Background/Aim: The mode of action of the somatostatin analog octreotide on neuro-endocrine tumour proliferation is largely unknown. Overexpression of the proto-oncogene Akt/PKB (protein kinase B) has been demonstrated in certain neuro-endocrine tumours: Akt activates downstream proteins including mTOR and p70S6K, which play an important role in cell proliferation. RAD001 (everolimus) is a novel agent that is being trialled in the treatment of neuro-endocrine tumours, and is known to interact with mTOR. We explored the mechanism of action of octreotide, RAD001, and their combination on cell proliferation and kinase activation in a neuro-endocrine tumour cell line (rat insulinoma cell line, INS1). Methods: Proliferation assays were used to determine the effects of octreotide, RAD001, and their combination on cell proliferation. Western blotting was used to characterize the expression of phosphorylated Akt, phosphorylated TSC2, phosphorylated mTOR, and phosphorylated 70S6K. Results: Treatment with octreotide and RAD001 inhibited proliferation and attenuated phosphorylation of all downstream targets of Akt: TSC2, mTOR, and p70S6K. Conclusions: In this cell model, octreotide and RAD001 appear to act through a similar pathway and inhibit the Akt-mTOR-p70S6 kinase pathway downstream of Akt. There may be some overlapping effects of the two inhibitors on the mTOR pathway, although it is likely that other additional effects may differentiate the two agents.

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.

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