Abstract 2626: Metabolic profiles and potential pharmacodynamic biomarkers in female Sprague-Dawley rats on a standard (4% fat) or Western (20% fat) diet and treated with known active or inactive chemopreventive agents
Authors: Thompson Matthew D. , Grubbs Clinton J. , Steele Vernon E. , Miller Mark S. , Moeinpour Fariba , Karoly Edward D. , Lubet Ronald A. 
Published: July 2016

The methylnitrosourea (MNU) - induced model of ER+ mammary cancers in female Sprague-Dawley rats has been routinely used in our laboratories for screening chemopreventive agents. In this study, we evaluated multiple known effective [tamoxifen, Targretin (an RXR agonist), Iressa (EGFR1 inhibitor)] or ineffective agents (Lipitor, metformin) in rats placed on either standard diet (20% fat) or a Western diet (20% fat, low calcium) at 43 days of age (DOA). Rats were given MNU at 50 DOA and administered the various agents or vehicle beginning at 57 DOA until the end of the study. Palpation of the rats showed that agents yielded the same results in rats on either diets. Somewhat surprisingly, metformin was ineffective in rats on either diet; confirming our lack of efficacy in a standard diet (Thompson, et al, Cancer Prev Res., 2015). To look for potential pharmacodynamics biomarkers, serum was obtained from the various groups at 78 days of age and at sacrifice; when a large tumor burden was observed in rats given vehicle, Lipitor, or metformin. Levels of approximately 500 metabolites were compared in the serum (Metabolon Research, Research Triangle Park, NC). We initially looked for metabolite changes related to different diets and found differential expression of alpha 10-undecanoate, 13-methylmyristic acid, 4-hydrox-benzoate, 2-amino-heptanpate, tocopherol and nicotinamide when comparing serum from rats on Western vs standard diets. Interestingly, each of the highly effective agents (tamoxifen, Targretin, and Iressa) yielded metabolic profiles that were strikingly different from rats given vehicle; based on unsupervised analysis. These metabolites become potential pharmacodynamic biomarkers for the highly effective doses of these agents. In contrast, the two negative agents did not yield a similar dichotomy between treated and vehicle serum. One could determine, however, metabolites which differed between metformin or Lipitor treated rats vs vehicle treated rats when performing a supervised analysis. We also compared serum for the early and late time points with either diet since the latter serum was from animals with a significant number of mammary cancers. We observed a number of metabolite changes including 4-OH butyrate, acetyl carnitine, oxalate, and threonate. These cancer related profiles will be discussed at greater length; in addition to the altered profiles caused by the administration of the various chemopreventive agents. Supported by NCI contract HHSN261201200021I.

Citation Format: Matthew D. Thompson, Clinton J. Grubbs, Vernon E. Steele, Mark S. Miller, Fariba Moeinpour, Edward D. Karoly, Ronald A. Lubet. Metabolic profiles and potential pharmacodynamic biomarkers in female Sprague-Dawley rats on a standard (4% fat) or Western (20% fat) diet and treated with known active or inactive chemopreventive agents. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2626.