Abstract 4928: Cyclooxygenase-1 as a target for molecular imaging of high grade serous ovarian cancer

Abstract

Abstract Ovarian cancer is the most lethal gynecologic malignancy. Most women diagnosed with high grade serous ovarian cancer, the most common subtype, present with advanced disease characterized by widespread peritoneal carcinomatosis. Non-invasive imaging plays a critical role in the management of ovarian cancer by confirming sites of disease, informing treatment interventions, and determining the effectiveness of treatment. However, current imaging methods are limited by relatively high false positive and false negative rates. The development of novel molecular imaging agents is urgently required. Emerging evidence from our group and others suggests that cyclooxygenase-1 (COX-1) is an important molecular target in ovarian cancer and distinguishes ovarian cancer from most other solid tumors, where COX-2 is the dominant isoform. COX-1 and COX-2 catalyze the rate-limiting step in the biosynthesis of prostaglandins and thromboxanes, which contribute to tumorigenesis by promoting tumor proliferation, escape from apoptosis, and angiogenesis. In this study, we examined COX-1 expression in high grade serous ovarian tumors using data extracted from The Cancer Genome Atlas (TCGA) and a tissue microarray (TMA) generated in our laboratory from 209 patients. Raw mRNA RNA-seq expression data from TCGA revealed that PTGS1, the gene encoding COX-1, is in the top 10% of genes expressed in ovarian cancer. Furthermore, mRNA expression of the COX-2-encoding gene, PTGS2, in ovarian tumors was significantly lower than COX-1 mRNA levels (p<0.00001, Mann-Whitney test), and COX-1 expression was selectively higher in ovarian tumors than in 11 other solid cancers in the TCGA PANCAN12 panel (p<0.00001 compared to COX-1 levels in ovarian tumors, Mann-Whitney test). We confirmed these findings at the protein level in our TMA. There was high COX-1 expression in a large subset of high grade serous tumors, but markedly lower expression in other epithelial ovarian cancer subtypes (endometrioid, mucinous and clear cell, p<0.0001, Mann-Whitney test). Having confirmed COX-1 as an attractive molecular target in high grade serous ovarian cancer, newly synthesized COX-1-selective compounds were screened in COX-1-expressing OVCAR-3 ovarian cancer cells. Two novel small molecule inhibitors of COX-1 (LM-9954 and LM-9955) inhibited COX-1 in biochemical assays and reduced prostaglandin synthesis in OVCAR-3 cells at nanomolar concentrations. The highly selective expression of COX1 in serous ovarian carcinoma provides a unique molecular screening opportunity and we are currently synthesizing 18F-conjugated forms of these agents to act as radiotracers in positron emission tomography (PET) imaging. Exploiting high COX-1 expression in high grade serous ovarian cancer with novel COX-1-targeted molecules has the potential to improve detection of this deadly disease. Citation Format: Andrew J. Wilson, Brian D. Lehmann, MD Jashim Ussin, Anna Elleman, Brenda Crews, Jeanette Saskowski, Jennifer Pietenpol, Lawrence J. Marnett, Dineo Khabele. Cyclooxygenase-1 as a target for molecular imaging of high grade serous ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4928. doi:10.1158/1538-7445.AM2014-4928