UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Small cell carcinoma of the ovary, hypercalcemic type : model development and preclinical drug testing Chen, Yuting (Shary)


Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive ovarian cancer that usually occurs in women in their 20s. As SCCOHT has a very low survival rate, an effective therapeutic solution is urgently needed. Genomic studies have demonstrated that concurrent dual loss of SMARCA4/A2, the two only ATPase of the SWI/SNF chromatin-remodeling complex, occurs in more than 90% SCCOHT cases, which opens the opportunity for developing targeted therapeutics for treating SCCOHT. One major challenge for preclinical studies is the discrepancy between preclinical and clinical outcomes. Although preclinical anti-cancer drugs are mostly tested in subcutaneous xenograft models, they do not provide a relevant environmental support for most cancer types. In contrast, orthotopical models potentially provides similar microenvironment for tumor development. However, the tumor growth monitoring is challenging for orthotopical tumours. To overcome these challenges, I developed SCCOHT cell lines stably expressing mKate2, a far-red fluorescent protein. The application of these SCCOHT cell lines in both subcutaneous and intrabursal models indicated that the fluorescent signals directly correlated to the tumor progression. Pathological analysis revealed intrabursal tumor contained histological features typical of SCCOHT, such as follicle-like structures. Metastasis and ascites were also observed in the intrabursal model. Thus, intrabursal model of SCCOHT mimics the microenvironment of SCCOHT tumors developed in patients; introducing a fluorescent signal provides a convenient monitoring method of the tumor development. Previous studies have shown an antagonism between the SWI/SNF complex components and the polycomb repressive complex 2 (PRC2) in regulating various gene expression. As dual loss of SMARCA4 and SMARCA2 is a definitive feature of SCCOHT, we hypothesize that pharmaceutical inhibition of the activity of PRC2 in SCCOHT may be a potential therapeutic approach. Accordingly, depletion of EZH2, the catalytic subunit of PRC2, or pharmacological inhibition of PRC2 by either GSK126 or EED226 suppressed the proliferation of SCCOHT cell lines. Furthermore, administration of 200 mg/kg EED226 twice daily significantly decreased tumor progression in mice bearing the fluorescent SCCOHT1 subcutaneous xenograft. Therefore, targeting PRC2 is a potential therapeutic strategy for treating SCCOHT and fluorescent imaging can be used to monitor tumor growth in preclinical studies.

Item Media

Item Citations and Data


Attribution-NonCommercial-NoDerivatives 4.0 International