This project is centered on the characterization of the mechanisms by which the tumor suppressor APC impacts epidermal growth factor receptor (EGFR) activation through two lipid signaling axes?prostaglandin E{2} (PGE{2}) and platelet-activating factor (PAF). Additionally, we will study how EGFR signals elicited by one or both of these axes affect colorectal carcinogenesis (CRC). Our first goal is to assess whether APC mutations activate EGFR through the PGE{2} axis. Our second goal is to determine the efficacy of combined inhibition of COX-2 and EGFR in a mouse model of colorectal tumorigenesis that accurately reflects CRC in the general population. This sub-aim mirrors our clinical study in Project 1. We will use mice that harbor oncogenic mutations in APC and also in KRAS, a commonly mutated gene that synergizes with mutated APC to increase disease severity. We hypothesize that both COX-2 and EGFR are critical for tumorigenesis in this context, so both of them must be inhibited in order to effectively treat tumors in the compound mutant mice. Third, we will test the hypothesis that lipid signals derived from activated immune cells and/or cancer cells participate in the pathogenesis of CRC, using in vitro and in vivo approaches. We will focus our studies on events mediated by phospholipid ligands of the platelet-activating factor (PAF) receptor (PAFR), a G protein-coupled receptor controlled by APC and that can activate EGFR in related systems. We hypothesize that signals generated following engagement of E-Prostanoid receptors and PAFR result in intestinal transactivation of EGFR, leading to the stimulation of cellular proliferation.
Our Specific Aims are:
Aim 1 : Dissect the signaling pathways linking APC to EGFR.
Aim 2 : Test the hypothesis that COX-2 and EGFR are critical for colorectal tumorigenesis in mice that harbor mutations in both APC and KRAS.
Aim 3 : Assess the impact of the platelet-activating factor/oxidized phospholipid (PAF/OxPL) axis on oncogenic responses.
Aim 4 : Determine if enhanced signaling by PAF/OxPL affects colon tumorigenesis in vivo.

Public Health Relevance

Colorectal cancer is a major public health problem and we propose to investigate how events such as inflammation and a gene mutation that is common in this disease affect the initiation and progression of colorectal cancer through a growth promoting receptor called EGFR.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA073992-15
Application #
8627125
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
15
Fiscal Year
2014
Total Cost
$279,869
Indirect Cost
$77,832
Name
University of Utah
Department
Type
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Samadder, N Jewel; Curtin, Karen; Pappas, Lisa et al. (2016) Risk of Incident Colorectal Cancer and Death After Colonoscopy: A Population-based Study in Utah. Clin Gastroenterol Hepatol 14:279-86.e1-2
Samadder, N Jewel; Smith, Ken Robert; Hanson, Heidi et al. (2016) Familial Risk in Patients With Carcinoma of Unknown Primary. JAMA Oncol 2:340-6
Li, Jun; Woods, Susan L; Healey, Sue et al. (2016) Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant. Am J Hum Genet 98:830-42
Samadder, N Jewel; Neklason, Deborah W; Boucher, Kenneth M et al. (2016) Effect of Sulindac and Erlotinib vs Placebo on Duodenal Neoplasia in Familial Adenomatous Polyposis: A Randomized Clinical Trial. JAMA 315:1266-75
Samadder, N J; Smith, K R; Mineau, G P et al. (2015) Familial colorectal cancer risk by subsite of primary cancer: a population-based study in Utah. Aliment Pharmacol Ther 41:573-80
Gammon, Amanda; Neklason, Deborah W (2015) Confidentiality & the Risk of Genetic Discrimination: What Surgeons Need to Know. Surg Oncol Clin N Am 24:667-81
Samadi, Abbas K; Bilsland, Alan; Georgakilas, Alexandros G et al. (2015) A multi-targeted approach to suppress tumor-promoting inflammation. Semin Cancer Biol 35 Suppl:S151-84
Samadder, N Jewel; Smith, Ken Robert; Hanson, Heidi et al. (2015) Increased Risk of Colorectal Cancer Among Family Members of All Ages, Regardless of Age of Index Case at Diagnosis. Clin Gastroenterol Hepatol 13:2305-11.e1-2

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