The Effect of a Ketogenic Diet Concomitant With Chemotherapy in Pancreatic Ductal Adenocarcinoma Survival and Its Associated Cachexia

Abstract Objectives To evaluate the effect of a KD alone or in combination with the current chemotherapeutic drug gemcitabine (GEM) on morbidity and mortality in a clinically relevant genetically engineered LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) mouse model of PDA. Methods At three months old, KPC mice tumor size was measured by high-resolution ultrasound imaging of the pancreas. Male and female mice were allocated to either a control diet (CD; % kcal: 14% protein, 70% carb, 16% fat), a KD (%kcal: 14% protein, <1% carb, 85% fat), a CD + GEM, or a KD + GEM groups. GEM was administered at a dose of 100 mg/kg by i.p. injections 2x/wk for 7 times. Forelimb grip strength, body composition, and non-fasting glucose and ketone levels were evaluated at baseline, monthly and at time of sacrifice. Mice were euthanized upon reaching an endpoint criteria, which included ascites, weight loss > 20%, and/or extreme lethargy. Blood was drawn via cardiac puncture. Tissues were dissected and stored for further analysis. Results KPC mice fed a KD plus GEM exhibited a significant increase in median survival when compared to those fed CD alone. Only KPC mice fed a KD plus gemcitabine exhibited a significant increase in median survival compared to KPC mice fed a CD. KPC mice fed a CD, either alone or in combination with chemotherapy, showed a time-dependent decline in muscle strength by 2 months of intervention. In contrast, KPC mice fed a KD, either alone or combined with chemotherapy, significantly maintained muscle strength after 2 months. To elucidate potential mechanisms underlying the beneficial effects of a KD in maintaining muscle strength, we initially examined, in gastrocnemius muscle, the activation state of mTOR signaling. The phosphorylated levels of S6 ribosomal protein (p-S6), a downstream target of mTOR, were increased in gastrocnemius isolated from KPC mice fed a KD, compared to CD-fed mice. Conclusions Our findings indicate that KD maximizes and preserves motor function strength during PDA progression and enhances median survival when combined with chemotherapy. Additional studies are underway to evaluate the mechanisms of how KD improves and preserves muscle strength in PDA. Funding Sources Research Support: Startup funds and a University of California Comprehensive Cancer Center award to GGM. NEC is supported with a fellowship from UC-MEXUS.