Combination Chemotherapy and In vivo Modeling of BRCA-deficient, High-grade Serous Ovarian Cancer

Ovarian cancer is the most fatal cancer in women with over 60% of patients succumbing to the disease. Mutations in a number of homologous recombination repair genes have been implicated in hereditary ovarian and breast cancer. Specifically, over half of ovarian cancer cases exhibit BRCA-deficiency by either germ line or somatic mutation, or epigenetic silencing. The importance of BRCA-deficiency is highlighted in its association with increased platinum sensitivity. Novel therapeutics such as PARP inhibitors have also been developed by exploiting the synthetic lethal phenotype of BRCA inactivation and PARP inhibition. However over 80% of patients still relapse with resistant disease. Therefore, strategies for more effective treatment are needed. The aim of this thesis was to investigate a chemotherapeutic ratiometric approach for treatment of ovarian cancer and provide a relevant pre-clinical model for evaluation of new therapeutic entities. The combination of carboplatin and olaparib resulted in profound synergism in BRCA-deficient high-grade serous ovarian cancer cell lines when carboplatin was administered at a higher molar ratio relative to olaparib. The combination achieved effective cytotoxicity by inducing greater DNA damage than either of the drugs alone. Synergism of carboplatin-olaparib combinations was also observed in a subset of BRCA-proficient cell lines, suggesting a potential for broader therapeutic applications. To further investigate the impact of BRCA status on therapeutic efficacy, a bioluminescent, BRCA-deficient xenograft model was developed. The model demonstrated characteristics resembling the disease clinically, including high disseminative tumor pattern, ascites production, and platinum sensitivity. Bioluminescent imaging as a means of non-invasion tumor monitoring correlated well with disease burden. Lastly, a systematic literature search identified potential limitations in utilization of bioluminescent imaging techniques in animal models. The correlation between bioluminescent signal and tumor burden is affected by many experimental aspects and it is difficult to identify a general limiting factor. Nonetheless, consideration must be given to methods of tumor measurement, heterogeneity of tumor cell population, and the location of the xenograft when developing the model. Overall, results presented herein provide encouraging data on the utilization of synergistic combinations and a valuable pre-clinical model for evaluation of such combinations for ovarian cancer treatment.

Department dc:contributor.department

Pharmaceutical Sciences

Year dc:date.issued

2020

Author dc:creator

• Shen, Yen Ting

Advisors dc:contributor.advisor

• Piquette-Miller, Micheline
• Allen, Christine J.

Handle dc:identifier.uri

http://hdl.handle.net/1807/121483

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/121483