Everolimus in the treatment of patients with advanced pancreatic neuroendocrine tumors: latest findings and interpretations
Open Access
- 29 July 2013
- journal article
- research article
- Published by SAGE Publications in Therapeutic Advances in Gastroenterology
- Vol. 6 (5), 412-419
- https://doi.org/10.1177/1756283x13496970
Abstract
Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of neoplasms with various clinical presentations. More than half of patients present with so-called nonfunctioning tumors with no hormone-related symptoms, whereas other tumors produce symptoms like gastric problems, ulcers, hypoglycemia, skin rash and diarrhea related to hormone production. The traditional treatment for pNETs over the last three decades has been cytotoxic agents, mainly streptozotocin plus 5-fluorouracil or doxorubicin. Most recently two new compounds have been registered worldwide for the treatment of pNETs, the mammalian target of rapamycin (mTOR) inhibitor everolimus and the tyrosine kinase inhibitor sunitinib. This paper concentrates on the use of mTOR inhibitors and the mechanisms of action. The mTOR pathway is altered in a number of pNETs. Everolimus (RAD001) is an orally active rapamycin analog and mTOR inhibitor. It blocks activity of the mTOR pathway by binding with high affinity to the cytoplasmic protein FKBP-12. The efficacy of everolimus in pNETs has been demonstrated in two multicenter studies (RADIANT 1 and 3). The RADIANT 3 study was a randomized controlled study in pNETs of everolimus 10 mg/day versus placebo, showing an increased progression-free survival (11.7 months versus 4.6 months) and hazard ratio of 0.35 ( p < 0.001). Current studies indicate that there is strong evidence to support the antitumor effect of rapalogs in pNETs. However, significant tumor reduction is very rarely obtained, usually in less than 10% of treated patients. Therefore, these drugs may be more effective in combination with other anticancer agents, including chemotherapy, targeted therapies as well as peptide receptor radiotherapy.Keywords
This publication has 44 references indexed in Scilit:
- Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast CancerNew England Journal of Medicine, 2012
- Decreased Lymphangiogenesis and Lymph Node Metastasis by mTOR Inhibition in Head and Neck CancerCancer Research, 2011
- DAXX / ATRX , MEN1 , and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine TumorsScience, 2011
- Targeting the phosphoinositide 3-kinase pathway in cancerNature Reviews Drug Discovery, 2009
- Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trialThe Lancet, 2008
- Cytoplasmic and nuclear distribution of the protein complexes mTORC1 and mTORC2: rapamycin triggers dephosphorylation and delocalization of the mTORC2 components rictor and sin1Human Molecular Genetics, 2008
- Rapamycin and mTOR kinase inhibitorsJournal of Chemical Biology, 2008
- Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AMLBlood, 2006
- A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomasBritish Journal of Cancer, 2006
- mTOR and cancer: insights into a complex relationshipNature Reviews Cancer, 2006