A multi-targeted tyrosine kinase inhibitor lenvatinib for the treatment of mice with advanced glioblastoma

Abstract

Glioblastoma is the most aggressive primary brain tumor that originates from the glial cells in adults. Aberrant angiogenesis is essential for malignant glioblastoma tumorigenesis, development and metastasis. Lenvatinib is a multi‑targeted anticancer agent that targets of receptor tyrosine kinases including vascular endothelial growth factor receptor 1 and 2, fibroblast growth factor receptor 1, platelet‑derived growth factor receptor β and v‑kit Hardy‑Zuckerman 4 feline sarcoma viral oncogene homolog. In the present study, the therapeutic effects of lenvatinib as a treatment for glioblastoma were investigated in vivo and in vitro. The maximum dose toxicity (MDT) and treatment‑associated adverse events of lenvatinib were identified by cytotoxicity assay in experimental mice. Increasing levels of the pro‑apoptosis genes caspase‑3, -8, -9 and -10 following lenvatinib treatment were determined by reverse transcription‑quantitative polymerase chain reaction, and apoptosis of the malignant gliomas cells was analyzed by FACS. In vivo treatment with lenvatinib for BV‑2 bearing male BALC/c nude mice was assessed via tumor growth suppression and long‑term observation of survival. Subsequent cytotoxic T lymphocyte responses were further analyzed to determine the in vivo efficacy of lenvatinib treatment in mice with glioblastoma. The MDT of lenvatinib was identified as 0.24 mg, with relatively few side effects and improved efficacy in mice. Lenvatinib (0.24 mg) significantly increased apoptosis in BV‑2, C6, BC3H1 and G422 glioma cell lines. Tumor growth was significantly inhibited and tumor‑bearing mice demonstrated an improved survival rate following treatment with lenvatinib. In conclusion, lenvatinib provided an effective treatment outcome, and the results of the present study may help to achieve a comprehensive therapeutic schedule for clinical application.

Brain Metastases From Differentiated Thyroid Carcinoma: Prevalence, Current Therapies, and Outcomes

“…Koutras et al [39] found that sunitinib was effective and safe for a patient with brain metastases from renal cell carcinoma. Another study showed that lenvatinib was effective in vitro and in vivo for the treatment of glioblastoma, thus suggesting good penetration in the blood-brain barrier of mice [40]. Several prospective clinical trials have focused on malignancies that commonly metastasize to the brain, such as melanoma and lung and breast cancers.…”

Integration of Computational Pipeline to Streamline Efficacious Drug Nomination and Biomarker Discovery in Glioblastoma

“…Furthermore, given the heterogeneity among these independent clinical studies, the consistency in our discoveries further justify their importance and presents numerous opportunities for follow-up studies. These drugs achieve tumor growth inhibition through a variety of mechanisms of actions, namely VEG-FRis, EGFRis, and MEKis, which have a rich history of study in the context of GBM [23][24][25][26][27][28][29][30][31][32][33]. Other targets identified that frequently show up in clinical studies include mammalian target of rapamycin (MTOR) and cyclin-dependent kinases (CDKs).…”

Safety and Efficacy of Sorafenib and Lenvatinib in Patients Who Underwent Surgery or Whole-Brain Radiotherapy for Brain Metastasis of Hepatocellular Carcinoma

“…On the other hand, the new-generation TKI, lenvatinib, has more potent activity against vascular endothelial growth factor and fibroblast growth factor receptors. In vivo studies on brain metastasis of thyroid cancers and advanced glioblastomas demonstrated that lenvatinib significantly inhibited tumor growth [ 22 , 23 ]. Taken together, the findings suggest that TKIs can be effective in the management of different grades of gliomas and specific brain metastases.…”