The pivotal role of mammalian target of rapamycin inhibition in the treatment of patients with neuroendocrine tumors

Existing Reviews

Please note, new claims can take a short while to show up.

No claims yet.

Annotation Summary

Term Occurence Count Dictionary
Bevacizumab 1 endocrinologydiseasesdrugs
Pasireotide 3 endocrinologydiseasesdrugs
VIPoma 1 endocrinologydiseases
cortisol 1 endocrinologydiseasesdrugs
hydroxychloroquine 1 endocrinologydiseasesdrugs
neuroendocrine tumor 6 endocrinologydiseases
sorafenib 1 endocrinologydiseasesdrugs
Octreotide 1 endocrinologydiseasesdrugs
carcinoid 3 endocrinologydiseases
everolimus 46 endocrinologydiseasesdrugs
sunitinib 4 endocrinologydiseasesdrugs

Graph of close proximity drug and disease terms (within 200 characters).

Note: If this graph is empty, then there are no terms that meet the proximity constraint.

Review

Having read the paper, please pick a pair of statements from the paper to indicate that a drug and disease are related.

Select Drug Character Offset Drug Term Instance
Bevacizumab 25928 Ongoing, not recruitingLocally advanced, recurrent, metastatic, or progressive pNET or carcinoid tumor Bevacizumab : Anti‐VEGF monoclonal antibody 72; inhibits angiogenesis 72c‐KIT, a receptor tyrosine kinase (type
Octreotide 5563 aligned in demonstrating clinically relevant antiproliferative effects with SSAs in patients with NET. Octreotide LAR is approved by the FDA for symptom control, particularly severe diarrhea/flushing episodes and symptoms
Pasireotide 22006 lanreotide Autogel, which preferentially bind to SSTR2 and SSTR5 and have moderate affinity for SSTR350. Pasireotide targets SSTR1,2,3 and SSTR5 with high affinity 50, 67. Pasireotide long‐acting release has been demonstrated
Pasireotide 22073 have moderate affinity for SSTR350. Pasireotide targets SSTR1,2,3 and SSTR5 with high affinity 50, 67. Pasireotide long‐acting release has been demonstrated to have equivalent efficacy to high‐dose octreotide LAR
Pasireotide 23722 phase 1 COOPERATE‐1 study; N = 36; NCT01263353; completedAdvanced pulmonary or gastrointestinal NET Pasireotide : SSA Mimics natural somatostatin 67; inhibits GH, cortisol, IGF‐1, and other hormones secreted in
cortisol 23784 completedAdvanced pulmonary or gastrointestinal NETPasireotide: SSA Mimics natural somatostatin 67; inhibits GH, cortisol , IGF‐1, and other hormones secreted in carcinoid tumors 67; controls symptoms such as diarrhea and
everolimus 594 needs remain. The treatment landscape for NET has evolved, with the approval of the targeted agents everolimus and sunitinib for the treatment of advanced pancreatic NET in 2011 followed by the approval of everolimus
everolimus 700 everolimus and sunitinib for the treatment of advanced pancreatic NET in 2011 followed by the approval of everolimus for the treatment of advanced nonfunctional gastrointestinal and lung NET in 2016. Mammalian target
everolimus 936 components of the mTOR pathway play pivotal roles in NET pathogenesis. Effects of the mTOR inhibitor everolimus have been well documented in preclinical and clinical studies, both as monotherapy and combination therapy.
everolimus 6335 VEGF–tyrosine kinase inhibitor (TKI) sunitinib (Pfizer Inc, New York, NY) and the mTOR inhibitor everolimus (Novartis Pharmaceuticals Corporation), have been approved in the United States and the European Union
everolimus 6758 pNET 18, 19. In 2016, demonstrated efficacy in the phase 3 RADIANT‐4 trial led to the expansion of everolimus ’ indication to include patients with progressive, unresectable, locally advanced or metastatic, nonfunctional
everolimus 9235 in the mTOR pathway.mTOR signaling and inhibition: clinical dataEverolimus as monotherapyEfficacy of everolimus as monotherapy in patients with advanced pNET was evaluated in the randomized phase 3 RADIANT‐3 study
everolimus 9364 patients with advanced pNET was evaluated in the randomized phase 3 RADIANT‐3 study that compared everolimus monotherapy with placebo 22. The primary end point was PFS, so crossover was allowed to address ethical
everolimus 9568 address ethical and recruitment considerations. PFS per adjudicated central review was 11.4 months with everolimus versus 5.4 months with placebo, resulting in reduced risk (65%) for disease progression or death with
