Abstract
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.
Highlights
Neuroendocrine neoplasms (NEN) are a diverse group of tumors mainly arising from the diffuse endocrine cells derived from the neural crest
There is a recruiting phase II clinical trial (RESUNET, NCT02713763) which aims to evaluate the efficacy of a rechallenge with sunitinib in advanced or metastatic WD pancreatic neuroendocrine tumors (P-NETs) which have already progressed to sunitinib in previous lines
Dual targeting of angiogenesis by the simultaneous administration of sunitinib and liposomal clodronate in RIP-Tag2 mice failed to show synergistic antiangiogenic efficacy [53,54]
Summary
Neuroendocrine neoplasms (NEN) are a diverse group of tumors mainly arising from the diffuse endocrine cells derived from the neural crest. These tumors have a complex clinical and biological behavior, which varies depending on the place of origin, the hormone production, and the histological differentiation. Patients with metastatic P-NETs disease present a median overall survival (OS) of about 3.6 years [2] and 5-year survival rate of 30.2%. 65% of P-NETs are diagnosed as unresectable or metastatic disease, with a consequent worse prognosis [3,4,5]. The aim of this review is to make a comprehensive overview about molecular pathways involved in P-NETs, focusing on angiogenesis and its mechanisms of resistance, from the basis to the clinic
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