TY - JOUR
T1 - Ketogenic diet and chemotherapy combine to disrupt pancreatic cancer metabolism and growth
AU - Yang, Lifeng
AU - TeSlaa, Tara
AU - Ng, Serina
AU - Nofal, Michel
AU - Wang, Lin
AU - Lan, Taijin
AU - Zeng, Xianfeng
AU - Cowan, Alexis
AU - McBride, Matthew
AU - Lu, Wenyun
AU - Davidson, Shawn
AU - Liang, Gaoyang
AU - Oh, Tae Gyu
AU - Downes, Michael
AU - Evans, Ronald
AU - Von Hoff, Daniel
AU - Guo, Jessie Yanxiang
AU - Han, Haiyong
AU - Rabinowitz, Joshua D.
N1 - Funding Information:
This work was supported by funding to J.D.R. from the US National Institutes of Health (NIH) (R01CA163591 and DP1DK113643), Stand Up to Cancer (SU2CAACR-DT-20-16), and Ludwig Cancer Research. L.Y. was supported by a postdoctoral fellowship from the New Jersey Commission on Cancer Research. W.L. was supported by NIH grant R50CA211437. J.Y.G. is supported by NIH grant R01CA237347-01A1, ACS grant 134036-RSG-19-165-01-TBG, Rutgers Busch Biomedical Grant, and the New Jersey Health Foundation. R.E. is a March of Dimes Chair in Molecular and Developmental Biology fellow at the Salk Institute and a Nomis Distinguished Scholar, and is supported by NIH (DK057978), the Lustgarten Foundation, the Don and Lorraine Freeberg Foundation, and a gift from the David C. Copley Foundation. L.Y. H.H. D.V.H and J.D.R. conceived the project and designed the experiments. L.Y. T.T. and S. Ng performed most experiments. L.W. S.D. performed MALDI imaging and data analysis. G.L. T.G.O. M.D. R.E. T.L. and J.Y.G. performed IHC staining and RNAseq analysis. X.Z. and L.W. performed acetate and ketone body measurements. A.C helped with data interpretation. M. M. helped with RNAseq data analysis. W.L. helped with LC-MS method development and data analysis. L.Y. performed statistical analysis. L.Y. M.N. and J.D.R. wrote the manuscript. All authors agreed to submit the manuscript, read and approved the final draft and take full responsibility of its content. J.D.R. is an adviser and stockholder in Kadmon Pharmaceuticals, Colorado Research Partners, L.E.A.F. Pharmaceuticals, Bantam Pharmaceuticals, Barer Institute, and Rafael Pharmaceuticals; a paid consultant of Pfizer; a founder, director, and stockholder of Farber Partners, Serien Therapeutics, and Sofro Pharmaceuticals; a founder and stockholder in Toran Therapeutics; inventor of patents and patent applications held by Princeton University, including a patent application related to ketogenic diet for cancer therapy.
Funding Information:
This work was supported by funding to J.D.R. from the US National Institutes of Health ( NIH ) ( R01CA163591 and DP1DK113643 ), Stand Up to Cancer ( SU2CAACR-DT-20-16 ), and Ludwig Cancer Research . L.Y. was supported by a postdoctoral fellowship from the New Jersey Commission on Cancer Research . W.L. was supported by NIH grant R50CA211437 . J.Y.G. is supported by NIH grant R01CA237347-01A1 , ACS grant 134036-RSG-19-165-01-TBG , Rutgers Busch Biomedical Grant, and the New Jersey Health Foundation . R.E. is a March of Dimes Chair in Molecular and Developmental Biology fellow at the Salk Institute and a Nomis Distinguished Scholar, and is supported by NIH ( DK057978), the Lustgarten Foundation, the Don and Lorraine Freeberg Foundation, and a gift from the David C. Copley Foundation.