everolimus 9682 versus 5.4 months with placebo, resulting in reduced risk (65%) for disease progression or death with everolimus treatment. Additionally, 64% of patients receiving everolimus achieved some degree of tumor shrinkage
everolimus 9744 for disease progression or death with everolimus treatment. Additionally, 64% of patients receiving everolimus achieved some degree of tumor shrinkage (including minor responses) versus 21% of patients receiving
everolimus 9874 degree of tumor shrinkage (including minor responses) versus 21% of patients receiving placebo. Notably, everolimus demonstrated a clinically and statistically significant prolongation of PFS regardless of previous chemotherapy
everolimus 10036 significant prolongation of PFS regardless of previous chemotherapy 36. Based on results from RADIANT‐3, everolimus was FDA‐approved specifically for patients with progressive advanced pNET 18. OS data from RADIANT‐3
everolimus 10216 advanced pNET 18. OS data from RADIANT‐3 were recently reported. Improvement in median OS was shown with everolimus (median OS, 44.02 months; 95% confidence interval [CI], 35.6–51.8) versus placebo (median OS, 37.7 months;
everolimus 10910 survival rates of 82.6% versus 74.9% and 67.7% versus 55.6% at 12 and 24 months, respectively, for everolimus versus placebo 38.Everolimus monotherapy in patients with other NET types is also being investigated
everolimus 11098 also being investigated in several ongoing trials. A phase 2 study in Europe, RAMSETE, investigated everolimus in patients with advanced (unresectable or metastatic), biopsy‐proven, nonfunctional NET with radiologic
everolimus 11351 disease (PD) with ≤3 prior systemic treatments. Of 73 patients enrolled, best response with monotherapy everolimus was stable disease (SD) in 55% 39. Median PFS was 185 days (95% CI, 158–255) 39. Moreover, disease
everolimus 11481 (SD) in 55% 39. Median PFS was 185 days (95% CI, 158–255) 39. Moreover, disease stabilization by everolimus was demonstrated in all patient subgroups, including stratification by previous therapy 39 and primary
everolimus 11655 stratification by previous therapy 39 and primary tumor location 40.A double‐blind, phase 3 study evaluated everolimus versus placebo (each plus best supportive care) in patients with advanced, nonfunctional gastrointestinal
everolimus 12427 significant and clinically meaningful 52% reduction in the relative risk of progression or death with everolimus versus placebo (HR 0.48 [95% CI, 0.35–0.67]; P < 0.00001), and a median PFS of 11.0 and 3.9 months,
everolimus 12780 0.50 [95% CI, 0.28–0.88] and HR 0.56 [95% CI, 0.37–0.84], respectively) 41. Based on this study, everolimus was approved by the FDA for the treatment of progressive, advanced, nonfunctional gastrointestinal and
everolimus 13136 metastases (NCT02031536). The primary objective of this study is to evaluate if the addition of adjuvant everolimus will result in an improvement in disease‐free survival, and the estimated primary completion date
everolimus 13349 October 2016.Other agents targeting mTOR as monotherapyIn contrast to antitumor efficacy seen with everolimus , temsirolimus (Pfizer Inc), an intravenously administered mTOR inhibitor, did not demonstrate similar
everolimus 15187 off‐target effects 45. For example, in a phase 2 study in patients with advanced RCC, treatment with everolimus plus bevacizumab was associated with moderate rates of grade 3/4 AEs that were consistent with the known
everolimus 15371 were consistent with the known AE profiles associated with the individual agents 46.Treatment with everolimus or temsirolimus in combination with other targeted agents has been investigated in patients with NET.
everolimus 16042 In both the RADIANT‐1 and RADIANT‐2 studies, it was hypothesized that combination therapy with everolimus plus octreotide LAR might enhance antitumor efficacy by simultaneously targeting upstream and downstream
everolimus 16396 52 and mTOR inhibition has shown antiproliferative effects in NET 31, 48, 53. Clinical efficacy of everolimus plus octreotide LAR in patients with advanced NET was demonstrated in the phase 2 RADIANT‐1 trial
