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Anti-VEGF antibody therapy does not promote metastasis in genetically engineered mouse tumour models
Mallika Singh1, Suzana S Couto, William F Forrest
1Genentech Inc, 1 DNA Way, South San Francisco, CA 94080, USA. msingh@gene.com
Abstract:
Resistance to anti-angiogenic therapy can occur via several potential mechanisms. Unexpectedly, recent studies showed that short-term inhibition of either VEGF or VEGFR enhanced tumour invasiveness and metastatic spread in preclinical models. In an effort to evaluate the translational relevance of these findings, we examined the consequences of long-term anti-VEGF monoclonal antibody therapy in several well-validated genetically engineered mouse tumour models of either neuroendocrine or epithelial origin. Anti-VEGF therapy decreased tumour burden and increased overall survival, either as a single agent or in combination with chemotherapy, in all four models examined. Importantly, neither short- nor long-term exposure to anti-VEGF therapy altered the incidence of metastasis in any of these autochthonous models, consistent with retrospective analyses of clinical trials. In contrast, we observed that sunitinib treatment recapitulated previously reported effects on tumour invasiveness and metastasis in a pancreatic neuroendocrine tumour (PNET) model. Consistent with these results, sunitinib treatment resulted in an up-regulation of the hypoxia marker GLUT1 in PNETs, whereas anti-VEGF did not. These results indicate that anti-VEGF mediates anti-tumour effects and therapeutic benefits without a paradoxical increase in metastasis. Moreover, these data underscore the concept that drugs targeting VEGF ligands and receptors may affect tumour metastasis in a context-dependent manner and are mechanistically distinct from one another.
Insights
Anti-angiogenic therapy using anti-VEGF antibodies effectively reduces tumor growth and improves survival without increasing metastasis. This contrasts with other drugs like sunitinib, highlighting distinct mechanisms in cancer treatment.
Area of Science:
- Oncology
- Cancer Biology
- Translational Research
Background:
- Anti-angiogenic therapies targeting VEGF (Vascular Endothelial Growth Factor) are crucial in cancer treatment.
- Recent studies suggested potential for increased tumor invasiveness with short-term VEGF/VEGFR inhibition.
- Translational relevance of these findings requires investigation in robust preclinical models.
Purpose of the Study:
- To evaluate the long-term effects of anti-VEGF monoclonal antibody therapy on tumor growth and metastasis.
- To compare the impact of anti-VEGF therapy with other agents like sunitinib in preclinical cancer models.
- To elucidate the distinct mechanisms of anti-VEGF agents versus other anti-angiogenic drugs regarding metastasis.
Main Methods:
- Utilized four well-validated genetically engineered mouse models of neuroendocrine and epithelial tumors.
- Administered long-term anti-VEGF monoclonal antibody therapy, alone and in combination with chemotherapy.
- Assessed tumor burden, overall survival, and incidence of metastasis.
- Analyzed effects of sunitinib in a pancreatic neuroendocrine tumor (PNET) model, including GLUT1 expression as a hypoxia marker.
Main Results:
- Long-term anti-VEGF therapy significantly decreased tumor burden and improved survival across all models.
- Neither short-term nor long-term anti-VEGF exposure increased metastasis incidence in autochthonous models.
- Sunitinib treatment, unlike anti-VEGF, enhanced tumor invasiveness and metastasis in the PNET model.
- Sunitinib increased GLUT1 expression (hypoxia marker) in PNETs, whereas anti-VEGF did not.
Conclusions:
- Anti-VEGF monoclonal antibody therapy demonstrates anti-tumor efficacy and survival benefits without paradoxical metastasis enhancement.
- Drug effects on tumor metastasis are context-dependent and mechanistically distinct between agents targeting VEGF ligands/receptors.
- These findings support the clinical utility of anti-VEGF therapies and differentiate their safety profile from other anti-angiogenic agents.
