Open Collections

Ji, Xiao Ye (Jennifer)

University of British Columbia

Clear cell ovarian cancer (CCOC) is a molecularly unique subtype of epithelial ovarian cancer for which treatment options are still limited. Patients with late stage CCOC do not respond to gold-standard platinum and taxane based chemotherapeutics, and effective targeted therapies for this cancer are still lacking. Due to its relative rarity, the molecular landscape of this ovarian cancer subtype has not been fully deciphered. In this thesis, I used global screening techniques to elucidate the proteomic and metabolomic landscapes of CCOC, compared to other common epithelial ovarian cancer subtypes. I found that CCOC is a unique entity compared to its other epithelial ovarian cancer counterparts in both its proteomic and metabolomic landscapes. I reported proteomic diversity within CCOC cases presented as subgroups of distinct molecular signatures. Moreover, through integrated proteometabolomic analysis, I identified aberrancies in purine metabolism, cysteine/glutathione metabolism, as well as glucose metabolism. I further demonstrated that available CCOC cell lines reflect the proteomic and metabolomic signatures in CCOC clinical samples. The heterogenous biology seen in clinical samples and cell lines suggests that the comprehensive understanding of this cancer require appropriate in-vitro models to represent its diverse molecular phenotypes. Lastly, our proteomic understanding led to the identification of the lack of an arginine synthesizing enzyme, arginosuccinate synthase, in CCOC and other rare ovarian cancer subtypes including small cell ovarian carcinomas hypercalcemic type. Cancers lacking this enzyme has been shown to be sensitive to a molecular agent depriving extracellular arginine. I show that this therapeutic agent was effective in curbing the growth of arginosuccinate synthase-negative rare ovarian cancers in-vitro and in in-vivo murine models, thus identifying a potential therapy for these very aggressive subtypes. My research provides the largest reported proteomic landscape of CCOC cases, in addition, I report the first metabolic landscape of CCOC and other ovarian cancer subtypes. Both will serve as valuable resources for further research into CCOC biology and therapeutic development. Furthermore, I demonstrate of how proteomic and metabolomic understanding can accelerate therapeutic development in rare ovarian cancers by using arginosuccinate synthase deficiency as an example.

Text

2023-06-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/79107

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/