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Pasireotide, a new somatostatin analogue, may represent Tumorigenesis and metastatic power in NENs seem to be
an effective therapeutic option in tumors that are conditioned by a great number of intracellular pathways,
refractory to octreotide or lanreotide. [52] In a phase III as transduction mechanisms involving receptor tyrosine
randomized, blinded study, pasireotide showed symptom kinases and G-protein coupled receptors. mTOR and
control comparable to octreotide but with an improved Jun N-terminal kinase seem to modulate their action by
[53]
PFS (P = 0.045). [Table 1b] contributing to increased cell growth and number.
Another drug, telotristat etiprate, inhibitor of serotonin Everolimus plus octreotide demonstrated a benefit in PFS
synthesis, was studied in patients with carcinoid for GEP-NETs patients with progressive disease. These
syndrome characterized by diarrhea. Kulke et al. [54] data emerged from the phase II RAD001 in advanced
[64]
and Pavel et al. [55] conducted a prospective single-arm neuroendocrine tumors trial (RADIANT-1). [Table 2]
study in patients with functional tumor and diarrhea (≥ 4
bowel movements/day) not well controlled by octreotide. Everolimus is currently approved for the treatment
Telotristat etiprate was shown to reduce both the of P-NETs in progressive disease, with or without
frequency of bowel movements and biochemical markers concomitant SSAs therapies, on the basis of the results
[65]
of carcinoid syndrome [Table 1c]. achieved from RADIANT-3 trial. [Table 2]
In contrast, there are no validated prospective A large prospective phase III multicentric study
clinical trials that guide the treatment of advanced (RADIANT-4) investigating the efficacy of everolimus
bronchopulmonary carcinoids. Small retrospective vs. placebo in progressive GI and BP-NETs has recently
mono-institutional data and subgroup analysis of some been completed. Everolimus has received approval for
multicentric trials involving gastro-entero-pancreatic this indication in early 2016.
NETs represent the only available results. In particular
SSAs seem to produce tumor stabilization in about 30- The mTOR inhibitors have rapidly become of clinical
70% of patients with low-grade BP-NETs. [56] interest in thoracic NETs. Everolimus (alone or in
combination with SSAs) was effective, according to
[57]
Filosso et al. demonstrated that octreotide is effective exploratory analysis of low- to intermediate-grade
in reducing symptoms of carcinoid syndrome and urinary advanced lung NETs in the large multicentric phase 3,
5-hydroxyindoleacetic acid values in patients with randomized, placebo-controlled RADIANT II study.
liver metastases of radically resected atypical bronchial These clinically significant data reinforce the necessity of
carcinoid. The efficacy of the drug seemed to be related further research of everolimus treatment regimens in this
to the expression of SST2 somatostatin receptors in the patient setting. [66,67] [Table 2]
pathologic tissue, as demonstrated by polymerase chain
reaction method [Table 1a]. In the setting of thoracic For this reason, the LUNA trial, exclusively enrolling
NETs, the first multicentric randomized prospective patients with thoracic NETs after disease progression, has
trial investigating either pasireotide in combination with been performed and awaits definite data consolidation. It
Mammalian target of rapamycin (mTOR) inhibitor or has examined the efficacy of everolimus in monotherapy,
pasireotide alone is still ongoing. everolimus in association with pasireotide, or pasireotide
alone. (ClinicalTrials. Gov Identifier: NCT01563354)
mTOR INHIBITORS
Another mTOR inhibitor, temsirolimus, was investigated
Everolimus, mTOR inhibitor, represents another important in NETs without any report of success. [68] However, a
option for NETs treatment. In fact, mTOR has been resistance to mTOR inhibition and a greater propensity
identified as a kinase activated in the Ras/Raf, MAPK, toward further metastasis was observed and seems to
Phosphoinositide 3-Kinase (PI3K)-Protein Kinase B be related to the loss of another fundamental target,
[58]
(AKT) pathway of GEP and BP-NETs. [Figure 1] phosphatase and tensin homologue (PTEN). [69-73] PTEN is
localized in the cytosol and in the nucleus, blocking PI3K
Recently, overexpression of mTOR and/or its pathway activity in the cytosol and securing the genome in the
targets has been shown to be very common in GEP- nucleus. Its starting through internalization correlates with
NETs, resulting in higher proliferative activity and to a reduction of AKT. [74-76] PTEN is frequently mutated
adverse clinical outcomes. [59,60] Furthermore, somatic in P-NETs and its low expression correlates with high
mutations of PI3K are individuated in a minority of grading. In particular, low expression in cytosol of lung
[77]
P-NETs and are described also in bronchopulmonary NETs indicates a category of patient with poor prognosis. [78]
carcinoids. PI3K/AKT/mTOR pathway, then, is especially
switched on among P-NETs promoting the principal IGF1 INHIBITORS
cellular functions. [61-63] Currently, a phase Ib trial with
everolimus in association with PI3K inhibitor is ongoing Insulin growth factor 1 (IGF1), a factor involved in
(ClinicalTrials. Gov Identifier: NCT02077933). tumor progression, is secreted by neuroendocrine
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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 31, 2016 ¦