Multitargeting strategy using lenvatinib and golvatinib: maximizing anti-angiogenesis activity in a preclinical...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Cancer cells often develop resistance to vascular endothelial growth factor (VEGF) inhibitors through various mechanisms.
• The angiopoietin-2 (Ang2) and Tie2 axis is a potential target for overcoming this resistance.
• Existing therapies face challenges in effectively inhibiting tumor angiogenesis and overcoming resistance.

Purpose of the Study:

• To investigate a novel therapeutic strategy combining multi-tyrosine kinase inhibitors lenvatinib and golvatinib to circumvent resistance to VEGF inhibitors.
• To evaluate the efficacy of this combination in preclinical cancer models by targeting the tumor microenvironment.

Main Methods:

• In vitro and in vivo studies using thyroid and endometrial cancer models.
• Combination therapy with lenvatinib (VEGF receptor, fibroblast growth factor receptor, RET inhibitor) and golvatinib (c-Met, Tie2, EphB4 inhibitor).
• Assessment of pericyte-mediated vessel stabilization, Tie2-expressing macrophage (TEM) differentiation, tumor perfusion, and apoptosis.

Main Results:

• The combination of golvatinib and lenvatinib inhibited pericyte-mediated vessel stabilization and TEM differentiation in vitro.
• Preclinical models showed inhibited pericyte network development and TEM infiltration.
• This led to severe tumor perfusion disorders and significant apoptosis, with tolerable side effects.

Conclusions:

• The strategic combination of lenvatinib and golvatinib effectively modulates the tumor microenvironment.
• This combination demonstrates potential in sensitizing cancers to VEGF inhibitors by targeting angiogenesis and associated cellular components.
• The findings support further investigation of this multi-targeted approach in cancer therapy.