Angiogenesis in NENs, with a focus on gastroenteropancreatic NENs: from biology to current and future therapeutic implications

Abstract

Neuroendocrine neoplasms (NENs) are highly vascularized malignancies arising from cells of the diffuse neuroendocrine system. An intricated cross-talk exists between NEN cells and the tumor microenvironment, and three main molecular circuits (VEGF/VEGFR pathway, FGF-dependent signaling and PDGF/PDGFR axis) have been shown to regulate angiogenesis in these neoplasms. Multiple randomized trials have investigated antiangiogenic agents over the past two decades, and sunitinib is currently approved for the treatment of advanced, progressive, G1/G2 pancreatic NENs. In recent years, two phase III clinical trials have demonstrated the efficacy and safety of surufatinib, a multi-tyrosine kinase angioimmune inhibitor, in patients with well-differentiated pancreatic and extrapancreatic NENs, and two studies of this agent are currently underway in Europe and US. The HIF-2α inhibitor belzutifan has recently received regulatory approval for the treatment of tumors arising in the context of Von-Hippel Lindau syndrome including pancreatic NENs, and a study of this drug in patients with sporadic tumors is presently ongoing. Combinations of antiangiogenic agents with chemotherapeutics and targeted drugs have been tested, with accumulating toxicities being a matter of concern. The potential of antiangiogenic agents in fine-tuning the immune microenvironment of NENs to enhance the activity of immune checkpoint inhibitors has been only partially elucidated, and further research should be carried out at this regard. Here, we review the current understanding of the biology of angiogenesis in NENs and provide a summary of the latest clinical investigations on antiangiogenic drugs in this malignancy.

Sex differences on multikinase inhibitors toxicity in patients with advanced gastroenteropancreatic neuroendocrine tumours

“…In recent years, there has been a growing interest in incorporating new drugs from the MKI family into the NET management algorithm [5]. Although, to date, none of them have obtained favourable results or approval at a global level, a significant effort has been made in the design of clinical trials that continues today.…”

“…1. The most meaningful differential toxicities in each trial were as follows: liver toxicity with pazopanib (62% [95% CI 41-80] male versus 95% [95% CI 73-100] female, p 0.02), aphonia with sorafenibbevacizumab (50% [95% CI 32-68] male versus 11% [95% CI 2-36] female, p 0.01), face oedema with sunitinib (10% [95% CI [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] male versus 41% [95% CI 27-58] female, p 0.0005) and bleeding with lenvatinib (0% [95% CI 0-13] male versus 21% [95% CI 8-44] female, p 0.0198) (Fig. 1).…”

“…Currently, only Sunitinib has a phase 3 randomised clinical trial in the Western population and is widely used in clinical practice [4]. Nevertheless, different molecules have been evaluated in phase 2 studies and in ongoing clinical trials, both as monotherapy and in combination [5]. The toxicity of MKI is one of the most important factors impacting their effectiveness, constituting a limiting factor related to therapeutic adherence and dose intensity [6].…”

Assessing the effectiveness and safety of surufatinib versus everolimus or sunitinib in advanced neuroendocrine neoplasms: insights from a real-world, retrospective cohort study using propensity score and inverse probability treatment weighting analysis

“…The follow-up was until November 2023. Genomic profiles for pNEN were clearer than epNEN, in which more abundant evidences demonstrated that molecular circuits regulating angiogenesis exerts a critical role throughout the development of pNEN ( 14 , 21 ). Furthermore, considering the differences in disease characteristics and indications, the included patients were divided into pNEN and epNEN patients, among whom the study analysis were made on surufatinib treatment cohort vs. sunitinib or everolimus (sunitinib + everolimus) treatment cohort for pNEN patients and surufatinib treatment cohort vs. everolimus treatment cohort for epNEN patients.…”