Calorie And Fat Restriction During Chemotherapy Improves Survival In Obese Mice With Syngeneic Acute Lymphoblastic Leukemia

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAObesity promotes the pathogenesis of many cancers, including acute lymphoblastic leukemia (ALL), the most common childhood malignancy. Clinical studies have shown that children who are obese at the time of ALL diagnosis have a greater risk of relapse than normal weight children; however, this risk may be attenuated if their weight normalizes over the majority of treatment. One possible explanation is that nutrient-deficiency may induce host, but not ALL, cell senescence, thereby augmenting chemotherapy specificity and efficacy. Here, we hypothesize that a calorie- and fat-restricted diet during chemotherapy differentially alters host and ALL cell metabolism, improving chemotherapy efficacy and overall survival of high-fat diet-induced obese mice with ALL.To test the effect of dietary restriction on survival, C57BL/6J mice were placed on a high-fat diet (60% calories from fat) upon weaning. At 20 weeks of age, obese and control mice were implanted with syngeneic BCR/ABL+ ALL cells. After a 7-day latency, half of the obese mice were switched onto a low-fat (10% calories from fat) diet. Concurrently, vincristine chemotherapy (0.5mg/kg/wk x 4wks) was initiated and mice were tracked for survival. Separate groups of implanted mice were sacrificed 1 day before, 1 day and 1 week after dietary restriction for bone marrow and spleen collection. BrdU incorporation and p-AKT(Ser 473), p-eIF2A(Ser51) and p-S6K(Thr412) levels in marrow and spleen ALL and host cells were analyzed via flow cytometry for changes in cell cycle and metabolism. Finally, we also evaluated the effect of dietary restriction on human ALL outcome, using an obese xenograft ALL model treated with vincristine, dexamethasone and L-asparaginase.Dieted obese C57BL/6J leukemic mice exhibited a greater percentage of weight loss over the first two weeks of chemotherapy compared to non-dieted obese mice (Dieted vs. non-dieted obese: -25.2±10.6% vs. -0.3±4.5%, pu003c0.001). Dieted obese leukemic mice had significantly higher survival than non-dieted obese and lean mice after 4 months (Dieted: 91.6%, Obese: 16.7%, Lean: 41.7%; n = 12/group; pu003c0.001). Flow cytometry of the murine bone marrow and spleen showed no diet-induced alterations in BrdU incorporation or AKT pathway activation in either host or ALL cells. Surprisingly, however, we did not observe a similar effect of dietary restriction on survival in the obese xenograft ALL model.Based on these findings, a calorie and fat restricted diet initiated at the onset chemotherapy improves overall survival in obese mice with syngeneic ALL, though this phenomenon was not observed in a human xenograft model. Further work is needed to explore the possibility of a dietary intervention as an effective potential adjuvant during chemotherapy in obese cancer patients.Citation Format: Jonathan Tucci, Waseem Alhushki, Xia Sheng, Steven D. Mittelman. Calorie and fat restriction during chemotherapy improves survival in obese mice with syngeneic acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1633. doi:10.1158/1538-7445.AM2015-1633