Ketogenic diet and chemotherapy combine to disrupt pancreatic cancer metabolism and growth

Lifeng Yang; Tara TeSlaa; Serina Ng; Michel Nofal; Lin Wang; Taijin Lan; Xianfeng Zeng; Alexis Cowan; Matthew McBride; Wenyun Lu; Shawn Davidson; Gaoyang Liang; Tae Gyu Oh; Michael Downes; Ronald Evans; Daniel Von Hoff; Jessie Yanxiang Guo; Haiyong Han; Joshua D. Rabinowitz

doi:10.1016/j.medj.2021.12.008

Ketogenic diet and chemotherapy combine to disrupt pancreatic cancer metabolism and growth

Lifeng Yang, Tara TeSlaa, Serina Ng, Michel Nofal, Lin Wang, Taijin Lan, Xianfeng Zeng, Alexis Cowan, Matthew McBride, Wenyun Lu, Shawn Davidson, Gaoyang Liang, Tae Gyu Oh, Michael Downes, Ronald Evans, Daniel Von Hoff, Jessie Yanxiang Guo, Haiyong Han, Joshua D. Rabinowitz^*

^*Corresponding author for this work

Medicine, Pulmonary Division

Research output: Contribution to journal › Article › peer-review

61 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	119-136.e8
Journal	Med
Volume	3
Issue number	2
DOIs	https://doi.org/10.1016/j.medj.2021.12.008
State	Published - Feb 11 2022

Funding

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. 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.

Keywords

NADH/NAD
Pre-clinical research
chemotherapy
ketogenic diet
ketone metabolism
pancreatic cancer
reactive oxygen species

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.medj.2021.12.008

Cite this

Yang, L., TeSlaa, T., Ng, S., Nofal, M., Wang, L., Lan, T., Zeng, X., Cowan, A., McBride, M., Lu, W., Davidson, S., Liang, G., Oh, T. G., Downes, M., Evans, R., Von Hoff, D., Guo, J. Y., Han, H., & Rabinowitz, J. D. (2022). Ketogenic diet and chemotherapy combine to disrupt pancreatic cancer metabolism and growth. Med, 3(2), 119-136.e8. https://doi.org/10.1016/j.medj.2021.12.008

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abstract = "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.",

keywords = "NADH/NAD, Pre-clinical research, chemotherapy, ketogenic diet, ketone metabolism, pancreatic cancer, reactive oxygen species",

author = "Lifeng Yang and Tara TeSlaa and Serina Ng and Michel Nofal and Lin Wang and Taijin Lan and Xianfeng Zeng and Alexis Cowan and Matthew McBride and Wenyun Lu and Shawn Davidson and Gaoyang Liang and Oh, {Tae Gyu} and Michael Downes and Ronald Evans and {Von Hoff}, Daniel and Guo, {Jessie Yanxiang} and Haiyong Han and Rabinowitz, {Joshua D.}",

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doi = "10.1016/j.medj.2021.12.008",

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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.

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

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KW - ketone metabolism

KW - pancreatic cancer

KW - reactive oxygen species

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Ketogenic diet and chemotherapy combine to disrupt pancreatic cancer metabolism and growth

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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