Zebrafish tumour xenograft models: a prognostic approach to epithelial ovarian cancer

Abstract

Epithelial ovarian cancer (EOC) is the gynaecological malignancy with highest mortality. Although adjuvant treatment with carboplatin and paclitaxel leads to an objective response in ~80% of these patients, a majority will relapse within two years. Better methods for assessing long-term treatment outcomes are needed. To address this, we established safe and efficacious doses of carboplatin and paclitaxel using IGROV-1 zebrafish-CDX models. Then fluorescently-labelled cell suspensions from 83 tumour biopsies collected at exploratory laparotomy of women with suspected EOC were generated and 37 (45%) were successfully implanted in zebrafish larvae. Among these 19 of 27 pathology-confirmed EOC samples (70%) engrafted. These zebrafish patient-derived tumour xenograft (ZTX) models were treated with carboplatin or paclitaxel and tumour growth/regression and metastatic dissemination were recorded. In a subgroup of nine patients, four ZTX models regressed during carboplatin treatment. All four corresponding patients had >24 months PFS. Furthermore, both ZTX models established from two patients having <24 months PFS failed to regress during carboplatin treatment. Seven of eight models seeding <6 metastatic cells were established from patients having >24 months PFS. In eleven of fourteen patients, FIGO stage I + II or III tumours gave rise to ZTX models seeding <4 or >4 metastatic cells, respectively. In conclusion, ZTX models predicted patients having >24 or <24 months PFS, based on response/no response to carboplatin. Furthermore, high metastatic dissemination in ZTX models correlated to shorter PFS and more advanced disease at diagnosis. These preliminary results suggest that ZTX models could become a useful prognostic tool in EOC treatment planning.

Zebrafish Avatars: Toward Functional Precision Medicine in Low-Grade Serous Ovarian Cancer

“…Most published work on zebrafish xenografting is based on analyzing tumor size, e.g., measuring the area or volume of the cells via a fluorescent signal [15,17]. However, we find that estimating tumor response is insufficient and inaccurate if only relying on changes in dye-based cell labeling.…”

“…During the past decade, zebrafish avatars entered the world of functional precision medicine from proof-of-concept studies involving a diverse set of cancer cell lines, evolving to experiments with zebrafish PDX models and, currently, the first co-clinical trials [17]. To date, nearly a thousand research papers have been published on the utility of zebrafish avatars in predicting tumor responses.…”

“…In contrast with other cancer types, only a few research groups have explored the utility of zAvatars for functional personalized medicine in ovarian cancer, and thus far, none have focused on low-grade serous ovarian cancer (LGSOC) [17,18]. LGSOC is relatively resistant to standard chemotherapy, likely due to its low proliferative activity in comparison with HGSOC.…”