Addressing the Role of Angiogenesis in Patients with Advanced Pancreatic Neuroendocrine Tumors Treated with Everolimus: A Biological Prospective Analysis of Soluble Biomarkers and Clinical Outcomes

Abstract

Simple Summary Despite the approval of new targeted therapies for pancreatic neuroendocrine tumors (PanNETs) over the past decades, the early identification of resistant tumors remains the major challenge, mainly because clear signs of tumor shrinkage are rarely achieved by imaging assessment. Starting from the hypothesis that angiogenesis can be implicated in the resistance to mTOR inhibitors, we evaluated a specific angiogenesis panel (through the measurement of soluble biomarkers for angiogenesis turnover, circulating endothelial cells, and circulating progenitors) as possible predictors of resistance to everolimus or everolimus efficacy in PanNETs. Our study showed that none of the investigated categories of biomarkers had a predictive value for everolimus resistance or efficacy. However, we suggest that circulating endothelial progenitors might be surrogate biomarkers for angiogenesis activity in PanNETs during everolimus treatment, and their baseline levels might correlate with survival outcomes. These data have never been reported before for NETs. Abstract Background: The success of targeted therapies in the treatment of pancreatic neuroendocrine tumors has emphasized the strategy of targeting angiogenesis and the PI3K/AKT/mTOR pathway. However, the major challenge in the targeted era remains the early identification of resistant tumors especially when the efficacy is rarely associated to a clear tumor shrinkage at by imaging assessment. Methods: In this prospective study (NCT02305810) we investigated the predictive and prognostic role of soluble biomarkers of angiogenesis turnover (VEGF, bFGF, VEGFR2, TSP-1) circulating endothelial cells and progenitors, in 43 patients with metastatic panNET receiving everolimus. Results: Among all tested biomarkers, we found a specific subpopulation of circulating cells, CD31+CD140b-, with a significantly increased tumor progression hazard for values less or equal to the first quartile. Conclusion: Our study suggested the evidence that circulating cells might be surrogate biomarkers of angiogenesis activity in patients treated with everolimus and their baseline levels can be correlated with survival. However, further studies are now needed to validate the role of these cells as surrogate markers for the selection of patients to be candidates for antiangiogenic treatments.

Circulating endothelial cells in pathophysiology

“…Recent evidence shows that patients with nasopharyngeal carcinoma undergoing treatment with chemotherapy (docetaxel + cisplatin) and an angiogenesis inhibitor (endostatin) experience a significant reduction in CEC numbers compared with those receiving chemotherapy alone [56]. This reduction is also evident during everolimus treatment in advanced pancreatic neuroendocrine tumours, supporting everolimus's role in inhibiting angiogenesis [57]. Similarly, the use of sorafenib, an antiangiogenic agent, leads to a decrease in CECs in hepatocellular cancer patients [58].…”

Role of Basic Fibroblast Growth Factor in Cancer: Biological Activity, Targeted Therapies, and Prognostic Value

“…Moreover, Chen et al, elucidated the interplay between the heparanase (HPA)/syndecan-1 (SDC1) axis and bFGF, suggesting HPA/SDC1 silencing as a valuable therapeutic strategy in decreasing bFGF [ 121 ]. Clinically, a case-control study, including 34 PDAC patients, shed light on the potential role of bFGF and PlGF as diagnostic biomarkers [ 122 ], thus supporting bFGF as a valuable candidate for anti-angiogenic treatments [ 123 ].…”

Identification of gene signatures related to hypoxia and angiogenesis in pancreatic cancer to aid immunotherapy and prognosis

“…The hypoxic prognostic model (HPM) was constructed as follows (1): review the literature through pubmed website to obtain hypoxia-related genes (2); take the intersection of hypoxiarelated genes and PC DEG (3); sequentially construct HPM by univariate Cox, last absolute shrinkage and selection operator (LASSO), multivariate Cox analysis was performed to construct HPM (4); calculate the patient's risk score calculated according to the prognostic model (5); divide patients into high and low risk groups based on the median value of the risk score (6); assess the prognostic efficacy of the prognostic model though Kaplan-Meier (KM) survival curve and receiver operating characteristic (ROC) curve. The angiogenic prognostic model (APM) was created in a way that was consistent with HPM.…”

“…Angiogenesis is one of the major contributors in tumor growth, infiltration and metastasis ( 5 ). Neovascularization, which develops inside tumor tissues and feeds tumor cells with nutrients, causes a rapid rise in the number of tumor cells, their volume, their infiltration of nearby tissues, and their propensity to metastasize ( 6 ). Since the first hypothesis that tumor growth is dependent on angiogenesis, the study of angiogenesis in solid tumors has drawn an increasing number of academics, and inhibiting tumor angiogenesis has emerged as a key method for modern tumor treatment ( 7 ).…”