1. Academic Validation
  2. Gene Expression Signatures Identify Novel Therapeutics for Metastatic Pancreatic Neuroendocrine Tumors

Gene Expression Signatures Identify Novel Therapeutics for Metastatic Pancreatic Neuroendocrine Tumors

  • Clin Cancer Res. 2020 Apr 15;26(8):2011-2021. doi: 10.1158/1078-0432.CCR-19-2884.
Aaron T Scott 1 Michelle Weitz 2 Patrick J Breheny 2 3 Po Hien Ear 1 Benjamin Darbro 3 4 Bart J Brown 3 5 Terry A Braun 3 5 Guiying Li 1 Shaikamjad Umesalma 6 Courtney A Kaemmer 6 Chandra K Maharjan 6 Dawn E Quelle 3 6 7 Andrew M Bellizzi 3 7 Chandrikha Chandrasekharan 3 8 Joseph S Dillon 3 8 Thomas M O'Dorisio 3 8 James R Howe 9 3
Affiliations

Affiliations

  • 1 Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA.
  • 2 College of Public Health, Department of Biostatistics, University of Iowa, Iowa City, IA.
  • 3 Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA.
  • 4 Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA.
  • 5 Center for Bioinformatics and Computational Biology, College of Engineering, University of Iowa, Iowa City, IA.
  • 6 Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA.
  • 7 Department of Pathology, Carver College of Medicine University of Iowa, Iowa City, IA.
  • 8 Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA.
  • 9 Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA. james-howe@uiowa.edu.
Abstract

Purpose: 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.

Experimental design: 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 in vitro using two pNET cell lines (BON-1 and QGP-1).

Results: 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.

Conclusions: 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 in vitro 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.

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