Jyrsijätutkimus. Tämän tutkimuksen lupaavien tulosten perusteella on käynnistetty RCT metastoivaa haimayöpää sairastavilla potilailla.https://www.cell.com/med/fulltext/S2666-6340(21
CLINICAL AND TRANSLATIONAL ARTICLE| VOLUME 3, ISSUE 2, P119-136.E8, FEBRUARY 11, 2022
Ketogenic diet and chemotherapy combine to disrupt pancreatic cancer metabolism and growth
Jessie Yanxiang Guo
Joshua D. Rabinowitz 12
•Ketogenic diet synergizes with classical chemotherapy to treat murine pancreas cancer
•In response to ketosis, tumors suppress glucose use and induce 3-hydroxybutyrate use
•Therapeutic benefit correlates with elevated tumor NADH/NAD ratio
•Survival gain from chemotherapy is roughly tripled in the ketogenic diet condition
Context and significance
Pancreatic ductal adenocarcinoma is one of most deadly cancers. Despite improvements in chemotherapy, survival remains terribly short. Dietary manipulation is an understudied strategy to improve cancer therapy. Ketogenic diet involves eating mainly fat with almost no carbohydrates. Using a mouse cancer model, we show that ketogenic diet changes pancreatic cancer metabolism and its response to chemotherapy, decreasing insulin and glucose use while increasing use of 3-hydroxybutyrate (a ketone body) and causing redox stress in cancer cells. This diet-driven change results in increased tumor sensitivity to chemotherapy, with ketogenic diet roughly tripling the survival benefits of chemotherapy alone. A randomized clinical trial testing whether these benefits translate to patients with metastatic pancreatic cancer is open and currently enrolling patients.
Ketogenic diet is a potential means of augmenting cancer therapy. Here, we explore ketone body metabolism and its interplay with chemotherapy in pancreatic cancer.
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.
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.
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).