Targeting clonal hematopoiesis to prevent hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common and deadly form of liver cancer. It typically arises in individuals with longstanding liver disease caused by viral infections, fatty liver disease, or alcohol use that lead to chronic inflammation in the liver and can eventually result in cancer.

In recent years, research has shown that early detection and treatment can improve outcomes. However, it is challenging to predict which patients with liver disease end up developing HCC, and which patients’ cancer will return after treatment, making it difficult to decide who would benefit most from aggressive early interventions.

To bridge this gap in cancer research and care, Dr. Robert Vanner, a medical oncologist and researcher at the Princess Margaret Cancer Centre in Toronto, will use new funds from an MOHCCN Clinician-Scientist Award to find new ways to prevent and treat HCC by focusing on a recently discovered factor that is linked to both inflammation and cancer formation in the liver, something researchers call clonal hematopoiesis.

"We have discovered that a common, age-related change in the blood system known as clonal hematopoiesis triggers inflammation within the liver, which creates a fertile environment for the development and growth of HCC,” explains Dr. Vanner. “In this context, being able to detect and combat clonal hematopoiesis has the potential to improve HCC prevention, detection and treatment.”

The research project will take a three-pronged approach to tackle this issue. First, the team will study liver tissues and tumours from patients to identify the specific inflammatory pathways activated by clonal hematopoiesis that lead to HCC. Armed with this knowledge, they will then test new treatments designed to block these inflammation pathways in preclinical models of HCC, with the hope of preventing tumour formation or relapse. Finally, the project will involve testing hundreds of HCC patients from across Canada for the presence of clonal hematopoiesis. By doing so, the researchers aim to determine whether this blood cell alteration can serve as a biomarker to predict which patients are most likely to experience a relapse after surgery, liver transplant, or ablation.

The potential impact of this research is significant. "We hope to identify a critical and targetable factor through which clonal hematopoiesis accelerates hepatocellular carcinoma growth," says Dr. Vanner. "This could offer a novel treatment strategy to help prevent hepatocellular carcinoma development or relapse." Such a strategy could improve the prognosis for patients with liver disease, offering a new way to intervene before cancer becomes life-threatening.

Dr. Vanner’s work is deeply informed by his experience as a medical oncologist, where he sees firsthand the devastating impact of advanced HCC. "Unfortunately, many patients’ cancer has progressed to the point of being incurable," he shares. "This provides daily motivation and inspiration to explore novel aspects of liver cancer biology that can be exploited to stop hepatocellular carcinoma and give patients longer, healthier lives."

The support from the MOHCCN is critical to the success of this project. By bringing together three MOHCCN Centres from across Canada, the project will harness the power of collaboration and cutting-edge genomic datasets to advance precision medicine.

"Our work could identify a population and setting in which to trial a precision intervention to stop HCC development or recurrence," Dr. Vanner notes. Additionally, the project will develop novel computational tools to identify clonal hematopoiesis, which could be used as a biomarker across all cancer types.

For Dr. Vanner, receiving the Clinician-Scientist Award is both an honor and a pivotal moment in his career. "This award provides critical funding to establish a laboratory dedicated to the study of clonal hematopoiesis in precision cancer medicine," he says. "The funding will jump-start an innovative research program that answers clinically-inspired questions to generate biological insights that can be translated into novel therapeutics."

The $225,000 award is for three years and will be matched by the University Health Network to total $450,000.