Prostate cancer is the leading cancer diagnosis for men in the United States and the second leading cause of cancer-related deaths. There is increasing evidence that diet is a modifiable risk factor in prostate cancer. Recent studies have explored various dietary approaches, including ultralow-carbohydrate diets, weight loss diets, supplementation with omega-3 fatty acids, pro- and anti-inflammatory diets, fasting, and even tea drinking, to determine their potential impact on prostate cancer risk or progression. This article examines the relationship between the ketogenic diet and prostate cancer, exploring the potential benefits and risks based on current research.
What is the Ketogenic Diet?
The ketogenic diet is a high-fat, low-carbohydrate diet that forces the body into a metabolic state called ketosis. Normally, the body breaks down carbohydrates into glucose to fuel cells. When carbohydrate intake is very low, the body begins to break down fat into ketones, which are then used as an alternative energy source. This metabolic shift has been explored for various health benefits, including weight loss and managing certain medical conditions like epilepsy.
Rationale for Investigating Keto Diets and Prostate Cancer
One hypothesis for the discrepancy in prostate cancer incidence between Western countries and countries like China and Japan is differences in dietary intake. Previous research has shown that the ketogenic diet may slow tumor growth, since the lack of glucose causes cancer cells to be deprived of energy.
Ketones and Immunotherapy
Xin Lu, the John M. and Mary Jo Boler Collegiate Associate Professor in the Department of Biological Sciences, and collaborators recently tackled a problem oncologists have battled: Prostate cancer is resistant to a type of immunotherapy called immune checkpoint blockade (ICB) therapy. Previous observations have shown that ketogenic diets can produce the ketone body beta-hydroxybutyrate, which has properties similar to histone deacetylase inhibitors. Histone deacetylase inhibitors are known to enhance the immunogenicity of cancer cells and improve the effectiveness of immune checkpoint blockade therapy.
Evidence from Preclinical Studies
Mouse Model Studies
Previous studies indicate that carbohydrate intake influences prostate cancer biology, as mice fed a no-carbohydrate ketogenic diet (NCKD) had significantly smaller xenograft tumors and longer survival than mice fed a Western diet.
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To determine whether diets containing 10% or 20% carbohydrate kcal showed similar tumor growth as NCKD, a total of 150 male severe combined immunodeficient mice were fed a Western diet ad libitum, injected with the human prostate cancer cell line LAPC-4, and then randomized 2 weeks later to one of three arms: NCKD, 10% carbohydrate, or 20% carbohydrate diets. Ten mice not injected were fed an ad libitum low-fat diet (12% fat kcal) serving as the reference in a modified-paired feeding protocol. Mice were sacrificed when tumors reached 1,000 mm3.
Despite consuming extra calories, all mice receiving low-carbohydrate diets were significantly lighter than those receiving a low-fat diet (P < 0.04). Among the low-carbohydrate arms, NCKD-fed mice were significantly lighter than the 10% or 20% carbohydrate groups (P < 0.05). Tumors were significantly larger in the 10% carbohydrate group on days 52 and 59 (P < 0.05), but at no other point during the study. Diet did not affect survival (P = 0.34). There were no differences in serum insulin-like growth factor-I or insulin-like growth factor binding protein-3 at sacrifice among the low-carbohydrate arms (P = 0.07 and P = 0.55, respectively). Insulin was significantly lower in the 20% carbohydrate arm (P = 0.03).
Impact on Tumor Growth and Survival:
The study revealed that mice consuming a low-carbohydrate diet (10-20% kcal carbohydrates) had similar tumor growth and overall survival to mice consuming NCKD. This finding is further supported by similar expression levels of PSA in all three groups.
Metabolic Effects:
Consistent with previous xenograft studies, NCKD-consuming mice ate ~10% more calories than the low-fat reference group but weighed less. The percentage of extra calories needed to maintain similar body weights across the low-carbohydrate arms decreased as the carbohydrate content in the diets increased. All three diets also lowered serum glucose levels and increased urinary ketone production by the time of sacrifice compared with levels before randomization.
Impact on IGF Axis:
Levels of IGF-I and the IGF-I:IGFBP-3 ratio trended to be higher in mice fed with the 20% carbohydrate diet. Insulin levels were significantly lower in the 20% carbohydrate group compared with all other groups (P = 0.03).
