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Examining the markers of vitamin C cytotoxicity in pancreatic ductal adenocarcinoma

University of British Columbia

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal forms of cancer, with a 5-year survival rate of less than 10%. Current challenges include limited therapeutic options and lack of biomarkers that predict treatment response. Therefore, I sought to determine if a recently rediscovered treatment, pharmacological vitamin C, has clinical utility in PDAC. I determined that PDAC cell lines have differential sensitivity at doses tested. Previous research in colorectal cancer indicated that KRAS mutations infer vitamin C sensitivity, which was a trend in my results. Therefore, I created two isogenic cell line models expressing either KRAS G12D or KRAS G12V. Testing depicted increased sensitivity in one model but none others, suggesting that factors beyond oncogenic KRAS alone may be needed to increase sensitivity to vitamin C treatment. Oncogenic KRAS is known to increase glycolysis through the Warburg effect. Interestingly, pharmacological vitamin C treatment is also hypothesized to affect this pathway. Therefore, I sought to determine the relationship between vitamin C and glycolysis to determine potential markers of vitamin C sensitivity. Testing glycolysis rates demonstrated that vitamin C inhibits glycolysis independent from vitamin C toxicity. Work by Daemen et al. identified that glycolytic inhibitors cause toxicity selective to glycolytic dependant cells, whereas lipogenic cells survive. Furthermore, they characterized our two vitamin C sensitive cell lines as glycolytic. To further understand if glycolytic dependence influences vitamin C sensitivity, I used glucose withdrawal to reduce the cell’s glycolytic dependence. In low glucose conditions, higher doses of vitamin C were needed compared to high glucose conditions, suggesting that glycolytic dependence does influence toxicity to vitamin C. Together, my results suggest that glycolytic dependence may be a good marker for determining vitamin C sensitivity. To test if vitamin C is toxic in KRAS mutated patient-derived models, PDAC-derived organoids were created and treated using vitamin C monotherapy and combination therapy with gemcitabine. Vitamin C showed toxicity as a monotherapy and increased toxicity when combined with gemcitabine. This is the first known use of organoids in testing vitamin C treatment and suggests, congruent with other research, that vitamin C alone and in combination has clinical utility.

Text

2019-04-02

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/69406

Interdisciplinary Oncology

University of British Columbia

UBCV

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