Treatment of advanced pancreatic neuroendocrine tumors: potential role of everolimus

Abstract

Pancreatic neuroendocrine tumors (PanNETs) are frequently diagnosed at unresectable stage and remain a medical challenge. Everolimus (RAD001, Afinitor(®), Novartis, Basel, Switzerland), an orally administered inhibitor of mammalian target of rapamycin (mTOR), was recently approved by the Food and Drug Administration to treat patients with advanced PanNETs. This review will examine the mechanism of action of everolimus, the function of mTOR and its inhibition, PanNETs and the mTOR pathway, and clinical trials of everolimus in PanNETs. Future investigations will focus on everolimus combination therapy to treat PanNETs and the discovery of predictive biomarkers for response to everolimus.

Keywords: PanNETs; RAD001; biomarker; everolimus; mTOR inhibitor; pancreatic neuroendocrine tumor.

Figure 1

mTOR controls responses to changes in the cellular environment. Abbreviations: mTOR, mammalian target of rapamycin; mRNA, messenger ribonucleic acid.

Figure 2

mTOR activation is controlled by the TSC1/TSC2 complex and Rheb. Abbreviations: Rheb GTP, ras homolog enriched in brain Guanosine-5′-triphosphate; LKB1, liver kinase B1; AMPK, adenosine monophosphate kinase; Akt, also known as protein kinase B (PKB); Rheb GTP, ras homolog enriched in brain guanosine diphosphate.

Figure 3

mTOR controls ribosome biogenesis and CAP-dependent mRNA translation. Abbreviations: mTOR, mammalian target of rapamycin; S6K1, S6 kinase beta-1; mRNA, messenger ribonucleic acid; TOP, polypyrimidine tract; 4E-BP1, 4E-binding protein 1; e1F-4E, elongation factor 4E; e1F-4A, elongation factor 4A; e1f-4F, elongation factor 4F; e1F-4G, elongation factor 4G; e1F-2, elongation factor 2; e1F-3, elongation factor 3; PABP, poly A binding protein; CAP, catabolic activator protein; GβL, G protein β-like.

Figure 4

mTOR controls responses to hypoxic stress. Abbreviations: mTOR, mammalian target of rapamycin; mRNA, messenger ribonucleic acid; V HL, Von Hippel–Lindau; HIF-1α, hypoxia-inducible factors 1 alpha; HIF-1β, hypoxia-inducible factors 1 beta; HIF-1, hypoxia-inducible factors 1; VEGF-A, vascular endothelial growth factor A; iNOS, inducible nitric oxide synthase; GβL, G protein β-like.

Figure 5

Growth factor signaling pathways are interconnected. Abbreviations: mTOR, mammalian target of rapamycin; mRNA, messenger ribonucleic acid; P13-K, phosphoinositide 3-kinase inhibitor; PDK1,2, phosphoinositide-dependent kinase-1; Abl, Abelson gene; Akt, protein kinase Akt; ER, estrogen receptor; Erk, extracellular-signal-regulated kinases; Ras, RAt sarcoma kinase; Raf, rapidly accelerated fibrosarcoma kinase; MEK, mitogen-activated protein kinase; PTEN, phosphatase and tensin homolog.