivo efficacy was assessed using orthotopic glioblastoma xenograft models in nude rats and NOD/SCID mice.
Main Results:
- Dactolisib demonstrated dose-dependent anti-proliferative effects and induced apoptosis in vitro.
- Western blot analysis confirmed dose-dependent inhibition of Akt phosphorylation.
- No significant survival benefit or tumor growth inhibition was observed in vivo, accompanied by severe side effects including hyperglycemia and elevated ALT.
Conclusions:
- Dactolisib exhibits potent anti-cancer activity against glioblastoma in vitro.
- The drug's in vivo efficacy is limited by significant toxicity and lack of therapeutic benefit in preclinical models.
- Further investigation into dactolisib's clinical utility for glioblastoma is warranted, considering its toxicity profile.
