Journal article
Gene Expression Signatures Identify Novel Therapeutics for Metastatic Pancreatic Neuroendocrine Tumors
Clinical cancer research, Vol.26(8), pp.2011-2021
04/15/2020
DOI: 10.1158/1078-0432.CCR-19-2884
PMCID: PMC7165057
PMID: 31937620
Abstract
Pancreatic neuroendocrine tumors (pNETs) are uncommon malignancies noted for their propensity to metastasize and comparatively favorable prognosis. Although both the treatment options and clinical outcomes have improved in the past decades, most patients will die of metastatic disease. New systemic therapies are needed.
Tissues were obtained from 43 patients with well-differentiated pNETs undergoing surgery. Gene expression was compared between primary tumors versus liver and lymph node metastases using RNA-Seq. Genes that were selectively elevated at only one metastatic site were filtered out to reduce tissue-specific effects. Ingenuity pathway analysis (IPA) and the Connectivity Map (CMap) identified drugs likely to antagonize metastasis-specific targets. The biological activity of top identified agents was tested
using two pNET cell lines (BON-1 and QGP-1).
A total of 902 genes were differentially expressed in pNET metastases compared with primary tumors, 626 of which remained in the common metastatic profile after filtering. Analysis with IPA and CMap revealed altered activity of factors involved in survival and proliferation, and identified drugs targeting those pathways, including inhibitors of mTOR, PI3K, MEK, TOP2A, protein kinase C, NF-kB, cyclin-dependent kinase, and histone deacetylase. Inhibitors of MEK and TOP2A were consistently the most active compounds.
We employed a complementary bioinformatics approach to identify novel therapeutics for pNETs by analyzing gene expression in metastatic tumors. The potential utility of these drugs was confirmed by
cytotoxicity assays, suggesting drugs targeting MEK and TOP2A may be highly efficacious against metastatic pNETs. This is a promising strategy for discovering more effective treatments for patients with pNETs.
Details
- Title: Subtitle
- Gene Expression Signatures Identify Novel Therapeutics for Metastatic Pancreatic Neuroendocrine Tumors
- Creators
- Aaron T Scott - University of IowaMichelle Weitz - University of IowaPatrick J Breheny - University of IowaPo Hien Ear - University of IowaBenjamin Darbro - University of IowaBart J Brown - University of IowaTerry A Braun - University of IowaGuiying Li - University of IowaShaikamjad Umesalma - University of IowaCourtney A Kaemmer - University of IowaChandra K Maharjan - University of IowaDawn E Quelle - University of IowaAndrew M Bellizzi - University of IowaChandrikha Chandrasekharan - University of IowaJoseph S Dillon - University of IowaThomas M O'Dorisio - University of IowaJames R Howe - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.26(8), pp.2011-2021
- DOI
- 10.1158/1078-0432.CCR-19-2884
- PMID
- 31937620
- PMCID
- PMC7165057
- NLM abbreviation
- Clin Cancer Res
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Grant note
- P30 CA086862 / NCI NIH HHS T32 CA148062 / NCI NIH HHS P50 CA174521 / NCI NIH HHS
- Language
- English
- Date published
- 04/15/2020
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Hematology, Oncology, and Blood & Marrow Transplantation; Stead Family Department of Pediatrics; Pathology; Biostatistics; Medical Genetics and Genomics; Surgery; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984183988902771
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