Brain tumors are tough to treat. ZFTA-RELA fusion-positive ependymomas are among the worst—affecting mostly children and young adults with few options beyond surgery and radiation. A recent study found something unexpected about how these tumors survive, and it might lead to new treatments.
An Unexpected Finding
Researchers studying ZFTA-RELA ependymomas were looking for the usual cancer mechanisms. Instead they found itaconate—a molecule almost always linked to immune cells, especially macrophages fighting infection.
Itaconate gets made by the ACOD1 enzyme (also called IRG1). In immune cells, it helps control inflammation and fights microbes. Finding it in brain tumor cells was surprising.
Metabolic profiling made the pattern clear. Among hundreds of metabolites tested, itaconate showed the biggest jump in ZFTA-RELA-positive cells compared to normal cells. This was not a minor side pathway—it looked central to how these tumors function.
The Feedback Loop
The relationship between ZFTA-RELA fusion proteins and itaconate was more than correlation. The fusion protein drives ACOD1 enzyme production, which makes itaconate. But the itaconate then feeds back to maintain the fusion protein that created it.
This becomes self-sustaining. More ZFTA-RELA fusion protein means more itaconate. More itaconate means more fusion protein maintained. Break any part and the system collapses.
The mechanism involves epigenetics. Itaconate blocks KDM5, an enzyme that normally removes activating marks from histones. When KDM5 is blocked, these marks build up on DNA regions controlling ZFTA-RELA expression. Itaconate creates a more open chromatin environment that keeps the cancer fusion gene actively transcribed.
Glutamine as Fuel
Making itaconate at the levels seen in these tumors takes serious metabolic input. Tracing experiments with isotope-labeled nutrients showed glutamine is the main carbon source. The tumors increase glutamine uptake and metabolism through the PI3K-AKT-mTOR pathway.
This pathway activates because ZFTA-RELA epigenetically silences PTEN, a tumor suppressor that normally restrains PI3K signaling. Without PTEN, metabolic machinery shifts into high gear, pulling in glutamine and converting it step by step into itaconate.
This glutamine dependency creates another weak point. When researchers deprived ZFTA-RELA cells of glutamine or blocked its transport, the tumors struggled to survive. Normal cells handled these interventions much better, suggesting a therapeutic window.
From Lab to Potential Treatments
Understanding disease mechanisms suggests where to intervene. This research identified several promising targets:
ACOD1 inhibition blocks itaconate production directly. Experiments with genetic knockout and small molecule inhibitors showed that removing ACOD1 activity slowed tumor growth dramatically and extended survival in animal models. The tumors could not maintain their cancer driver without the itaconate feedback loop.
Glutamine metabolism blockade attacks the fuel supply. A brain-penetrant glutamine antagonist called JHU-083 showed strong results, reducing tumor burden and lowering ZFTA-RELA protein levels. Combining this with ACOD1 inhibition worked even better.
PI3K-mTOR inhibition addresses the upstream signaling that drives glutamine uptake. Combined with glutamine blockade, this approach eliminated spinal metastases in preclinical models—a major advance since metastatic spread often kills patients with these tumors.
Beyond One Cancer Type
Itaconate as a cancer-promoting metabolite challenges established thinking. For years itaconate was viewed as an immunomodulatory molecule with potential anti-inflammatory benefits. Finding it functioning as what the researchers call an “oncometabolite” raises questions about other cancer types.
The metabolic-epigenetic coupling shown here may represent a broader principle. Cancer cells frequently rewire metabolism, and these changes often affect gene expression through chromatin modifications. The ZFTA-RELA ependymoma case provides a clear example of how these processes can lock together in a self-sustaining cancer circuit.
For patients and families facing ZFTA-RELA ependymoma, these findings bring real hope. Current treatments offer limited benefit for recurrent or metastatic disease. The targeted approaches identified here—particularly combinations hitting multiple points in the pathway—could reach clinical trials within a reasonable timeframe.
Some of these therapeutic strategies use drugs already being tested in other contexts (glutamine antagonists, PI3K-mTOR inhibitors). Drug repurposing or combination approaches can sometimes move faster than developing new agents from scratch.
