3084 - Mitochondrial Pyruvate Carrier as a Potential Therapeutic Target for Radiomodulation of PDAC

Purpose/Objective(s):

Pancreatic Ductal Adenocarcinoma (PDAC) is the third most deadly cancer in the United States, with a relative 5-year survival rate of only about 13%. The tumoricidal effect of stereotactic body radiation therapy (SBRT) against PDAC is often limited by the tumor’s radioresistant nature. Moreover, radiation-induced small bowel toxicity often results in early withdrawal of treatment and subsequent tumor recurrence. Mitochondrial metabolism such as oxidative phosphorylation (OXPHOS) or the TCA cycle are potentially druggable targets in PDAC, and both are heavily driven by mitochondrial pyruvate influx. In the present study using a PDAC mouse model, we examined the effect of the Mitochondrial Pyruvate Carrier (MPC) inhibitor, UK5099, as a radio-modulator in pancreatic SBRT.

Materials/Methods:

C57bl6 male mice (8-10 weeks) were injected subcutaneously with KPC pancreatic tumor cells. Mice with 100mm³ tumor size were exposed to fractionated abdominal irradiation (4 Gy x 4 Doses) and then treated with/without UK5099 3mg/kg every other day for 12 days. Mice were monitored for tumor growth, and tumor size was measured until it reached 2 cm³. In a parallel study, non-tumor bearing mice were exposed to lethal doses of partial body irradiation and then treated with/without UK5099 to determine the effect of UK5099 in mitigating radiation-induced gastrointestinal syndrome.

Results:

Irradiated mice receiving UK5099 demonstrated significant tumor growth delay compared to irradiated or untreated control mice (p<0.003, p<0.0001, respectively). Moreover, non-tumor bearing mice exposed to lethal doses of irradiation demonstrated significant improvement in survival with mitigation of intestinal epithelial injury with UK5099 treatment compared to untreated and irradiated controls. Finally, our study in ex vivo intestinal organoids demonstrated that inhibition of mitochondrial pyruvate transport minimizes the radiation-induced mitochondrial ROS production and oxidative stress, thereby rescuing intestinal stem cells from radiation toxicity.

Conclusion:

This preclinical study clearly demonstrated that inhibition of MPC sensitizes PDAC to abdominal irradiation while mitigating the radiation toxicity in the healthy intestinal epithelium. Therefore, in the context of PDAC, MPC can be considered a potential target to promote an improved therapeutic ratio with abdominal irradiation.