The Role of mTOR in Neuroendocrine Tumors: Future Cornerstone of a Winning Strategy?

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Term Occurence Count Dictionary
Pasireotide 2 endocrinologydiseasesdrugs
carcinoid 3 endocrinologydiseases
everolimus 39 endocrinologydiseasesdrugs
neuroendocrine tumor 2 endocrinologydiseases
Octreotide 2 endocrinologydiseasesdrugs

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Select Drug Character Offset Drug Term Instance
Octreotide 34410 (Phase)YearPopulationTreatmentsPFS (HR)RemarksRADIANT-1 (II)2010160 panNET(I) Everolimus (II) Everolimus + Octreotide LAR9.716.7No comparison between strataRADIANT-2 (III)2011429 mixed (carcinoid syndrome)Everolimus +
Octreotide 34521 LAR9.716.7No comparison between strataRADIANT-2 (III)2011429 mixed (carcinoid syndrome)Everolimus + Octreotide LAR vs. pbo + Octrotide LAR16.4 vs. 11.3(HR: 0.77)Not significant by central radiology analysisRADIANT-3
Pasireotide 34866 vs. pbo11 vs. 3.9(HR: 0.48)Concomitant SSA not allowedLUNA trial (II)2017124 thoracic (lung thymic) Pasireotide EverolimusEverolimus + Pasireotide8.512.511.8No comparison among armsYear: year of publication; pbo:
Pasireotide 34900 0.48)Concomitant SSA not allowedLUNA trial (II)2017124 thoracic (lung thymic)PasireotideEverolimusEverolimus + Pasireotide 8.512.511.8No comparison among armsYear: year of publication; pbo: placebo; SSA: somatostatin analog;
everolimus 1763 particular, has been demonstrated in preclinical studies and late clinical trials. mTOR inhibition by everolimus is an established therapeutic target in NETs, but there are no identified predictive or prognostic factors.
everolimus 1929 are no identified predictive or prognostic factors. This review is focused on the role of mTOR and everolimus in NETs, from preclinical studies to major clinical trials, and future perspectives involving mTOR in
everolimus 2872 features. This can explain effectiveness of the same treatment, such as somatostatin analogs (SSA) or everolimus , across different types of NET. Everolimus (former RAD001, Novartis), is a potent and selective inhibitor
everolimus 3597 by the RAD001 in Advanced Neuendocrine Tumors (RADIANT) series of clinical trials. In these studies, everolimus proved to be effective in lung, pancreatic, gastroenteric and unknown/other origin well-differentiated/low-grade
everolimus 14857 supported by many findings, lastly by the clinical efficacy shown by the rapamycin analog (rapalog), everolimus .Studies on preclinical models of panNETs (e.g., RIP1-Tag2 oncomice) showed that activating alterations
everolimus 23135 reported a decrease in pAkt (Ser473) as well in Beta-TC3 cell lines when exposed to the combination of everolimus and erlotinib [[21]]. Similarly, everolimus showed a significant antiproliferative effect in the rat-derived
everolimus 23179 Beta-TC3 cell lines when exposed to the combination of everolimus and erlotinib [[21]]. Similarly, everolimus showed a significant antiproliferative effect in the rat-derived insulinoma cell line, INS1, that was
everolimus 23591 [[89]].Commercial cell lines of TCs and ACs (i.e., H727 and H720, respectively) showed different sensitivity to everolimus . In particular, when exposed to everolimus, sensitive cell lines, that is, H720, showed an increase
everolimus 23634 and H720, respectively) showed different sensitivity to everolimus. In particular, when exposed to everolimus , sensitive cell lines, that is, H720, showed an increase in pS6K, but a decrease in pAkt (Ser473). On
everolimus 24104 observed [[45]]. A similar pattern was observed in panNETs: exposure of cell lines to rapamyicin and everolimus induced reduction in phosphorylation of S6K and 4EBP1, with a secondary increase in pAkt (Ser473) [[7],[90]].