What Comes Next
Science progresses in steps, and this research is a significant one. It establishes itaconate as a real player in cancer biology, not just an immune cell curiosity. It shows how metabolic and epigenetic processes can entangle to drive cancer. Most importantly, it points to concrete therapeutic strategies worth serious exploration.
The coming years will show whether these preclinical findings translate to human benefit. Early indicators look promising—the mechanisms are well-defined, the targets are druggable, and the therapeutic window appears favorable. For a tumor type that has resisted treatment advances, that combination offers real reasons for optimism.
Research like this reminds us that even in the precision medicine era, fundamental biology still surprises. Sometimes the most important discoveries come from looking carefully at what is right in front of us—and being willing to reconsider what we think we know about molecules like itaconate.
Frequently Asked Questions
What is itaconate and where is it normally found?
Itaconate is a small molecule metabolite produced by the ACOD1 enzyme (also called IRG1). Until recently, it was known almost exclusively as a product of immune cells—particularly macrophages responding to bacterial infection. In immune contexts, itaconate helps regulate inflammation and has antimicrobial properties. Finding it in cancer cells was unexpected and suggests new roles for this metabolite.
What makes ZFTA-RELA ependymomas so difficult to treat?
These are aggressive brain tumors that primarily affect children and young adults. The ZFTA-RELA gene fusion drives the cancer, but standard treatments—surgery and radiation—offer limited options when tumors recur or spread. Metastatic disease to the spine is particularly dangerous and often fatal. The lack of effective targeted therapies has made these tumors especially challenging for oncologists.
How does itaconate actually promote cancer growth?
Itaconate creates a self-sustaining feedback loop. The ZFTA-RELA fusion protein drives production of itaconate. The itaconate then blocks an enzyme called KDM5, which normally removes activating marks from histones. Without KDM5 activity, these activating marks accumulate on the DNA regions controlling the ZFTA-RELA gene itself. This epigenetic change keeps the cancer-driving fusion gene actively expressed. Break the loop at any point and the system collapses.
What is glutamine’s role in this process?
Glutamine serves as the primary raw material for itaconate synthesis. The tumors enhance glutamine uptake and metabolism through the PI3K-AKT-mTOR pathway, which gets activated when ZFTA-RELA epigenetically silences the PTEN tumor suppressor. This metabolic rewiring allows the tumors to produce large amounts of itaconate. Blocking glutamine supply or metabolism starves the tumors of the fuel they need to maintain their cancer-driving machinery.
What treatment approaches does this research suggest?
Three main strategies emerged from this work: blocking ACOD1 to stop itaconate production directly, interfering with glutamine metabolism to cut off the fuel supply, and inhibiting PI3K-mTOR signaling to reduce glutamine uptake. In preclinical models, combinations of these approaches worked better than single treatments. The glutamine antagonist JHU-083 and PI3K-mTOR inhibitors are particularly promising since they can reach the brain and have shown activity in other cancer types.
How soon could these findings reach patients?
Some of the therapeutic strategies use drugs already in development or testing for other conditions. Glutamine antagonists and PI3K-mTOR inhibitors have been studied in various cancer types. This means clinical trials for ZFTA-RELA ependymoma could potentially start sooner than if entirely new drugs needed development. However, moving from preclinical models to approved treatments typically takes several years even in the best cases.
Could itaconate play a role in other cancers?
That is a real possibility. The finding that itaconate can function as an “oncometabolite” challenges the previous view of it as purely an immune modulator. The metabolic-epigenetic coupling demonstrated in this study may represent a broader principle that applies to other cancer types. Researchers will likely investigate itaconate levels in other tumors to see if similar mechanisms operate elsewhere.
What is epigenetic regulation and why does it matter here?
Epigenetics refers to changes in gene expression that do not involve alterations to the DNA sequence itself. In this case, histone modifications—chemical marks on the proteins that package DNA—control whether the ZFTA-RELA fusion gene is active or silent. Itaconate influences these marks by inhibiting KDM5, an enzyme that removes activating modifications. This epigenetic mechanism allows the tumors to maintain high expression of their cancer-driving fusion protein.