Complementary Strategies for Prostate Cancer Prevention and Management
Division of Cancer PreventionProstate cancer is the most common cancer diagnosis and the second deadliest cancer among men in the United States. Additionally, men living in Western countries are six times more likely to be diagnosed with prostate cancer compared to the rest of the world. This discrepancy has been in part attributed to differences in dietary intake as men in developing countries, who adopt a Western diet, experience a greater incidence of prostate cancer. It is unclear, however, whether the increased risk associated with a Western diet is due to a greater intake of fat, carbohydrates, or total calories.
With NCI funding*, Stephen J. Freedland, M.D., Associate Professor of Surgery and Pathology in the Department of Surgery at Duke University School of Medicine, has been studying the impact of both carbohydrate and fat intake on prostate cancer biology with the goal of developing novel, non-toxic complementary treatments, including dietary modification and phytopharmaceuticals (plant-based drugs), aimed at slowing prostate cancer progression. Dr. Freedland and colleagues had previously shown that mice fed a no-carbohydrate ketogenic diet (NCKD: 84% fat–0% carbohydrate–16% protein) demonstrated significantly reduced prostate tumor growth (~30%) and prolonged survival compared to mice fed a Western diet**.
“Mice consuming NCKD also had a decrease in signaling of the insulin-like growth factor (IGF) pathway, which is known to be involved in prostate cancer progress and this was confirmed in follow up studies,” said Dr. Freedland. “The problem is that a zero carbohydrate diet is not feasible for humans. So the question was: how low is low? Would a low-carbohydrate diet, similar to that of the Atkins diet, provide the same protective benefits as NCKD?”
The first set of studies demonstrates that mice consuming less restrictive low-carbohydrate diets (10% to 20% kcal carbohydrates) have similar tumor growth, overall survival, and IGF signaling as mice fed NCKD***. “The results of these data are now being tested in clinical studies and approximately 30 men are already enrolled****,” said Dr. Freedland. “A second study, funded by NCI*****, is set to open early next year.”
The challenge is that a behavioral change such as diet is notoriously difficult to implement in both healthy individuals and sick patients, regardless of the diet being tested. Men on a Western diet typically consume 30-40% of their total caloric intake from fat and epidemiological and experimental data suggest consuming higher levels of dietary fat may negatively impact prostate cancer progression. It remains unknown, however, whether total fat or the cholesterol found in fat sources is associated with disease progression, as excess dietary fat is linked to high-serum cholesterol levels.
In a separate study, Dr. Freedland and colleagues searched for natural dietary interventions, including resveratrol and pomegranate that could be added to a Western diet to slow tumor growth; however, it was found that neither of these interventions had an impact. What they did find was that blocking cholesterol uptake with a cholesterol-lowering drug proved effective in slowing the growth of aggressive tumors.
In two independent studies, Dr. Freedland and colleagues demonstrated that daily treatment with the cholesterol-uptake inhibitor ezetimibe (Zetia®) delayed the rapid development of prostate cancer in animal models that mimic aggressive disease in humans. Although ezetimibe appeared to slow the growth of aggressive prostate tumors, this intervention did not impact slow-growing tumors.
NCI Division of Cancer Prevention Program Director Young Kim, Ph.D., commented, “When these mice are fed a high-fat diet that is linked to high-serum cholesterol levels (a typical Western diet), blocking cholesterol uptake significantly reduces the size of the prostate cancer. Dr. Freedland’s group is providing new insight into the use of cholesterol-lowering agents as prevention for aggressive prostate cancer.”
* Grant number: 5R01CA131235-05
** Freedland, S.J., Mavropoulos, J., Wang, A., Darshan, M., Demark-Wahnefried, W., Aronson, W.J., … Issacs, W.B. (2008). Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis. Prostate, 1(68), 11-19.
** Mavropoulos, J.C., Buschemeyer, W.C. 3rd, Tewari, A.K., Rokhfeld, D., Pollak, M., Zhao, Y., … Freedland, S.J. (2009). The effects of varying dietary carbohydrate and fat content on survival in a murine LNCaP prostate cancer xenograft model. Cancer Prevention Research, 2(6), 557-565.
*** Masko, E.M., Thomas, J.A. 2nd, Antonelli, J.A., Lloyd, J.C. Phillips, T.E., Poulton, S.H., … Freedland, S.J. (2010). Low-carbohydrate diets and prostate cancer: how low is “low enough?”. Cancer Prevention Research, 3(9), 1124-1131.
**** Clinicaltrials.gov identifier: NCT00932672
***** Grant number: 1K24CA160653-01