Epigenetic Therapy Augments Classic Chemotherapy in Suppressing the Growth of 3D High-Grade Serous Ovarian Cancer Spheroids over an Extended Period of Time

Recurrent high-grade serous ovarian cancer (HGSC) is clinically very challenging and prematurely shortens patients’ lives. Recurrent ovarian cancer is characterized by high tumor heterogeneity; therefore, it is susceptible to epigenetic therapy in classic 2D tissue culture and rodent models. Unfortunately, this success has not translated well into clinical trials. Utilizing a 3D spheroid model over a period of weeks, we were able to compare the efficacy of classic chemotherapy and epigenetic therapy on recurrent ovarian cancer cells. Unexpectedly, in our model, a single dose of paclitaxel alone caused the exponential growth of recurrent high-grade serous epithelial ovarian cancer over a period of weeks. In contrast, this effect is not only opposite under treatment with panobinostat, but panobinostat reverses the repopulation of cancer cells following paclitaxel treatment. In our model, we also demonstrate differences in the drug-treatment sensitivity of classic chemotherapy and epigenetic therapy. Moreover, 3D-derived ovarian cancer cells demonstrate induced proliferation, migration, invasion, cancer colony formation and chemoresistance properties after just a single exposure to classic chemotherapy. To the best of our knowledge, this is the first evidence demonstrating a critical contrast between short and prolonged post-treatment outcomes following classic chemotherapy and epigenetic therapy in recurrent high-grade serous ovarian cancer in 3D culture.

复发性高级别浆液性卵巢癌（Recurrent high-grade serous ovarian cancer, HGSC）临床诊疗极具挑战性，会显著缩短患者的生存周期。复发性卵巢癌以高肿瘤异质性为特征，因此在经典二维组织培养与啮齿类动物模型中，其对表观遗传治疗较为敏感。但遗憾的是，该类模型中的良好疗效并未很好地转化至临床试验中。
本研究借助为期数周的三维球体模型（3D spheroid model），对比了经典化疗与表观遗传治疗对复发性卵巢癌细胞的疗效。令人意外的是，在本模型中，单剂紫杉醇（paclitaxel）单独给药可在数周内促使复发性高级别浆液性上皮性卵巢癌细胞呈指数级增殖。与之相反，帕比司他（panobinostat）治疗不仅可逆转这一促增殖效应，还能抑制紫杉醇给药后癌细胞的再增殖。
本研究同时证实了经典化疗与表观遗传治疗的药物敏感性差异。此外，仅经单次经典化疗暴露后，三维培养来源的卵巢癌细胞即可出现增殖、迁移、侵袭、癌集落形成及化疗耐药能力的显著增强。据我们所知，本研究首次在三维培养体系中证实，复发性高级别浆液性卵巢癌经经典化疗与表观遗传治疗后，其短期与长期治疗结局存在显著差异。