For more than a century, scientists have sought to understand cancer through the lens of uncontrolled cell division (the genetic mutations that drive relentless growth). However, an older, often overlooked idea has persisted alongside this framework: that cancer is, at least in part, a disease of metabolism.
Now, new research into a rare and very deadly liver cancer may be bringing that idea back into sharper focus. At work published in CANCERSa team led by Robert Nagourney at the Nagourney Cancer Institute has identified a surprising vulnerability in fibrolamellar carcinoma – a rare form of liver cancer that mainly affects teenagers and young adults. Instead of responding to conventional chemotherapy, these tumors appear extremely sensitive to drugs that disrupt cellular metabolism.
The findings suggest that, at least for this cancer, the key to treatment may not lie in DNA damage or cell cycle control, but in the biochemical pathways that fuel tumor cells.
A rare and stubborn disease
Fibrolamellar carcinoma is one of the most challenging cancers that doctors face. Mostly affecting individuals between the ages of 15 and 25, it is rare – fewer than a thousand cases are diagnosed each year worldwide – and extremely resistant to standard chemotherapy.
Surgical removal remains the primary treatment, but recurrence is common. For patients with advanced disease, options are limited and outcomes are often poor.
Part of the difficulty lies in the biology of the tumor. Fibrolamellar cancer is associated with a particular genetic rearrangement, known as DNAJB1-PRKACA, which alters cell signaling pathways. However, this mutation has not easily translated into effective targeted therapies. Nagourney’s work suggests this may be because researchers have been looking in the wrong place.
Rather than focusing solely on genetic drivers, the research team investigated how these tumors behave functionally (how they respond to therapeutic agents and how they process energy).
Using a technique known as ex vivo programmed cell death assay (EVA/PCD), tumor samples taken from patients were exposed to a wide range of drugs. The method, developed at the Nagourney Cancer Institute, allows researchers to observe how cancer cells respond to treatment before those therapies are administered to the patient.
Standard chemotherapeutic agents produced little effect, confirming the clinical reality of treatment resistance. However, when the researchers tested drugs that interfere with cellular metabolism, a very different picture emerged: the tumors seemed remarkably sensitive.
To explore this further, the team turned to mass spectrometrya powerful analytical tool capable of measuring metabolic byproducts in blood and tissues with high precision.
The results, according to Nagourney, were unmistakable: the metabolic profile of the tumor differed significantly from that of normal tissue.
“These metabolic signatures were clearly distinguished,” he noted, suggesting that fibrolamellar carcinoma is determined as much by its metabolic state as by genetic mutations.
The concept that cancer is linked to altered metabolism is not new. In the 1920s, biochemist Otto Warburg proposed that cancer cells rely on a special way of producing energy – now known as the “Warburg effect”. This theory argued that tumor cells prefer to use glycolysis instead of oxidative phosphorylation, even in the presence of oxygen.
For decades, however, cancer research has been dominated by genetic approaches, with metabolism often treated as a downstream consequence rather than a primary driver.
The last one advances in metabolism (the study of small molecules involved in cellular processes) are changing this view. Techniques such as targeted mass spectrometry now allow researchers to quantify metabolic pathways in detail, opening new avenues for understanding tumor biology.
The fibrolamellar findings add to this growing body of evidence, suggesting that, in some cancers, metabolic disruption may be not only a feature but also an underlying cause. If fibrolamellar tumors depend on altered metabolic pathways, then drugs that disrupt those pathways may provide an effective treatment strategy. Unlike conventional chemotherapy, which broadly targets rapidly dividing cells, metabolic therapies can be more selective—interfering with processes that cancer cells disproportionately rely on.
There are already several such drugs, originally developed for other indications. Repurposing these agents for rare cancers could accelerate translation from research to clinical use.
Additionally, the ability to test drug responses directly in patient-derived tumor samples provides a more personalized approach. Rather than relying on population-level data, clinicians can tailor treatment based on each tumor’s unique metabolic profile.
The Canadian context: Growing interest in metabolomics
The implications of this work resonate beyond a single rare cancer. Canada, for example, has become a center for metabolic research, supported by initiatives such as The Genome of Canada AND Metabolomics Innovation Center at the University of Alberta. These programs are applying metabolic profiling in areas ranging from cancer diagnostics to precision medicine.
Canadian researchers have already demonstrated that metabolic signatures can help distinguish tumor types, predict treatment response and identify new therapeutic targets. The fibrolamellar study strengthens the case for deeper integration of metabolomics into clinical oncology. It also highlights the potential to combine metabolic analysis with functional testing, linking what tumors are doing chemically with how they respond to drugs.
Challenge and caution
Despite the promise, the approach is not without challenges. Metabolism is highly complex, involving interconnected pathways that vary between tissues and individuals. Targeting one pathway may lead to compensatory changes elsewhere, reducing therapeutic effectiveness.
There are also practical considerations. Techniques such as mass spectrometry require specialized equipment and expertise, although advances in instrumentation are making these tools more accessible. For rare cancers such as fibrolamellar carcinoma, patient numbers remain small, making large-scale clinical trials difficult. Collaboration between institutions—such as that seen in this study with the FibroFighters Foundation (https://fibrofighters.org)—will be essential.
