Background: Pancreatic ductal adenocarcinoma (PDAC) remains very challenging to treat with mean 5-year survival of approx. 6%, leading to PDAC’s status as the 4th most deadly cancer in the US. Diet induced obesity (DIO) has been shown to promote both increased incidence and growth of PDAC. Simultaneously DIO promotes muscle loss and the loss of immune surveillance in tumors. Cachexia, a chronic catabolic process in which muscle mass is lost, is a common feature of PDAC. We have previously shown that while leucine driven mTOR activation protects muscle mass in tumor bearing mice it also promotes tumor growth. Hence, we sought to test the potential of a leucine metabolite, β-hydroxy-β-methyl-butyrate, to protect against cachexia in a PDAC model while antagonizing DIO mediated tumor growth. We further sought to determine if HMB treatment would alter gemcitabine response in tumors from obese animals.
Methods: C57BL/6 mice consuming either control or high fat diet, bearing Panc02 tumors, were treated with HMB alone or in combination with gemcitabine. Muscle size was determined using Feret’s diameter measured from H&E stained cross sections. Immunohistochemistry staining was performed for Ki-67 and CD3. Tumor transcriptomic analysis was preformed using Affymetrics microarray. In vitro characterization HMB modulated signaling in C2C12 myotubes, Panc02 cells, and bone marrow derived macrophages treated with pro-inflammatory signaling molecules.
Results: a) HMB significantly increases muscle fiber size and mTOR signaling; b) HMB reduces DIO increased tumor volume; c) HMB significantly synergizes with gemcitabine to suppress PDAC growth in obese mice; and d) HMB reverts DIO mediate immune suppression and promotes tumor immune surveillance.
Discussion: Antagonism of DIO promoted PDAC tumor growth, by HMB, and promotion of immune surveillance may offer significant synergy with standard therapy or, immune targeted therapies in PDAC.
Citation Format: Michael F. Coleman, Kristyn A. Liu, Xiaohu Tang, Salvador Fabela, Laura M. Lashinger, Zhengrong Cui, Stephen D. Hursting. β-Hydroxy-β-Methylbutyrate supplementation preserves muscle mass and reduces tumor growth in obese mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1090.