What a person eats, and when a person eats, could offer important augmentation to cancer therapy, and three speakers during an American Association for Cancer Research Symposium discussed preclinical studies and trials trying to connect metabolism and tumors.
Tumor-associated mutations in CRY2
Katja A. Lamia, PhD, Scripps Research Institute, discussed her lab’s work trying to understand molecular connections between circadian clocks and cancer. Studies indicate that disruption of circadian rhythms enhances cancer risk, but researchers are in the very early stages of deciphering the underlying mechanisms that could lead to novel therapeutic approaches.
Lamia noted that many labs in the past decade have established molecular connections between circadian clock proteins and cancer-relevant pathways, with the discovery of some small-molecule chemical modulators of different circadian clock proteins, including cryptochrome circadian regulator 1 (CRY1) and cryptochrome circadian regulator 2 (CRY2). Lamia’s lab has focused on the CRY proteins because they evolve from UV light-activated DNA repair enzymes.
A pair of missense mutations of CRY, S532L and D347H, have a big impact on cell growth but seem to have different impacts on the molecular functions, Lamia said.
“When we used gene set enrichment analysis, we found that there was a striking suppression of P53 target genes in the cells that are expressing either one of these CRY2 missense mutations,” Lamia said. “Clearly, this has the potential to have a big impact on cell growth. We don’t know the mechanisms by which these mutations seem to suppress P53.”
An erratic lifestyle can disrupt circadian rhythms and lead to many chronic diseases, including an increased risk of cancer. A key component of that is eating without any regard to the time of day or night. Satchidananda Panda, PhD, Salk Institute for Biological Studies, said that time-restricted feeding (TRF) is a way that circadian rhythms could protect, and in some cases possibly reverse, disease risk.
In mouse models where one group had ad libitum access to food and the other group had TRF in a window of no more than 10 hours, the TRF group, which had the same caloric intake and quality as the other group, were better protected from obesity, diabetes, and metabolic disease. Panda also noted that the TRF group was completely protected from fatty liver disease, with significantly healthier mitochondria in the liver of the mice, while the ad libitum group showed mitochondria disruption.
Panda also discussed unpublished study results that show that some TRF effects are sex-specific. TRF protects male mice from weight gain and decreases adipose tissue, but it was not the same for female mice. But both the male and female mice saw prevention of excessive fat deposits in the liver in addition to improvements in fasting insulin, glucose tolerance, and lipopolysaccharide-induced mortality.
“This is something to keep in mind when doing some of the time-restraining experiments in humans to test whether the change in weight loss is disproportionately less than the metabolic benefits that we expect from the human studies,” Panda said. “In fact, some of the human studies have reported that the extent of metabolic benefits under TRF is much more than what you expect from weight loss.”
Benefits from ketogenic diet
Joshua D. Rabinowitz, MD, PhD, Lewis-Sigler Institute & Department of Chemistry, Princeton University, talked about his ongoing work considering whether a ketogenic diet can slow tumor growth.
Tumors use the tricarboxylic acid (TCA) cycle and also depend on their mitochondria, but they rely on it less than normal tissues, Rabinowitz said. In normal tissues, ATP production from carbohydrate is decoupled from glucose catabolism. Rabinowitz said that when cells need to proliferate, they turn on the ability to uptake glucose, but when they don’t need to proliferate, they don’t always consume glucose.
Tumors may require glycolytic ATP, Rabinowitz said, which may offer an explanation why eating a ketogenic diet low in carbohydrates and high in fats could impede tumor growth. A ketogenic diet also suppresses insulin, which suppresses PI3K signaling, a major ontogenetic pathway. The ketogenic diet also induces ketone bodies in the bloodstream, and Rabinowitz and colleagues are interested in the possibility that those ketone bodies could have anticancer properties.
In a mouse model for pancreatic cancer, Rabinowitz noted, a ketogenic diet alone didn’t impact tumor growth.
“However, study did show that if we augment the stress on the tumors by giving them chemotherapy—the triple chemo of abraxane, gemcitabine and cisplatin—combined with a keto diet, tumor growth substantially shrinks, survival benefit about doubles in terms of median survival benefit than the chemotherapy alone, and perhaps more importantly than that, there is an increase in long-term survival,” Rabinowitz said.
That’s led to a human randomized trial (NCT04631445) with patients receiving triple chemotherapy to study whether a ketogenic diet can help pancreatic cancer patients. Enrollment in the trial is open now, Rabinowitz said.