everolimus 24451 targets, by multi-target inhibitors or by combinations of drugs.Given the prominent clinical role of everolimus , the identification of a predictive factor of response to mTOR inhibition would be of paramount importance
everolimus 24781 lung NETs, mostly TCs, higher expression of mTOR and p-mTOR (Ser2448) was associated to response to everolimus in vitro [[91]]. However, no clinical predictive marker has been identified so far.5. Clinical TrialsClinical
everolimus 24927 clinical predictive marker has been identified so far.5. Clinical TrialsClinical activity and efficacy of everolimus was evaluated in the RAD001 in Advanced Neuendocrine Tumors (RADIANT) saga of trials (Table 1). The
everolimus 25316 chemotherapy. Objective response rate (ORR), the primary endpoint, was 9.6% in 115 patients receiving everolimus single agent (stratum 1). Time to tumor progression (TTP) was a secondary endpoint. Interestingly, TTP
everolimus 25461 tumor progression (TTP) was a secondary endpoint. Interestingly, TTP was 9.7 and 16.7 months in the everolimus single agent and in the everolimus plus octreotide long-acting release (LAR) stratum (stratum 2, n =
everolimus 25496 secondary endpoint. Interestingly, TTP was 9.7 and 16.7 months in the everolimus single agent and in the everolimus plus octreotide long-acting release (LAR) stratum (stratum 2, n = 45), respectively [[92]]. These results
everolimus 25803 the stratum 2 of RADIANT-1, the RADIANT-2 trial was started. It was a randomized phase III trial on everolimus vs. placebo, both added to therapy with octreotide LAR, in advanced functioning NETs. The trial enrolled
everolimus 26018 429 patients. A median progression-free survival (PFS) of 16.4 and 11.3 months was observed in the everolimus and placebo arm, respectively. The PFS observed in the combination arm confirmed the good results of
everolimus 26439 analysis of the baseline population, furthermore, showed an imbalance in known prognostic characteristics: everolimus arm had a higher proportion of lung primary NETs, moderately differentiated tumors, proportion of previous
everolimus 26741 placebo arm [[93]]. The final analysis for overall survival (OS) showed 29.2 vs. 35.2 months in the everolimus and placebo arm, respectively. This difference was not statistically significant. After correction for
everolimus 26947 correction for the baseline imbalances, the difference remained not significant [[94]]. The combination of everolimus and a SSA has been recently explored in NETs of thoracic origin by the LUNA trial (Table 1). This was
everolimus 27306 which patients were randomized to receive pasireotide, a SSA with high affinity for SSTR1, 3 and 5, or everolimus or both, in 3 non-comparative arms. The primary end-point, the proportion of progression-free patients
everolimus 27545 deeming the three treatment options as active in the study population. Median PFS for the pasireotide, everolimus and the combination arm was 8.5, 12.5 and 11.8 months, respectively. However, these have to be considered
everolimus 27965 was a randomized double-blind placebo-controlled phase III clinical trial evaluating the efficacy of everolimus in panNETs. Four-hundred-and-ten patients affected by low- to intermediate-grade panNET were randomized
everolimus 28091 Four-hundred-and-ten patients affected by low- to intermediate-grade panNET were randomized to receive everolimus or placebo. Crossover was allowed after confirmed progression. A median PFS of 11 vs. 4.6 months was
everolimus 28219 Crossover was allowed after confirmed progression. A median PFS of 11 vs. 4.6 months was observed in the everolimus and placebo arm, respectively [[96]]. Final data from the RADIANT-3 trial showed a non-significant difference
everolimus 28405 showed a non-significant difference between the two treatment arms: OS was 44 and 37.7 months in the everolimus and placebo arm, respectively. Since this result was likely affected by the crossover, an exploratory
