Abstract
Ornithine Decarboxylase (ODC) a key enzyme in polyamine biosynthesis is often overexpressed in cancers and contributes to polyamine-induced cell proliferation. We noted ubiquitous expression of ODC1 in our published endometrial cancer gene array data and confirmed this in the cancer genome atlas (TCGA) with highest expression in non-endometrioid, high grade, and copy number high cancers, which have the worst clinical outcomes. ODC1 expression was associated with worse overall survival and increased recurrence in three endometrial cancer gene expression datasets. Importantly, we confirmed these findings using quantitative real-time polymerase chain reaction (qRT-PCR) in a validation cohort of 60 endometrial cancers and found that endometrial cancers with elevated ODC1 had significantly shorter recurrence-free intervals (KM log-rank p = 0.0312, Wald test p = 5.59e-05). Difluoromethylornithine (DFMO) a specific inhibitor of ODC significantly reduced cell proliferation, cell viability, and colony formation in cell line models derived from undifferentiated, endometrioid, serous, carcinosarcoma (mixed mesodermal tumor; MMT) and clear cell endometrial cancers. DFMO also significantly reduced human endometrial cancer ACI-98 tumor burden in mice compared to controls (p = 0.0023). ODC-regulated polyamines (putrescine [Put] and/or spermidine [Spd]) known activators of cell proliferation were strongly decreased in response to DFMO, in both tumor tissue ([Put] (p = 0.0006), [Spd] (p<0.0001)) and blood plasma ([Put] (p<0.0001), [Spd] (p = 0.0049)) of treated mice. Our study indicates that some endometrial cancers appear particularly sensitive to DFMO and that the polyamine pathway in endometrial cancers in general and specifically those most likely to suffer adverse clinical outcomes could be targeted for effective treatment, chemoprevention or chemoprevention of recurrence.
Highlights
Endometrial cancer is the most common gynecological malignancy in developed countries
Because we found high ODC1 expression we chose to focus on this important polyamine synthesis gene
We further explored the expression of ODC1 in endometrial cancers noting significantly elevated expression in both endometrioid and serous cases the two main histotypes of endometrial cancer (Fig 1A and S1 Fig)
Summary
Endometrial cancer is the most common gynecological malignancy in developed countries. Unlike most other common cancers the numbers of endometrial cancers are increasing and the death rate rises annually. To this point recent American Cancer Society estimates indicate there will be 61,380 newly diagnosed uterine corpus cancers and 10,920 deaths in 2017[1]. The NCI indicates the death rate will rise again this year, a trend that has continued for over 40 straight years[2] These increases are likely due to increased obesity, a major risk factor for endometrial cancer and to age trends of the population. Neither of these trends are expected to change in coming years with 122,000 annual new cases expected by 2030[3]. Patients with local recurrence (stage II) have an approximately 68% 5-year survival rate, stage III tumors 47–58% whereas those with distant recurrence and metastasis a dismal 15–17%[2,6,7,8]
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