Abstract A07: Intersection of mTORC1 and COX2 pathways as potential therapeutic targets in a mouse model of endometrial cancer

Abstract

Abstract Endometrial cancer (EMC) is the most common gynecological malignancy, causing approximately 8,000 deaths each year in the United States. The underlying causes of EMC are not clearly understood, and treatment options for patients with advanced stages are limited. In human EMCs, the most common genetic mutations are detected in the phosphatase and tensin homologue (Pten) gene. Mutations of p53 are also found in EMC, but this alteration primarily occurs in poorly differentiated carcinomas. Animal models that spontaneously develop cancers are powerful tools for studying the mechanisms underlying cancer initiation and progression and for developing treatment strategies. We previously generated mouse models which spontaneously develop EMC by conditional uterine deletion of Pten (Ptend/d) or Pten and p53 (Pten/p53d/d) by Cre/loxP technology; we mated females with floxed alleles of Pten and/or p53 with males expressing Cre recombinase driven by the progesterone receptor promoter. Ptend/d mice developed EMC with 100% penetrance by 30-day of age, and Pten/p53d/d females developed a more aggressive form of this disease by an earlier age, 21-day old. Uteri of mice of both lines show heightened levels of cyclooxygenase 2 (COX2) and mammalian target of rapamycin complex 1 (mTORC1) activity, which is also seen in human EMC. However, it is not clear whether they are the critical players in cancer progression and whether they work in parallel or synergistically. Thus the purposes of this study are to determine whether (1) pharmacological inhibition of COX2 and/or mTORC1 signaling pathways can reduce the progression of EMC, and (2) inhibition of COX2 signaling can reduce mTORC1 activity and vice versa. Ptend/d females and their control littermates (Ptenf/f) were treated with rapamycin (an inhibitor of mTORC1 signaling) and/or celecoxib (an inhibitor of COX2 activity) by oral gavages every alternate day beginning on 30 days of age for 29 days. We found that although treatment with rapamycin or celecoxib singly attenuated tumor growth, maximum reduction in tumor growth and progression was noted for Ptend/d females receiving both rapamycin and celecoxib. We also observed similar effects in Pten/p53d/d females, with maximal reduction in tumor progression with combined rapamycin and celecoxib treatment. With this data in hand, we next sought to examine the molecular effects of inhibiting mTORC1 and COX2 signaling. Cell culture systems could often be suitable to examine interactions among signaling pathways. Thus, we established a uterine EMC cell line from Pten/p53d/d uteri and examined the effects of rapamycin or celecoxib on COX2 or mTORC1 signaling, respectively. We found that rapamycin reduces COX2 mRNA/protein levels and that celecoxib reduces mTORC1 activity, suggesting that COX2 and mTORC1 activities are cross-regulated and synergistically exacerbate EMC. Thus, a combined treatment with celecoxib and rapamycin may be an effective therapeutic strategy for combating EMC. This study was supported in parts by grants from NIH-P01-CA-77839 (S. K. D) and Ohio Cancer Research Associates (T.D.). Citation Format: Takiko Daikoku, Jumpei Terakawa, Sudhansu K. Dey. Intersection of mTORC1 and COX2 pathways as potential therapeutic targets in a mouse model of endometrial cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A07.