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Advances in small bowel neuroendocrine neoplasia.

ABSTRACT: This review aims at summarizing progress in clinical trials and basic science redefining the diagnosis and treatment of well differentiated small intestine neuroendocrine tumors (SI-NET).Two clinical trials demonstrated antitumor activity of the long-acting somatostatin analogues octreotide long-acting release and lanreotide for advanced SI-NET. The mammalian target of rapamycin (mTOR) inhibitor everolimus is another treatment option for patients with SI-NET, but awaits definitive proof of benefit in the ongoing RAD001 In Advanced Neuroendocrine Tumors study (RADIANT-4). Two whole exome/genome-sequencing studies reported in the past year provided the first genome-wide analysis of large sets of SI-NET at nucleotide resolution. Candidate therapeutically relevant alterations were found to affect SRC, SMAD genes, aurora kinase A, epidermal growth factor receptor, heat shock protein 90, and platelet-derived growth factor receptor as well as mutually exclusive amplification of RAC-alpha serine/threonine-protein kinase (AKT1) or AKT2 and other alterations of PI3K/Akt/mTOR signaling genes. The gene CDKN1B is inactivated by small insertions/deletions in 8% of patients with SI-NET suggesting cell cycle inhibitors as new candidate drugs for SI-NET. Circulating tumor cells and tumor-derived RNA in the blood are promising clinical tests for SI-NET.Clinical and genomic research may merge in the near future to re-shape clinical trials and to define the 'personalized' treatment options for patients with SI-NET.

SUBMITTER: Banck MS

PROVIDER: S-EPMC4388306 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Advances in small bowel neuroendocrine neoplasia.

Banck Michaela S MS Beutler Andreas S AS

Current opinion in gastroenterology 20140301 2

<h4>Purpose of review</h4>This review aims at summarizing progress in clinical trials and basic science redefining the diagnosis and treatment of well differentiated small intestine neuroendocrine tumors (SI-NET).<h4>Recent findings</h4>Two clinical trials demonstrated antitumor activity of the long-acting somatostatin analogues octreotide long-acting release and lanreotide for advanced SI-NET. The mammalian target of rapamycin (mTOR) inhibitor everolimus is another treatment option for patients ...[more]

PMID: 24441281

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Project description:Small intestinal (SI) neuroendocrine tumors (NET) are increasing in incidence, however little is known about their biology. High throughput techniques such as inference of gene regulatory networks from microarray experiments can objectively define signaling machinery in this disease. Genome-wide co-expression analysis was used to infer gene relevance network in SI-NETs. The network was confirmed to be non-random, scale-free, and highly modular. Functional analysis of gene co-expression modules revealed processes including 'Nervous system development', 'Immune response', and 'Cell-cycle'. Importantly, gene network topology and differential expression analysis identified over-expression of the GPCR signaling regulators, the cAMP synthetase, ADCY2, and the protein kinase A, PRKAR1A. Seven CREB response element (CRE) transcripts associated with proliferation and secretion: BEX1, BICD1, CHGB, CPE, GABRB3, SCG2 and SCG3 as well as ADCY2 and PRKAR1A were measured in an independent SI dataset (n = 10 NETs; n = 8 normal preparations). All were up-regulated (p<0.035) with the exception of SCG3 which was not differently expressed. Forskolin (a direct cAMP activator, 10(-5) M) significantly stimulated transcription of pCREB and 3/7 CREB targets, isoproterenol (a selective ß-adrenergic receptor agonist and cAMP activator, 10(-5) M) stimulated pCREB and 4/7 targets while BIM-53061 (a dopamine D(2) and Serotonin [5-HT(2)] receptor agonist, 10(-6) M) stimulated 100% of targets as well as pCREB; CRE transcription correlated with the levels of cAMP accumulation and PKA activity; BIM-53061 stimulated the highest levels of cAMP and PKA (2.8-fold and 2.5-fold vs. 1.8-2-fold for isoproterenol and forskolin). Gene network inference and graph topology analysis in SI NETs suggests that SI NETs express neural GPCRs that activate different CRE targets associated with proliferation and secretion. In vitro studies, in a model NET cell system, confirmed that transcriptional effects are signaled through the cAMP/PKA/pCREB signaling pathway and that a SI NET cell line was most sensitive to a D(2) and 5-HT(2) receptor agonist BIM-53061.

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Advances in small bowel neuroendocrine neoplasia.

Publications

Advances in small bowel neuroendocrine neoplasia.

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