Targeting Angiogenesis in Pancreatic Neuroendocrine Tumors: Resistance Mechanisms

• Published in: International journal of molecular sciences Vol. 20; no. 19; p. 4949
• Main Authors: Pozas, Javier, San Román, María, Alonso-Gordoa, Teresa, Pozas, Miguel, Caracuel, Laura, Carrato, Alfredo, Molina-Cerrillo, Javier
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08-10-2019; MDPI
• Subjects: Angiogenesis; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Animals; antiangiogenic; Antiangiogenic agents; Antiangiogenics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biomarkers; Chemotherapy; Classification; Clinical trials; Clinical Trials as Topic; Conserved sequence; Diarrhea; Disease Management; Drug Resistance, Neoplasm - genetics; Growth factors; Hormones; Humans; Medical prognosis; Metastasis; Molecular biology; Molecular Targeted Therapy; Mutation; Neoplasm Grading; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - etiology; Neovascularization, Pathologic - metabolism; Neuroendocrine tumors; Neuroendocrine Tumors - diagnosis; Neuroendocrine Tumors - drug therapy; Neuroendocrine Tumors - etiology; Neuroendocrine Tumors - metabolism; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - diagnosis; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - etiology; Pancreatic Neoplasms - metabolism; Patients; Peptides; Radiation therapy; Radioisotopes; resistance; Review; Somatostatin; sunitinib; Sunitinib - pharmacology; Sunitinib - therapeutic use; Targeted cancer therapy; Treatment Outcome; Tumors; sunitinib; antiangiogenic; neuroendocrine tumors; resistance
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20194949

Despite being infrequent tumors, the incidence and prevalence of pancreatic neuroendocrine tumors (P-NETs) has been rising over the past few decades. In recent years, rigorous phase III clinical trials have been conducted, allowing the approval of several drugs that have become the standard of care in these patients. Although various treatments are used in clinical practice, including somatostatin analogues (SSAs), biological therapies like sunitinib or everolimus, peptide receptor radionuclide therapy (PRRT) or even chemotherapy, a consensus regarding the optimal sequence of treatment has not yet been reached. Notwithstanding, sunitinib is largely used in these patients after the promising results shown in SUN111 phase III clinical trial. However, both prompt progression as well as tumor recurrence after initial response have been reported, suggesting the existence of primary and acquired resistances to this antiangiogenic drug. In this review, we aim to summarize the most relevant mechanisms of angiogenesis resistance that are key contributors of tumor progression and dissemination. Furthermore, several targeted molecules acting selectively against these pathways have shown promising results in preclinical models, and preliminary results from ongoing clinical trials are awaited.