Therapeutic target identification and treatment strategies based on (epi)genetic features of ovarian clear cell carcinoma

Ovarian clear cell carcinoma (OCCC) is a rare subtype of ovarian cancer with poor prognosis when diagnosed at advanced stage. These patients are treated with platinum-based chemotherapy. The last decades, no further improvement of overall survival has been achieved. OCCC shows distinct genetic features compared to other ovarian cancer subtypes. Around 50% OCCC cases carry mutations in the tumor suppressor gene ARID1A, and <10% in TP53. In this thesis, we therefore used a strategy to activate wild-type p53 by targeting MDM2, which is a repressor protein of p53, with a small molecule and to combine this drug with cisplatin. The combination was effective although future optimization is warranted. Next, the DNA damage response pathway was blocked by targeting ATR resulting in sensitization of OCCC cells to cisplatin. To identify new targets that are specifically active in ARID1A mutant OCCC, genome-wide DNA methylation profiles of patient tumors and cell lines were determined. Several genes were found that are differentially methylated and differentially expressed and are associated with ARID1A mutant status. These genes may serve as potential new therapeutic targets of ARID1A mutant OCCC. At last, to test those novel drug strategies, OCCC patient-derived-xenograft (PDX) models have been established. The pathological, genomic and epigenetic resemblance between PDX models and match patient tumors was revealed, supporting the usage of these models as in vivo OCCC models for future translational studies.
In conclusion, we established in vivo OCCC models and identified novel targets and drug combinations that warrants further investigation.