Considering the bigger picture in the treatment of cancer: new findings from the team taking on our Cachexia challenge

Cachexia is a complex wasting syndrome characterised by severe weight loss from skeletal muscle and fatty tissue that can’t be reversed by nutritional therapy. Up to 80% of people with advanced cancer develop cachexia and it’s also associated with other chronic illnesses, but the underlying causative mechanisms are not fully understood.

The CANCAN team, taking on our Cachexia challenge, hypothesise that cachexia is a tumour-driven metabolic imbalance. Guided by this hypothesis, the team aims to expand the mechanistic understanding of cachexia and build a platform to develop therapeutic approaches that could reverse cachexia, with the hope of improving quality of life and, ultimately, survival for people with cancer.

Following a recent review article from the team on cancer cachexia in Cell, the team has now published its first research paper since the start of their programme in June 2022. In the new study, the team explored the effects of a ketogenic diet in mouse models of cancer cachexia.

A ketogenic diet (containing high-fat, moderate-protein and low-carbohydrate levels) can encourage cells to enter a state of ketogenesis, meaning they metabolise fat into ketone bodies to use as an energy source. Some studies are exploring whether a ketogenic diet can be used to target cancer cells’ dependency on glucose; however, the current understanding of this approach is still in its early stages, and clinical studies have not yet demonstrated significant benefits.

“A particular concern arises in cancers associated with inflammation and elevations of the inflammatory molecule interleukin (IL)-6, which is common in pancreatic, lung and colorectal cancers. In these cases, the body's ability to utilise a ketogenic diet appears to be diminished,” says Professor Tobias Janowitz of Cold Spring Harbor Laboratory, US, co-team lead of CANCAN and lead author of the study.

“Given that our research focuses on cachexia, we wondered whether the potential anti-tumour effects of a ketogenic diet might be overshadowed by the strain it puts on the body.”

To investigate this, the team utilised two IL-6-associated mouse models of cancer cachexia – one of pancreatic cancer and one of colorectal cancer – and fed the mice either with a ketogenic diet or with normal feed.

“The first and most striking finding was that the mice fed a ketogenic diet had smaller tumours – tumour growth slowed down – but they experienced cachexia sooner."

Dr Miriam Ferrer, postdoctoral researcher in Tobias’ group at Cold Spring Harbor Laboratory, who conducted the research.

Despite the anti-tumour effects of the ketogenic diet in mice, the accelerated onset of cachexia resulted in shorter overall survival.

Looking mechanistically into this uncoupling of tumour growth from overall survival, the team found the differing effects were the result of the biochemical interaction of two simultaneously occurring pathways that both depend on the same cofactor molecule – NADPH.

As the cancer cells broke down the lipids from the ketogenic diet, it caused a build-up of toxic lipid by-products. Under normal circumstances, detoxification of these lipid by-products requires the NADPH-dependent glutathione system, but the elevated levels of lipids from the ketogenic diet saturated the pathway. This resulted in oxidative damage and, ultimately, ferroptosis (a type of iron-dependent cell death) in the cancer cells.

But in the rest of the body, the depleted NADPH levels were having a detrimental impact.

“The overactivation of the pathway needed to detoxify the higher amount of lipids was causing cell death in the tumour cells, whereas systemically in the rest of the body, it was causing the depletion of NADPH that was impairing corticosterone synthesis,” says Miriam.

Corticosterone (the equivalent to cortisol in humans) is a steroid hormone associated with stress and the regulation of metabolism under stressful conditions, and its synthesis in the adrenal glands depends on NADPH.

With NADPH levels depleted on the ketogenic diet, mice were unable to produce sufficient corticosterone to adapt their metabolism. Ultimately, this resulted in the accelerated onset of cachexia.

“Our study emphasises the importance of considering the overall effects of an intervention on the entire body, rather than solely focusing on tumour growth,” 

Dr Tobias Janowitz, co-team lead of CANCAN

Importantly, the team were able to reverse the cachexia-accelerating effects of the ketogenic diet and extend survival when they treated mice with Dexamethasone - a corticosteroid commonly used as supportive care for people with cancer undergoing standard care.

“By replenishing the hormones, we were able to better protect the body while still effectively combating the cancer,” says Tobias.

Because the ketogenic diet was still leading to the accumulation of lipid biproducts in the tumour and ferroptosis of the cancer cells, but the rest of the body was supplemented with the hormone it needed to adapt to the stressful metabolism, overall survival was extended.

Based on these results, the team is now working to fine-tune corticosteroid timing and dosage in model systems to widen the window for effective cancer therapies in combination with a ketogenic diet.

Although the models used in the research recapitulate clinical disease progression from early cancer to cachexia, it’s important to note that these findings have not been confirmed in humans, and further studies are needed.

“These new findings from the CANCAN team are very interesting and shed new light on the complexities of targeting metabolic imbalance in cancer and cachexia. I look forward to seeing how the team build on these findings as their programme progresses, so that we can ultimately find ways to improve outcomes for those affected by cancer and cachexia.” 

Dr David Scott, Director of Cancer Grand Challenges

The CANCAN team is funded by Cancer Research UK and the National Cancer Institute.

Read the Cell Metabolism paper.

Written by Bethan Warman, with thanks to Miriam and Tobias for their input.