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/2/11
Y1 - 2022/2/11
N2 - Background: Ketogenic diet is a potential means of augmenting cancer therapy. Here, we explore ketone body metabolism and its interplay with chemotherapy in pancreatic cancer. Methods: Metabolism and therapeutic responses of murine pancreatic cancer were studied using KPC primary tumors and tumor chunk allografts. Mice on standard high-carbohydrate diet or ketogenic diet were treated with cytotoxic chemotherapy (nab-paclitaxel, gemcitabine, cisplatin). Metabolic activity was monitored with metabolomics and isotope tracing, including 2H- and 13C-tracers, liquid chromatography-mass spectrometry, and imaging mass spectrometry. Findings: Ketone bodies are unidirectionally oxidized to make NADH. This stands in contrast to the carbohydrate-derived carboxylic acids lactate and pyruvate, which rapidly interconvert, buffering NADH/NAD. In murine pancreatic tumors, ketogenic diet decreases glucose's concentration and tricarboxylic acid cycle contribution, enhances 3-hydroxybutyrate's concentration and tricarboxylic acid contribution, and modestly elevates NADH, but does not impact tumor growth. In contrast, the combination of ketogenic diet and cytotoxic chemotherapy substantially raises tumor NADH and synergistically suppresses tumor growth, tripling the survival benefits of chemotherapy alone. Chemotherapy and ketogenic diet also synergize in immune-deficient mice, although long-term growth suppression was only observed in mice with an intact immune system. Conclusions: Ketogenic diet sensitizes murine pancreatic cancer tumors to cytotoxic chemotherapy. Based on these data, we have initiated a randomized clinical trial of chemotherapy with standard versus ketogenic diet for patients with metastatic pancreatic cancer (NCT04631445). Funding: NIH R01CA163591, R50CA211437, R01CA237347-01A1, R01DK057978; NJCCR; NJHF; SU2C-AACR-DT-20-16; ACS134036-RSG-19-165-01-TBG; Rutgers Busch Biomedical Grant; Freeberg Foundation; Copley Foundation; Ludwig Cancer Research.
AB - Background: Ketogenic diet is a potential means of augmenting cancer therapy. Here, we explore ketone body metabolism and its interplay with chemotherapy in pancreatic cancer. Methods: Metabolism and therapeutic responses of murine pancreatic cancer were studied using KPC primary tumors and tumor chunk allografts. Mice on standard high-carbohydrate diet or ketogenic diet were treated with cytotoxic chemotherapy (nab-paclitaxel, gemcitabine, cisplatin). Metabolic activity was monitored with metabolomics and isotope tracing, including 2H- and 13C-tracers, liquid chromatography-mass spectrometry, and imaging mass spectrometry. Findings: Ketone bodies are unidirectionally oxidized to make NADH. This stands in contrast to the carbohydrate-derived carboxylic acids lactate and pyruvate, which rapidly interconvert, buffering NADH/NAD. In murine pancreatic tumors, ketogenic diet decreases glucose's concentration and tricarboxylic acid cycle contribution, enhances 3-hydroxybutyrate's concentration and tricarboxylic acid contribution, and modestly elevates NADH, but does not impact tumor growth. In contrast, the combination of ketogenic diet and cytotoxic chemotherapy substantially raises tumor NADH and synergistically suppresses tumor growth, tripling the survival benefits of chemotherapy alone. Chemotherapy and ketogenic diet also synergize in immune-deficient mice, although long-term growth suppression was only observed in mice with an intact immune system. Conclusions: Ketogenic diet sensitizes murine pancreatic cancer tumors to cytotoxic chemotherapy. Based on these data, we have initiated a randomized clinical trial of chemotherapy with standard versus ketogenic diet for patients with metastatic pancreatic cancer (NCT04631445). Funding: NIH R01CA163591, R50CA211437, R01CA237347-01A1, R01DK057978; NJCCR; NJHF; SU2C-AACR-DT-20-16; ACS134036-RSG-19-165-01-TBG; Rutgers Busch Biomedical Grant; Freeberg Foundation; Copley Foundation; Ludwig Cancer Research.
KW - NADH/NAD
KW - Pre-clinical research
KW - chemotherapy
KW - ketogenic diet
KW - ketone metabolism
KW - pancreatic cancer
KW - reactive oxygen species
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U2 - 10.1016/j.medj.2021.12.008
DO - 10.1016/j.medj.2021.12.008
M3 - Article
C2 - 35425930
AN - SCOPUS:85124214778
SN - 2666-6359
VL - 3
SP - 119-136.e8
JO - Med
JF - Med
IS - 2
ER -