everolimus 16625 results from RADIANT‐1 led to the subsequent phase 3 RADIANT‐2 study, in which efficacy of combined everolimus and an SSA was evaluated in 429 patients with low‐grade or intermediate‐grade NET. The addition
everolimus 16757 evaluated in 429 patients with low‐grade or intermediate‐grade NET. The addition of octreotide LAR to everolimus led to a trend toward improved PFS, with a 23% reduction in the estimated risk for progression (median
everolimus 17941 P = 0.140).The combination of antiangiogenic agents such as the anti‐VEGF monoclonal antibody bevacizumab with everolimus might also be a feasible approach because the VEGF signaling pathway acts through the PI3K/mTOR pathway
everolimus 18430 into the PI3K/mTOR signaling pathway. A phase 2 study (NCT00607113) demonstrated antitumor activity of everolimus plus bevacizumab in patients with low‐grade or intermediate‐grade NET. The primary end point was
everolimus 18658 biomarkers. Perfusion computed tomography was used as a functional biomarker of efficacy 57. Addition of everolimus to bevacizumab monotherapy resulted in greater decreases in tumor blood flow than bevacizumab alone
everolimus 18819 decreases in tumor blood flow than bevacizumab alone (15%; P = 0.02), and addition of bevacizumab to everolimus monotherapy led to a 21% decrease in tumor blood flow (P = 0.01). At 6 months, median PFS was 14.4 months
everolimus 19130 (median OS was not reached) 57.In another randomized phase 2 trial, CALBG 80701 (NCT01229943) efficacy of everolimus plus bevacizumab was assessed versus everolimus alone in 150 patients with locally advanced or metastatic
everolimus 19178 phase 2 trial, CALBG 80701 (NCT01229943) efficacy of everolimus plus bevacizumab was assessed versus everolimus alone in 150 patients with locally advanced or metastatic pNET; the primary end point was PFS 58. Median
everolimus 19625 with monotherapy (HR, 0.75; 95% CI, 0.42–1.33; 49 OS events; 1‐sided P = 0.16). Treatment with everolimus plus bevacizumab was associated with a significantly higher response rate (31%) versus everolimus alone
everolimus 19723 with everolimus plus bevacizumab was associated with a significantly higher response rate (31%) versus everolimus alone (12%; P = 0.005). While this superior PFS is proof of concept for enhanced efficacy with combination
everolimus 20268 13.2 months and 34.0 months, respectively 59.Additional findings from recently presented data evaluating everolimus or temsirolimus plus various targeted agents are encouraging. In a phase 1 study in patients with advanced
everolimus 20555 HealthCare Pharmaceuticals Inc., Whippany, NJ), the broadly targeted VEGFR‐TKI, plus 10 mg daily of everolimus was the MTD for this combination. Per independent review of best objective response, tumor shrinkage
everolimus 22754 agents, the alkylating agent temozolomide has demonstrated preliminary activity in combination with everolimus and acceptable tolerability in patients with pNET 79. In a phase 1/2 study of 43 patients with low‐
everolimus 22906 with pNET 79. In a phase 1/2 study of 43 patients with low‐ or intermediate‐grade pNET receiving everolimus plus temozolomide, this combination showed acceptable safety; the most commonly occurring grade 3 or
everolimus 23537 other agentsAgent(s) in combination with mTOR inhibitorsStudyType of NETMechanism of action of non‐ everolimus componentEverolimus + pasireotide long‐acting releaseOpen‐label, phase 1 COOPERATE‐1 study;
everolimus 27417 A phase 2 study evaluated BEZ235 in 31 patients with advanced pNET who progressed on treatment with everolimus . SD was achieved by 51.6% of patients after 16 weeks of treatment. However, many patients discontinued
everolimus 28124 single‐institution study evaluated the recommended phase 2 dose (RP2D) for the combination of cixutumumab, everolimus , and octreotide LAR in patients with WD‐NET. The RP2D of this combination was found to be cixutumumab
everolimus 28291 of this combination was found to be cixutumumab 10 mg/m2, octreotide LAR 20 mg IM q 21 days, and everolimus 10 mg daily 87.Moving beyond the combination of mTOR and either SSAs or VEGF pathway inhibitors is
everolimus 28544 resistance. All drug therapies have resistance mechanisms. For example, a potential escape mechanism for everolimus might involve upregulation of PI3K and other pro‐survival pathways 81, 88, 89, 90. Interestingly,
