Continued Assessment of the Fasting Mimicking Diet as an Adjuvant Cancer Therapy
The fasting mimicking diet resulted from efforts to understand how nutrient sensing systems in cells respond to a lower calorie intake. The question of interest was this: at what level of calorie intake do the benefits of fasting start to emerge, and at what level of calorie intake are most of the benefits present? Does one actually have to reduce calorie intake to zero to obtain all of the benefits? As it turns out, no. Low calorie intake, on the order of 600-750 calories per day, is almost as good as fasting when sustained for week or so.
On the basis of these results, a specific fasting mimicking medical diet was then commercialized and put through the FDA process as an adjuvant treatment for cancer patients, where it continues to show benefits in human trials. This is the usual consequence of the excessive costs of medical regulation, in that the only way for a cheap therapy to be used is to first turn it into a patented, expensive therapy, but it served to bring funding into a part of the field that usually lacks the incentives to attract investment. For the rest of us, it is easy enough to use the fasting mimicking approach to improve health and metabolism without the expensive, regulated diet. It is simply a set of targets for calorie and micronutrient intake over a period of time, and leads to sustained improvements in measures of metabolism.
Fasting mimicking diets (FMDs) have the potential to enhance the efficacy of a wide variety of cancer treatments, weakening cancer cells by a process we termed differential stress sensitization (DSS) while strengthening normal cells by a response termed differential stress resistance (DSR). The effects of fasting/FMD in inducing DSS in both in vitro and in vivo models were previously shown to be mediated, in part, by the reduction of circulating IGF-1 and glucose levels. In a mouse leukemia model, fasting alone reversed the progression of both B cell and T cell acute lymphoblastic leukemia (ALL) but did not affect acute myeloid leukemia (AML).
Here we show that cycles of FMD induce significant anti-leukemia efficacy and cancer-free survival when combined with vincristine, in part by activating T-cell-dependent anti-cancer effects. Fasting/FMD alone causes a trend for increasing autophagy, but when fasting/FMD is combined with vincristine, a significant and consistent downregulation of autophagy markers is observed. This role of autophagy in the FMD/VC-dependent toxicity to ALL cells is confirmed by the effect of the combination of vincristine with the autophagy inhibitor chloroquine, which also promotes p53 modulation, apoptosis, and cancer-free survival in agreement with the established role of p53 in mediating cell death in AML and in solid malignancies.
Fasting/FMD and other dietary restrictions have also been tested clinically in a number of clinical trials. In a prospective, nonrandomized, controlled trial of 40 patients, the potential benefits of caloric restriction were shown (The Improving Diet and Exercise in ALL (IDEAL)) in the efficacy of chemotherapy in patients newly diagnosed with B-ALL. This intervention resulted in a low minimal residual disease risk, high-circulating adiponectin and low insulin resistance. In a randomized controlled study of 131 patients with HER2-negative early-stage breast cancer, FMD cycles significantly enhanced the effects of neoadjuvant chemotherapy on the radiological and pathological tumor response. A short-term fasting-mimicking diet was also well tolerated during chemotherapy in patients with ovarian cancers and appeared to improve quality of life and fatigue. In conclusion, FMD cycles have high potential to be effective in increasing the toxicity of a range of therapies against ALL and other blood cancers and should be tested in randomized clinical trials, especially in combination with immunotherapy and low toxicity cancer therapies.
In summary, we present a new strategy for improving leukemia treatment by combining FMD with chemotherapy to promote the killing of ALL cells in part by an immune-dependent mechanism. Fasting/FMD has been shown to reduce chemotherapy-associated toxicity in pre-clinical and clinical studies and thus represents a safe and potentially effective treatment adjunct for leukemia patients which should be tested clinically.