everolimus 28589 the crossover, an exploratory analysis in order to correct for crossover of patients from placebo to everolimus was performed: corrected survival rates were 82% and 75% at 12 months and 67% and 55.6% at 24 months
everolimus 28705 performed: corrected survival rates were 82% and 75% at 12 months and 67% and 55.6% at 24 months for everolimus and placebo arm, respectively (HR 0.60) [[97]]. The last act so far of the RADIANT series was the RADIANT-4
everolimus 28983 clinical trial lead in non-functioning extra-pancreatic NETs. 302 patients were randomized to receive everolimus or placebo. Concomitant SSA treatment was not allowed. Median PFS, the primary endpoint, was 11.0 and
everolimus 29114 Concomitant SSA treatment was not allowed. Median PFS, the primary endpoint, was 11.0 and 3.9 months in the everolimus and placebo arm, respectively. Preliminary analysis of survival seemed to show a benefit for everolimus
everolimus 29218 everolimus and placebo arm, respectively. Preliminary analysis of survival seemed to show a benefit for everolimus over placebo: data were not mature, but the 25th percentile of survival was evaluated to be at 23.7
everolimus 29488 efforts made, no clinical and/or pathological biomarker has been identified so far to predict response to everolimus in any of the studies considered.Based on the results of these trials, everolimus is approved for the
everolimus 29570 predict response to everolimus in any of the studies considered.Based on the results of these trials, everolimus is approved for the treatment of advanced pancreatic, gastro-intestinal and lung NETs.6. Future PerspectivesOver
everolimus 29823 enrolled in the RADIANT trials and a consistent, reproducible median PFS of about 11 months was observed: everolimus , and thus mTOR inhibition, has become a cornerstone in the management of NET patients of pancreatic
everolimus 30141 outcomes through combinations and sequences.There are over 20 active enrolling studies in NETs involving everolimus , alone or in combination with other biologic or chemotherapy agents. There are as much as over 40 studies
everolimus 30420 clinicaltrials.gov) [[99]].Recently, a phase II study on BEZ235, a mTORC1 and mTORC2 inhibitor, vs. everolimus was conducted in panNETs. The rationale of BEZ235 therapy was to prevent feedback loops via growth factors,
everolimus 31060 randomized phase III trial in advanced well-differentiated panNETs evaluating the optimal sequence between everolimus followed by streptozotocin and 5-fluorouracile and the opposite one. Primary endpoint is PFS from randomization
everolimus 32978 are patients’ selection and development of acquired resistance. A predictive marker of response to everolimus (or to PI3K/Akt/mTOR inhibition in general) would allow treating physicians to prescribe the drug to
Select Disease Character Offset Disease Term Instance
carcinoid 17698 catalytic subunit alfa (PI3KCA) [[79]].DNA from 54 primary lung NETs, including low grade (17 typical carcinoid s (TCs) and 8 atypical carcinoids (ACs)) and high grade NETs (17 large cell neuroendocrine carcinomas
carcinoid 17730 [[79]].DNA from 54 primary lung NETs, including low grade (17 typical carcinoids (TCs) and 8 atypical carcinoid s (ACs)) and high grade NETs (17 large cell neuroendocrine carcinomas and 12 small cell neuroendocrine
carcinoid 34489 Everolimus (II) Everolimus + Octreotide LAR9.716.7No comparison between strataRADIANT-2 (III)2011429 mixed ( carcinoid syndrome)Everolimus + Octreotide LAR vs. pbo + Octrotide LAR16.4 vs. 11.3(HR: 0.77)Not significant by
neuroendocrine tumor 1628 in many human diseases, including cancer. Its predominant role in tumorigenesis and progression of neuroendocrine tumor s (NETs), in particular, has been demonstrated in preclinical studies and late clinical trials. mTOR
neuroendocrine tumor 34269 in yellow spheres: phosphate group.ijms-19-00747-t001_Table 1Table 1Clinical trials on Everolimus in neuroendocrine tumor s (NET).Title (Phase)YearPopulationTreatmentsPFS (HR)RemarksRADIANT-1 (II)2010160 panNET(I) Everolimus

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