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Abstract
As more knowledge on molecular alterations favoring carcinogenesis and spreading of gastroenteropancreatic endocrine tumors has become available, a number of targeted agents interfering with key growth and angiogenic pathways have been explored in preclinical and clinical studies. The mTOR inhibitor Everolimus, and the multi-target antiangiogenetic agent Sunitinib, have been shown to be effective and thus have been approved by the FDA for treatment of pancreatic endocrine tumors. However, there is little data on the primary resistance to targeted agents on these tumors. The goals of the present review are to elucidate the possible advantage of combined treatments in overcoming induced resistances, and to identify biomarkers able to predict clinical efficacy. Moreover, the role of interesting targets for which a strong biological rationale exists, and specific inhibitors are available, such as the Src Family Kinases and the Hedgehog Pathway, are discussed. There is now need for more preclinical studies on cell lines and animal models to provide a stronger preclinical background in this field, as well as clinical trials specifically comparing one targeted therapy with another or combining different targeted agents.
Highlights
Gastroenteropancreatic endocrine tumors (GEP ETs) represent a heterogeneous group of neoplasms deriving from the gastrointestinal (GI) tract and pancreas diffuse neuroendocrine system [1]. considered rare entities, their incidence seems to be increasing by up to five cases per100,000 persons per year [2]
The mammalian target of rapamycin is a highly conserved serine/threonine kinase that regulates cell cycle and metabolism in response to environmental factors. mTOR mediates signaling transduction downstream of receptor tyrosine kinases, playing a critical role in different proliferative signals mediated through the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) pathway
A number of preclinical and clinical investigations have been aimed at evaluating the efficacy of mTOR kinase inhibitors that would inhibit both mTORC1 as well as mTORC2, or dual PI3K/mTOR inhibitors
Summary
Gastroenteropancreatic endocrine tumors (GEP ETs) represent a heterogeneous group of neoplasms deriving from the gastrointestinal (GI) tract and pancreas diffuse neuroendocrine system [1]. As far as medical treatment is concerned, several options have been proposed in the past, including somatostatin analogues [6], peptide receptors radionuclide therapy (PRRT) [7], and systemic chemotherapy [8]. Despite these therapeutic tools, the majority of advanced GEP-ETs have a progressive behaviour, in those cases with higher Ki67 value [9,10]. The mTOR inhibitor, Everolimus, and the multi-target antiangiogenetic agent, Sunitinib, have been shown to be effective in prolonging progression-free survival (PFS) in advanced progressive pancreatic endocrine tumors (PETs), and have been approved by the FDA for treatment of this disease [14]. The present review will summarize existing data on targeted therapies for GEP ETs, focusing on combined treatments and novel targeted agents
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