New evidence in mice suggests that a fasting-mimicking diet, combined with the drugs bortezomib and rituximab, could be an effective approach for treating chronic lymphocytic leukemia (CLL). The findings, based on preclinical models and two CLL patients, suggest that targeting “starvation escape pathways” could be a strategy warranting further investigation.
The fasting-mimicking diet (FMD) is a plant-based diet low in calories and protein. It consists of adhering to a low-calorie diet on day one (maximum of 600 Kcal) and an ultra-low-calorie diet (maximum of 300 Kcal) on days two through five. This pattern is repeated every three to four weeks in cycles.
Previous research suggests that following this diet is safe and may lead to improved metabolic and tumor responses in cancer patients. A small clinical trial from 2022 in Italy demonstrated long-lasting tumor remissions with standard anticancer therapies alongside cyclic FMD. Among the patients analyzed, five individuals with advanced solid tumors experienced complete and long-lasting tumor responses.
The new study, published in the journal Cancer Research on January 19th, looked at the effects of fasting and fasting-mimicking diet cycles in animal models of CLL. CLL is a blood cancer in which the bone marrow produces too many lymphocytes, a type of white blood cell. It is the most common type of leukemia in adults.
This work in mice “shows that when leukemia tumors are challenged with the fasting-mimicking diet, they become more dependent on the activity of the proteasome, which degrades damaged proteins,” Valter D. Longo, Ph.D., professor of gerontology and biological science at the University of Southern California (USC) and director of the USC Longevity Institute, wrote in an email interview with MHE.
In the new study, fasting-mimicking conditions in mouse CLL models had mild cytotoxic effects. This triggered the activation of apoptosis, also known as programmed cell death. Additionally, in CLL cells, the fasting conditions promoted an increase in proteasome activity that served as a starvation escape pathway. This shows that CLL cells attempt to activate the proteasome in order to avoid starvation.
Bortezomib (brand name: Velcade) is approved for treating mantle cell lymphoma and multiple myeloma in certain situations. Bortezomib works by blocking proteasomes, which are responsible for breaking down proteins. This causes a buildup of unwanted proteins in cells, leading to cell death. Researchers are also studying the use of bortezomib for treating other types of cancer.
To enhance the apoptosis-promoting effects of fasting conditions, the researchers combined the fasting-mimicking diet with bortezomib, a proteasome inhibitor, and rituximab, an anti-CD20 antibody. Pharmacological blockage of this escape pathway with bortezomib resulted in a strong enhancement of the pro-apoptotic effects of starvation conditions. This combination therapy delayed CLL progression and significantly prolonged mouse survival in CLL models.
The results suggest that targeting starvation escape pathways, such as the proteasome activity, could be an effective treatment strategy for CLL. The findings highlight the potential of combining FMD cycles with bortezomib and rituximab in future clinical trials for CLL. More research in humans is needed to evaluate the effectiveness of this combination therapy in clinical trials.
“We show that proteasome inhibitors synergize with FMD in killing cancer cells,” Longo stated.
“In the paper, we also show initial preliminary evidence for the ability of FMD cycles to delay the progression of CLL in a few human cases in the absence of drugs (only FMD), setting the stage for a new trial to combine proteasome inhibiting drugs and FMD cycles in human trials,” Longo said.