Prognostic and predictive role of the PI3K–AKT–mTOR pathway in neuroendocrine neoplasms
- 235 Downloads
Neuroendocrine neoplasms (NENs) are considered a heterogeneous and rare entity. Its natural history is influenced by multiple clinicopathological characteristics, which guide the management of these patients. The development of molecular biology reveals that the PI3K–AKT–mTOR pathway plays a relevant role in tumorigenesis and progression of NENs. Mammalian target of rapamycin (mTOR) inhibitors, targeted agents that block this pathway, has improved outcomes in neuroendocrine tumors (NETs). Different therapeutic approaches, such as somatostatin analogs, chemotherapy, peptide receptor radionuclide therapy, and targeted agents, have shown benefits in the treatment of NETs. However, there are not any established prognostic or predictive biomarkers to select the best therapy option to individualize treatment. Although a relation between alterations in the PI3K–AKT–mTOR pathway and clinical outcomes has not been found, these anomalies are considered attractive biomarkers. Additional molecular analysis should be integrated in future clinical trials’ design to identify potential predictive or prognostic biomarkers.
KeywordsNeuroendocrine neoplasm Neuroendocrine tumors PI3K–AKT–mTOR pathway Predictive Prognostic mTOR Inhibitors
Compliance with ethical standards
The manuscript does not contain clinical studies or patient data.
Conflict of interest
EG. has served as advisor and delivered lectures for Novartis, Pfizer, and IPSEN. P.G. T.A-G, and O.M-S declare no conflict of interest related to this publication.
- 4.The International Agency for Research on Cancer, Bosman FT, Carneiro F. WHO classification of tumours of the digestive system. Lyon: World Health Organization classification; 2010. p. 417Google Scholar
- 6.Caplin ME, Baudin E, Ferolla P, Filosso P, Garcia-Yuste M, Lim E, et al. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. 2015;26(8):1604–20.CrossRefPubMedGoogle Scholar
- 21.Corbo V, Beghelli S, Bersani S, Antonello D, Talamini G, Brunelli M, et al. Pancreatic endocrine tumours: mutational and immunohistochemical survey of protein kinases reveals alterations in targetable kinases in cancer cell lines and rare primaries. Ann Oncol. 2011;23(1):127–34.CrossRefPubMedPubMedCentralGoogle Scholar
- 22.von Wichert G, Jehle PM, Hoeflich A, Koschnick S, Dralle H, Wolf E, et al. Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells. Can Res. 2000;60(16):4573–81.Google Scholar
- 24.Poncet G, Villaume K, Walter T, Pourreyron C, Theillaumas A, Lépinasse F, et al. Angiogenesis and tumor progression in neuroendocrine digestive tumors. YJSRE. 2009;154(1):68–77.Google Scholar
- 30.Wang L, Ignat A, Axiotis CA. Differential expression of the PTEN tumor suppressor protein in fetal and adult neuroendocrine tissues and tumors: progressive loss of PTEN expression in poorly differentiated neuroendocrine neoplasms. Appl Immunohistochem Mol Morphol. 2002;10(2):139–46.PubMedGoogle Scholar
- 37.Chiu CW, Nozawa H, Hanahan D. Survival benefit with proapoptotic molecular and pathologic responses from dual targeting of mammalian target of rapamycin and epidermal growth factor receptor in a preclinical model of pancreatic neuroendocrine carcinogenesis. J Clin Oncol. 2010;28(29):4425–33.CrossRefPubMedPubMedCentralGoogle Scholar
- 40.Zurita AJ. Circulating protein and cellular biomarkers of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol May Suppl abstract. (abstract no. 4079) Google Scholar
- 45.Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide lar in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27(28):4656–63.CrossRefPubMedGoogle Scholar
- 47.Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016;387(10022):968–77.CrossRefPubMedGoogle Scholar
- 55.Zurita AJ, Khajavi M, Wu H-K, Tye L, Huang X, Kulke MH, et al. Circulating cytokines and monocyte subpopulations as biomarkers of outcome and biological activity in sunitinib-treated patients with advanced neuroendocrine tumours. Br J Cancer. 2015;112(7):1199–205.CrossRefPubMedPubMedCentralGoogle Scholar