HDAC inhibitor shows promise as part of new combination therapy for high-risk liver cancer in children

Researchers and medical experts at Baylor College of Medicine are tackling the alarming rise of (HB), the most prevalent among children. Over the past decade, HB cases have surged globally, marking the steepest increase among all pediatric solid tumors.

Addressing this concerning trend, a team spearheaded by Baylor's researchers has devised a promising treatment strategy, as detailed in the Journal of Hepatology. Dr. Andrés F. Espinoza, a general resident in Baylor's Michael E. DeBakey Department of Surgery and the study's lead author, emphasized the urgency, stating, “High-risk disease translates to high relapse and mortality rates.”

The study explores a novel combination therapy incorporating an inhibitor targeting histone deacetylase (HDAC), an enzyme found at elevated levels in HB . Dr. Espinoza noted, “Previous studies hinted at HDAC inhibitors as potential HB treatments, but there's been a dearth of published preclinical data on such therapies.”

To gauge the efficacy of the innovative combination therapy, the team devised a preclinical testing framework utilizing clinically relevant HB models. Their efforts offer hope for advancing treatments and improving outcomes for those affected by this devastating disease.

Identifying an effective new combination therapy

The research journey began with the screening of various HDAC inhibitors to assess their efficacy in targeting patient-derived HB cell lines cultured in the laboratory. Among the tested inhibitors, panobinostat emerged as the most potent in eradicating .

Subsequently, the team delved into investigating whether supplementing current chemotherapy protocols with panobinostat could enhance tumor response. Their experimentation involved screening these combined treatments using patient-derived spheroids, three-dimensional derived from human tumor samples. Results unveiled that integrating panobinostat into the treatment regimen alongside vincristine and irinotecan exhibited superior efficacy in eliminating tumor cells compared to other combinations.

Transitioning from lab-based studies to animal models, the researchers evaluated the new combination therapy, dubbed VIP (vincristine, irinotecan, and panobinostat), in four aggressive HB models derived from high-risk, relapsed, and treatment-resistant HBs. Molecular profiling of the tumors in the animal models revealed a of mutations and molecular markers akin to those observed in human tumor samples, underscoring the translational relevance of the findings.

Notably, unlike previous studies that focused on treating small-sized tumors, this investigation targeted large tumors. Dr. Sanjeev A. Vasudevan, the corresponding author and associate professor of surgery at Baylor, highlighted the promising outcomes, stating, “After just one week of therapy, the tumors treated with VIP exhibited a significant reduction in volume and alpha fetoprotein levels, a key tumor marker.”

These compelling findings pave the way for considering VIP therapy as a promising and potentially effective option for patients grappling with currently untreatable high-risk, relapsed, or refractory HB.

Source: Baylor College of Medicine

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