Regulation of liver metastasis and anti-VEGF therapy resistance in PNETs

Metastatic disease, in which the primary tumor spreads, accounts for about 90% of cancer deaths. Cancer drugs that inhibit primary tumor growth in preclinical studies often fail to inhibit the metastatic growth in clinical trials. Pancreatic neuroendocrine tumors (PNET), in which liver metastases are present in 40% of patients at diagnosis, account for approximately 3-5% of all pancreatic cancers, but the incidence has steadily increased over recent decades. Still, the therapeutic options of targeted drugs remain limited for PNET patients. Although angiogenesis inhibitors that target vascular endothelial growth factor (VEGF) signaling pathway have made meaningful advances in the treatment of PNET, drug resistance via metastatic recurrence limits therapeutic success. Therefore, understanding the mechanism of metastatic growth in the liver, the most common site of metastasis in PNET, and resistance to inhibitors of VEGF signaling is necessary to improve therapeutic outcomes of patients with PNET. Vascular destabilization is recognized as a hallmark of tumor growth and metastasis. Angiopoietin-2 (Ang2), which binds to the receptor tyrosine kinase Tie2, is a potent vascular destabilizing factor. Emerging evidence suggests that vascular destabilization facilitates tumor immune evasion by impairing immune effector cell infiltration. Using a spontaneous PNET mouse model, our preliminary study showed that prolonged VEGF inhibition promoted liver metastatic growth, which was accompanied with elevated Ang2 levels in the vasculature of liver metastases (VLM) and vascular leakage. Furthermore, we found pharmacologic Ang2 inhibition suppresses liver metastatic growth and improves the survival. Ang2 inhibition also reduced vascular leakage and increased CD8+ T-cell infiltration in metastases. In the proposed study, we aim to determine whether Ang2 functions as an escape for VEGF inhibitors which consequently leads to resistance through vascular destabilization and immune evasion in PNET liver metastases. The proposed project, which associates Ang2/Tie2 signaling-mediated VLM remodeling to immunosuppression and liver metastatic growth, will provide a framework for strategies to improve anti-VEGF efficacy.