CANCAN

CANCAN is tackling the cachexia challenge, which was set in 2020. Cachexia is a debilitating wasting syndrome, where extensive weight loss cannot be reversed with nutritional therapy alone. This multifactorial condition is often accompanied by fatigue, widespread tissue and organ dysfunction, and a significantly diminished quality of life, limiting a patients’ ability to tolerate systemic cancer therapies and imparting poor prognosis. While the major manifestation of cachexia is muscular atrophy, when the challenge was set, it was  becoming clear that cachexia was a systemic phenomenon arising from a complex set of interactions between the tumour and the patient, through metabolism, the immune, endocrine and central nervous systems. However, despite its prevalence and major clinical implications, relatively little was known about the molecular basis of this wasting condition and there was a lack of effective treatments. The CANCAN team aims to deepen understanding of the mechanisms underlying cancer cachexia and develop therapeutic strategies that could reverse it. By working across the spectrum from the lab to the clinic and back, the team hopes to improve the outlook for patients with this debilitating syndrome.

CANCAN is co-led by:

Dr Marcus DaSilva Goncalves

Dr Tobias Janowitz 

Professor Eileen White 

The team unites clinicians, advocates and scientists with expertise in cancer, metabolism, neuroendocrine function, immunology and more, across 14 institutions across the US and UK, creating the world’s first virtual cachexia institute.

Cancer imposes metabolic stress on the body, diverting nutrients to meet its high energy demands at the expense of the patient. The team hypothesizes that cancer cachexia results from this systemic metabolic imbalance driven by tumour-intrinsic factors and neuroendocrine dysregulation – and targeting this metabolic imbalance, or its upstream mediators, holds the key to finding the first successful therapy to alleviate it. 

The team is pursuing three pillars of basic research to understand the interconnected components of cachexia biology, underpinned by a large clinical study to define clinical subtypes, with the ultimate goal of developing personalised therapeutic approaches: 

• Exploring cancer cachexia as a systemic metabolic imbalance 
• Identifying tumour-secreted factors driving cancer cachexia 
• Understanding how neuroendocrine dysregulation drives cancer cachexia by altering food intake and nutrient processing 
• Integrating the pillars: identify distinct clinical subtypes of cancer cachexia 

The team is using diverse sophisticated approaches towards these aims, from preclinical models through to human metabolic profiling, investigating host-tumour interactions and effects on systemic metabolic flux using isotope tracing, imaging mass spectroscopy, dynamic nuclear imaging, and dietary and pharmacologic interventions.

In mouse models of cachexia, the team have already showed that while a ketogenic diet can delay tumour growth by causing cancer cell death via ferroptosis, systemically it causes impaired corticosterone biosynthesis, which enhances cachexia. This work highlights the need to evaluate the effects of systemic interventions on the host, and identifies the use of dexamethasone, to counteract the acceleration of cachexia. The team have also demonstrated that a systemic increase in LIF can induce cachexia in mice, and that liver-specific knockout of the LIF receptor is enough to rescue this. The team identified the critical signalling pathways downstream, highlighting the potential for therapeutically activating PPARα, to restore lipid homeostasis in the liver.

The team are utilising data and biospecimens from TRACERx, a major Cancer Research UK-funded programme profiling patients’ progression from lung cancer diagnosis to cure or relapse, to study cachexia development across different disease stages. By analysing body composition parameters the team have already identified criteria which show prognostic value, as well as finding that individuals who had developed cachexia displayed distinct tumour genomic and transcriptome profiles. The team also highlighted GDF15 as a potential mediator of cachexia.

Towards identifying neuroendocrine pathways of cachexia, the team has already contributed towards work identifying that specific neurons in the area postrema within the hindbrain are critical to the function of IL-6, which is produced peripherally by the tumour, in mediating cachexia. Critically this work showed that manipulating IL-6 or its receptor, specifically within the brain, or removing area postrema neurons, can reduce cachexia and  prolong lifespan.

The CANCAN team proposes that cancer cachexia is not a single disease but rather has several diverse subtypes with differing biomedical and physiological characteristics – currently, all people with cancer cachexia are considered a homogeneous group.

Alongside their basic and preclinical work, the team is conducting the largest multi-centre, longitudinal cohort study among patients at high risk for cachexia, collaborating with two of the largest healthcare networks in the US: Kaiser Permanente Northern California and the National Cancer Institute Community Oncology Research Program (NCORP) Research Base. The team have already identified a candidate hormonal contributor to cachexia and have also started enrolment for a phase 2 clinical trail to test the effect of pioglitazone, an antidiabetic drug, on cachexia.

Explore CANCAN's scientific publications

Explore our news articles about CANCAN

The team has already made important and insightful discoveries. It will continue to develop these and other lines of investigation over the course of the programme. Establishing a comprehensive understanding of the mechanisms underlying cancer cachexia will pave the way for the development of effective interventions that can improve treatment response, quality of life, and survival outcomes for patients affected by this debilitating condition.

To learn more, visit CANCAN's website, which is managed and updated by the team itself.