Killing Cancer with Keto: An Investigation about the Efficacy of a Ketogenic Diet to Treat and Prevent Castration Resistant Prostate Cancer and Clear Cell Renal Cell Carcinoma

Cancer research has made great strides over recent decades. However, not every cancer patient has benefited from these recent advancements. This is due to several reasons. In terms of Castration Resistant Prostate Cancer (CRPC) it is resistant to immune checkpoint blockade (ICB) antibodies for Programmed Death 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4). One mechanism by which this occurs is by means of downregulating Major Histocompatibility Complex 1 (MHC-I). MHC-I is responsible for presenting cell, and therefore cancer cell, antigen to T-Cells which initiates the immunological synapse and therefore killing the cancer cell. Herein, we show that CRPC is sensitized to ICB with the naturally occurring metabolite Beta-Hydroxybutyrate (BHB) by means of a cyclical ketogenic diet (CKD) through inhibiting histone deacetylation and therefore upregulating MHC-I. The same phenotype was observed with a BHB supplemented diet (BD) implying that BHB is the causal factor and not a lack of carbohydrates. Furthermore, the rare genetic disease Von Hippel Lindau (VHL) has no long-term effective treatment with little side effects. VHL is characterized with an inactive VHL protein which increases the presence of Hypoxia Induced Factor 2 alpha (HIF2a). VHL causes tumors to arise in patients throughout the nervous system but also the kidney resulting in Clear Cell Renal Cell Carcinoma (ccRCC). We also observed that a cyclical ketogenic diet (CKD) and a BD were able to inhibit the growth of human ccRCC as an intervention therapy but more surprising was that a prophylactic CKD regiment was able to prevent ccRCC from growing. This was associated with a significant decrease of HIF2a and an increase in ferroptosis markers such as 4-hydroxynonenal (4-HN). Overall, these findings show that it is possible for a ketogenic diet and its main metabolite to treat and prevent previously cancers with no currently effective treatment.