Anti-proliferative and anti-secretory effects of everolimus on human pancreatic neuroendocrine tumors primary cultures: is there any benefit from combination with somatostatin analogs?

Abstract

Therapeutic management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is challenging. The mammalian target of rapamycin (mTOR) inhibitor everolimus recently obtained approval from the Food and Drug Administration for the treatment of patients with advanced pancreatic neuroendocrine tumors (pNETs). Despite its promising antitumor efficacy observed in cell lines, clinical benefit for patients is unsatisfactory. The limited therapeutic potential of everolimus in cancer cells has been attributed to Akt activation due to feedback loops relief following mTOR inhibition. Combined inhibition of Akt might then improve everolimus antitumoral effect. In this regard, the somatostatin analog (SSA) octreotide has been shown to repress the PI3K/Akt pathway in some tumor cell lines. Moreover, SSAs are well tolerated and routinely used to reduce symptoms caused by peptide release in patients carrying functional GEP-NETs. We have recently established and characterized primary cultures of human pNETs and demonstrated the anti-proliferative effects of both octreotide and pasireotide. In this study, we aim at determining the antitumor efficacy of everolimus alone or in combination with the SSAs octreotide and pasireotide in primary cultures of pNETs. Everolimus reduced both Chromogranin A secretion and cell viability and upregulated Akt activity in single treatment. Its anti-proliferative and anti-secretory efficacy was not improved combined with the SSAs. Both SSAs did not overcome everolimus-induced Akt upregulation. Furthermore, caspase-dependent apoptosis induced by SSAs was lost in combined treatments. These molecular events provide the first evidence supporting the lack of marked benefit in patients co-treated with everolimus and SSA.

Role of the tumor microenvironment in digestive neuroendocrine tumors

“…Moreover, relevant differences between GEP-NET cell lines have been recently emphasized by whole-exome sequencing and constitute another source of uncertainty when extrapolating results to the clinical setting (Vandamme et al 2015). An alternative way could be studies on primary cultures of human GEP-NETs tumor, representing an affordable and individualized approach of the tumor biology and response to treatment from bench to bedside (Mohamed et al 2017). Alternative options to optimally reproduce the in vivo landscape of the TME could be the use of microencapsulated SI-NET cells (Rokstad et al 2012), as well as the development of animal models of spontaneous PNETs could be a solution (Yu 2016).…”

Molecular challenges of neuroendocrine tumors (Review)

“…One of the predominant pathways is mTOR pathway that was highlighted in this review. The presence of the feedback loops though has to be seriously considered when it comes to combination treatment of somatostatin analogues and mTOR inhibitors (145,146). There still obvious challenges when it comes to drug resistance in clinical trials setting.…”

“…When used alone, they were able to induce apoptosis, but that effect was lost in combined treatments. Thus, based on the evidence there is no indication of beneficial effect in NETs for cotreatment with everolimus (146). The resistance of treatments also can be explained by presence of the cancer stem cells, which is very controvercial issue for NETs and there is not much evidence for the presence of CSC in these tumors, however some of dual targeted therapies reported to prevent drug resistance (147)(148)(149)(150)(151).…”

Targeted therapy of gastroenteropancreatic neuroendocrine tumours: preclinical strategies and future targets

“…Treatment of NET cells in vitro with a combination of the mTORC1 inhibitor rapamycin or everolimus plus the somatostatin analogue octreotide has caused controversial results in different models. The combination of mTORC1 inhibitors plus octreotide caused no enhanced anti-tumour activity in comparison to mTORC1 inhibition alone in human NET cell lines BON1 and H727 ( 66 , 68 , 86 ) and primary tumour cells in vitro . The lack of effect of octreotide in BON1 and H727 cells might be because of the fact that these cell lines do not express a sufficient amount of somatostatin receptor type 2 ( 87 ) and it does not seem an appropriate model in this setting.…”