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Enhancing Immunotherapy
Lu's study explored the potential of dietary interventions - specifically a cyclic ketogenic diet regimen and a pre-ketone supplement - to enhance the efficacy of immune checkpoint blockade therapy in prostate cancer. Prostate cancer is notably resistant to immune checkpoint blockade due to its immunosuppressive tumor microenvironment and low immunogenicity.
Lu found that both a cyclic ketogenic diet and a pre-ketone supplement called 1,3-butanediol, which generates beta-hydroxybutyrate, significantly delayed tumor growth and enhanced the efficacy of immune checkpoint blockade therapy in immune checkpoint blockade-resistant prostate cancer models. The cyclic ketogenic diet and pre-ketone supplementation increased the expression of major histocompatibility class I molecules on cancer cells - making them more detectable to the immune system - and modulated the TIME to favor antitumor immunity.
The effectiveness of a cyclic ketogenic diet and pre-ketone supplementation can be attributed to the dual action of beta-hydroxybutyrate (BHB). BHB acts as an endogenous histone deacetylase inhibitor, enhancing the presentation of tumor antigens on cancer cells and making them more recognizable to immune cells.
Concerns and Conflicting Evidence
While some studies suggest potential benefits, other research raises concerns about the ketogenic diet and cancer. A study by researchers at the Herbert Irving Comprehensive Cancer Center (HICCC) found that in a mouse model of breast cancer, mice fed with a ketogenic diet experienced significantly more lung metastases compared to those on a control diet.
The researchers observed a noticeable reduction in primary tumor growth in the ketogenic group compared to the control group. However, they also saw that the ketogenic diet promoted tumor metastasis. The ketogenic diet-induced metastasis is dependent on a protein called BACH1, which has been linked to enhanced metastatic potential in breast and lung cancers.
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The findings from Gu’s laboratory provide some the first insights about the effects of diet, in this case a ketogenic diet and cancer metastasis.
Clinical Trials and Human Studies
Stephen J. Freedland, MD, of Cedars-Sinai Medical Center in Los Angeles, California, and director of its Center for Integrated Research in Cancer and Lifestyle, said, “There is an increasing body of literature that says your diet matters. At the same time, there are a lot of things that could explain these associations. People who can afford lots of plant-based foods tend to have higher socioeconomic status, for example.”
What’s needed, Freedland said, are more randomized trials to test the hypotheses emerging from the longitudinal cohort studies.
Nutritionist Pao-Hwa Lin, PhD, of Duke University in Durham, North Carolina, has been working for several years with Freedland on trials of nutrition interventions. In 2020, Freedland and Lin published results from a pilot study of 57 men who had been treated with surgery or radiation for localized prostate cancer but had a PSA recurrence and were randomized to an ultralow-carbohydrate diet or no restrictions for 6 months. The investigators saw that PSA doubling times, an intermediate measure of tumor growth rate, were slower among those consuming the low-carb diet.
Currently they are wrapping up a trial that randomizes men who have been scheduled for radical prostatectomy to daily supplementation with walnuts, a natural source of polyphenols and omega-3 acids. This time, the aim is to determine whether gene expression in tumors changes in response to supplementation.
The researchers are also recruiting for a study in men being treated for metastatic prostate cancer. This study randomizes patients to a fasting-mimicking diet, which is a type of intermittent fasting, or no dietary restrictions for 6 months.
Longo, who is consulting on Lin and Freedland’s trial, “has proven that the diet is helpful in treatment outcomes for breast cancer. So we connected and decided to test it and see if it’s helpful in prostate cancer as well.”
Considerations for Dietary Recommendations
Freeland pointed out and explained why most clinicians don’t make dietary recommendations to their newly diagnosed patients.
“A new prostate cancer patient already gets easily an hour discussion of treatment options, of pros and cons. Patients often become overwhelmed. And then to extend it further to talk about diet, they’ll end up even more overwhelmed.” Moreover, he said, current evidence offers doctors few take-home messages to deliver besides avoiding sugar and processed foods.
Future Research Directions
Lu noted that several unanswered questions and challenges remain, including the precise molecular mechanisms through which BHB reprograms immune cell metabolism and function. Further research is needed to determine the optimal dosing and regimen of pre-ketone supplements for humans.
The next steps in Lu's group involve further preclinical studies to refine the combination therapy and explore its effects on other cancer types. She hopes her study will attract interest from the medical community to initiate clinical trials that test the safety and efficacy of the pre-ketone supplement combined with immune checkpoint blockade therapy for patients with advanced prostate cancer.
Lin hopes that she and Freedland will one day be able to test a diet that is both lower carb and anti-inflammatory in men with prostate cancer.