Abstract #0831

Hyperpolarized dehydroascorbate reveals ascorbate-mediated oxidative stress increases flux through the pentose phosphate pathway in cancer

Nathaniel Kim¹, Marjan Berishaj¹, Elisa de Stanchina², Manish Shah³, Lewis Cantley⁴, and Kayvan Keshari¹

¹Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, United States, ²Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States, ³Weill Cornell Medicine, New York-Presbyterian Hospital, New York, NY, United States, ⁴Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY, United States

Synopsis

HP DHA was demonstrated as an imaging agent for probing the biochemical response to ascorbate therapy in patient derived xenograft (PDX) models of cancer. Changes in DHA/ascorbate metabolism were observed in PDX tumors after prolonged treatment, mirroring the observed treatment response to high dose ascorbate. Metabolomic studies showed that high dose ascorbate therapy induced oxidative stress, leading to increased flux through the pentose phosphate pathway (PPP). DNA damage repair mutants exhibit lower baseline flux through the PPP and are more sensitized to ascorbate induced ROS. These results demonstrate a new method for assessing oxidative stress in vivo using HP DHA.

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