Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and extremely therapy-resistant cancer. It is estimated that up to 80% of PDAC patients present with cachexia, a multifactorial disorder characterized by the involuntary and ongoing wasting of skeletal muscle that affects therapeutic response and survival. During the last decade, there has been an increased interest in exploring dietary interventions to complement the treatment of PDAC and associated cachexia. Ketogenic diets (KDs) have gained attention for their anti-tumor potential. Characterized by a very low carbohydrate, moderate protein, and high fat composition, this diet mimics the metabolic changes that occur in fasting. Numerous studies report that a KD reduces tumor growth and can act as an adjuvant therapy in various cancers, including pancreatic cancer. However, research on the effect and mechanisms of action of KDs on PDAC-associated cachexia is limited. In this narrative review, we summarize the evidence of the impact of KDs in PDAC treatment and cachexia mitigation. Furthermore, we discuss key cellular mechanisms that explain KDs’ potential anti-tumor and anti-cachexia effects, focusing primarily on reprogramming of cell metabolism, epigenome, and the gut microbiome. Finally, we provide a perspective on future research needed to advance KDs into clinical use.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and deadly disease with a five-year survival rate of ~10% [1]
80% of PDAC patients suffer from cachexia, a complex metabolic disorder characterized by loss of skeletal muscle mass (SKM)
Shukla et al showed that mice fed a Ketogenic diets (KDs) exhibited less tumor burden along with reduced proliferation of tumor cells when compared to a chow diet [65]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and deadly disease with a five-year survival rate of ~10% [1]. 80% of PDAC patients suffer from cachexia, a complex metabolic disorder characterized by loss of skeletal muscle mass (SKM). There are no effective strategies to mitigate PDAC-induced cachexia For this reason, new treatment strategies for PDAC and PDAC-associated cachexia are needed, and the exploration of dietary interventions is a critical component. Numerous animal studies have tested the effects of KDs on tumor growth and survival, including pancreatic cancer (PC), with the majority showing promising results [4]. Evidence on the effect and mechanisms of action of KDs on PDAC-associated cachexia is sparse. In this review article, we discuss the potential beneficial role of KDs as a complimentary dietary therapy for PDAC treatment and associated-cachexia, and summarize the cellular mechanisms modulated by a KD
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