everolimus 29955 which of these treatment options will provide greater benefit in patients with NET. The mTOR inhibitor everolimus is currently approved for lung and gastrointestinal NET and pNET, but shows promise for use in the adjuvant
hydroxychloroquine 29009 91. The most commonly used drug to inhibit autophagy has been chloroquine and its active derivative hydroxychloroquine , which affect late‐stage autophagy 92, 93, 94. Novel autophagy inhibitors such as N‐acetyl cysteine
sorafenib 20435 encouraging. In a phase 1 study in patients with advanced gastrointestinal or pNET, 200 mg twice daily of sorafenib (Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ), the broadly targeted VEGFR‐TKI, plus 10 mg
sunitinib 609 The treatment landscape for NET has evolved, with the approval of the targeted agents everolimus and sunitinib for the treatment of advanced pancreatic NET in 2011 followed by the approval of everolimus for the
sunitinib 6275 functional NET 14, 15, 16, 17. Since 2011, two targeted agents, the VEGF–tyrosine kinase inhibitor (TKI) sunitinib (Pfizer Inc, New York, NY) and the mTOR inhibitor everolimus (Novartis Pharmaceuticals Corporation),
sunitinib 14144 its maximum tolerated dose (MTD) 43. However, agents with broad target specificity, such as the TKI sunitinib , might be less suitable for combination therapy given the enhanced toxicity stemming from cumulative
sunitinib 14414 proportion of patients with renal cell carcinoma (RCC) and other solid tumors who were treated with sunitinib plus bevacizumab (Genentech, Inc., South San Francisco, CA) experienced grade 3/4 adverse events (AEs),
Select Disease Character Offset Disease Term Instance
VIPoma 5685 approved by the FDA for symptom control, particularly severe diarrhea/flushing episodes and symptoms of VIPoma s 14, whereas lanreotide was recently FDA‐approved for patients with unresectable, well‐ or moderately
carcinoid 22235 have equivalent efficacy to high‐dose octreotide LAR for symptom control in patients with refractory carcinoid syndrome 78. Other combination therapy examples with mTOR inhibitors include erlotinib (Genentech, Inc.),
carcinoid 23834 SSA Mimics natural somatostatin 67; inhibits GH, cortisol, IGF‐1, and other hormones secreted in carcinoid tumors 67; controls symptoms such as diarrhea and flushing 68Open‐label, phase 1 extension of COOPERATE‐1
carcinoid 25913 NCT01010126; Ongoing, not recruitingLocally advanced, recurrent, metastatic, or progressive pNET or carcinoid tumorBevacizumab: Anti‐VEGF monoclonal antibody 72; inhibits angiogenesis 72c‐KIT, a receptor tyrosine
neuroendocrine tumor 117 MedicineThe pivotal role of mammalian target of rapamycin inhibition in the treatment of patients with neuroendocrine tumor sAlexandria T. PhanBhuvanesh Dave1Houston Methodist Hospital Cancer CenterHoustonTexasPublication date
neuroendocrine tumor 380 (collection): 10/2016AbstractAbstractSignificant advances have been made toward understanding the biology of neuroendocrine tumor s (NET) in terms of defining prognosis and improving clinical management; however, many unmet needs remain.
neuroendocrine tumor 1628 5(10):2953–2964IntroductionEncouraging advances have been made toward understanding the biology of neuroendocrine tumor s (NET) in terms of defining prognosis and improving clinical management. Per the Surveillance, Epidemiology,
neuroendocrine tumor 26306 factor 1; IGF‐1R, insulin‐like growth factor 1 receptor; mTOR, mammalian target of rapamycin; NET, neuroendocrine tumor s; PDGFR, platelet‐derived growth factor receptor; pNET, pancreatic neuroendocrine tumors; SSA, somatostatin
neuroendocrine tumor 26396 rapamycin; NET, neuroendocrine tumors; PDGFR, platelet‐derived growth factor receptor; pNET, pancreatic neuroendocrine tumor s; SSA, somatostatin analog; VEGFR, vascular endothelial growth factor receptor.John Wiley & Sons, LtdFigure
neuroendocrine tumor 26668 combination with mTOR inhibitors in patients with NET. Adapted from: Dong et al., New strategies for advanced neuroendocrine tumor s in the era of targeted therapy 63, with permission from AACR.Novel agents along the mTOR pathwayVarious

You must be authorized to submit a review.