Targeting the mTOR Signaling Pathway in Neuroendocrine Tumors

Abstract

Opinion statementNeuroendocrine tumors (NETs) are a heterogeneous group of malignancies characterized by variable but most often indolent biologic behavior. Well-differentiated NETs can be broadly classified as either carcinoid or pancreatic NET. Although they have similar characteristics on routine histologic evaluation, the 2 tumor subtypes have different biology and respond differently to treatment, with most therapeutic agents demonstrating higher response rates in pancreatic NETs compared with carcinoid. Until recently, systemic treatment options for patients with advanced NETs were limited. However, improvements in our understanding of signaling pathways involved in the pathogenesis, growth, and spread of NETs have translated into an expansion of treatment options. Aberrant signaling through the mechanistic pathway of rapamycin (mTOR) pathway has been implicated in neuroendocrine tumorigenesis. Additionally, altered expression of mTOR pathway components has been observed in NETs and has been associated with clinical outcomes. Targeting the mTOR pathway has emerged as an effective treatment strategy in the management of advanced NETs. In a randomized, placebo-controlled study of patients with advanced pancreatic NET, treatment with the mTOR inhibitor everolimus was associated with improved progression-free survival (PFS). Largely based upon these data, everolimus has been approved in the United States and Europe for the treatment of patients with advanced pancreatic NET. The activity of everolimus remains under investigation in patients with carcinoid tumors. In a randomized study of patients with advanced carcinoid tumors associated with carcinoid syndrome, the addition of everolimus to octreotide was associated with improved PFS compared with octreotide. However, the results did not meet the prespecified level of statistical significance based on central review of radiographic imaging. Results from a randomized study examining the efficacy of everolimus in patients with nonfunctional gastrointestinal and lung NETs are awaited. In addition, further investigation is needed to determine whether primary tumor site or other clinical and molecular factors can impact response to mTOR inhibition. Although everolimus can slow tumor progression, significant tumor reduction is rarely obtained. Targeting multiple signaling pathways is a treatment strategy that may provide better tumor control and overcome resistance mechanisms involved with targeting a single pathway. Results of ongoing and future studies will provide important information regarding the added benefit of combining mTOR inhibitors with other targeted agents, such as VEGF pathway inhibitors, and cytotoxic chemotherapy in the treatment of advanced NETs.

Everolimus in the treatment of neuroendocrine tumors: efficacy, side-effects, resistance, and factors affecting its place in the treatment sequence

“…Upregulation of mTOR signaling components[7–11], downregulation of its upstream negative regulators; phosphatase and tensin homolog deleted on chromosome 10 [PTEN] and tuberous sclerosis complex 2 [TSC2] [12–14], and genomic mutation of mTOR pathway[15,16] in NETs were reported from numerous groups. The anti-proliferative effect of mTOR pathway inhibition was reported in preclinical models of NETs [12,17], and thus it was a promising therapeutic target[6,18]. The efficacy and safety of everolimus, an oral inhibitor of the mTOR pathway[19], in patients with advanced NETs of different origins was examined in a series of phase II/III clinical studies; RADIANT trials (Table 1) [20–23].…”

Therapeutic Benefit of Selective Inhibition of p110α PI3-Kinase in Pancreatic Neuroendocrine Tumors

“…Taken together, these data suggest that the PI3K/AKT/mTOR pathway might be functionally relevant in the progression of PanNETs and indicate that it is an exciting setting to test PI3K/AKT/mTOR pharmacological intervention. Indeed, everolimus, an mTOR allosteric inhibitor is currently being used to treat patients with advanced PanNETs (5, 14, 15). A phase II clinical trial has showed efficacy of everolimus in metastatic PanNETs after failure of chemotherapy (5, 15).…”

Next-generation sequencing of salivary high-grade neuroendocrine carcinomas identifies alterations in RB1 and the mTOR pathway

“…Taken together, all 4 cases demonstrated either a CNV alteration or a PTEN somatic mutation that would be predicted to activate the mTOR pathway. mTOR inhibitors are already used to treat other cancer types, including other neuroendocrine tumors, and may have clinical utility in patients with salivary high-grade NECs (Chan and Kulke, 2014;Dienstmann et al, 2014).…”