Summary of Study ST002354

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001511. The data can be accessed directly via it's Project DOI: 10.21228/M8CQ6T This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

Study ID	ST002354
Study Title	Combination of TP-252 and Naproxen elicit tumor protective Eicosanoid changes.
Study Summary	Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Patients with the genetic disorder Familial Adenomatous Polyposis (FAP) develop hundreds to thousands of polyps that unless removed by prophylactic colectomy will progress to CRC at an early age. Non-steroidal anti-inflammatory drugs (NSAIDs) and -3 marine polyunsaturated fatty acids (PUFA), such as eicosapentaenoic acid (EPA), have been evaluated for their chemopreventive potential in delaying the onset of CRC in high-risk patients. In this study, we determined whether the NSAID, naproxen, alone or in combination with a chemically-stable form of EPA (TP-252), affects tumor formation in the ApcPirc rat model. When compared to control diet, animals fed naproxen or HD TP-252 had 66%, and 82% fewer tumors respectively. However, when fed a combination of naproxen and HD TP-252, animals exhibited a 95% reduction in tumor formation and a 98% reduction in tumor volume, respectively. To elucidate potential mechanisms of tumor protection, a comprehensive, targeted lipidomic analysis was performed on colonic mucosa to determine changes in eicosanoid metabolism. Animals receiving TP-252 alone or in combination with naproxen had significantly reduced mucosal levels of pro-inflammatory -6 eicosanoids (PGE2, 5-HETE, and 14,15-DiHETrE), along with a simultaneous increase in anti-inflammatory EPA-derived -3 eicosanoids. Our colonic mucosal lipidomic analysis also uncovered several potential pharmacodynamic (PD) lipid biomarkers, including resolvin E2, 9-HEPE, 12-HEPE and 18-HEPE, that were increased in both the tissue and plasma of rats receiving TP-252 and were significantly correlated with tumor protection. Further studies with this drug combination should be focused on dose optimization and the role of EPA-derived lipid mediators in CRC initiation and progression.
Institute	UConn Health
Last Name	Beach
First Name	Ryan
Address	263 Farmington Avenue, Farmington CT 06030
Email	rbeach@uchc.edu
Phone	860-679-8703
Submit Date	2022-11-21
Raw Data Available	Yes
Raw Data File Type(s)	wiff
Analysis Type Detail	LC-MS
Release Date	2022-12-22
Release Version	1

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Treatment:

Treatment ID:	TR002455
Treatment Summary:	Rats were fed two doses of TP-252 equivalent to consuming 1.3 and 2.6 g/kg/day for LD TP-252 and HD TP-252, respectively. Alternatively, rats were also fed a diet containing 2% EPA-FFA in their diet (equivalent to 1.14 g/kg/day of EPA). In groups receiving naproxen, the dose of naproxen was 11.4 mg/kg/day, or roughly 4 mg/rat/day. These treatment groups were carried out for the 20 weeks, and then animals were sacrificed and tissue collected and analyzed.

Treatment ID:

TR002455

Treatment Summary:

Rats were fed two doses of TP-252 equivalent to consuming 1.3 and 2.6 g/kg/day for LD TP-252 and HD TP-252, respectively. Alternatively, rats were also fed a diet containing 2% EPA-FFA in their diet (equivalent to 1.14 g/kg/day of EPA). In groups receiving naproxen, the dose of naproxen was 11.4 mg/kg/day, or roughly 4 mg/rat/day. These treatment groups were carried out for the 20 weeks, and then animals were sacrificed and tissue collected and analyzed.