Study Identifies MAGEA3 as Novel Therapeutic Target in Hepatocellular Carcinoma

Manipulating the expression of MAGEA3 can help block the growth of hepatocellular carcinoma.

MAGEA3 may be an effective therapeutic target in helping to slow the progression of hepatocellular carcinoma (HCC), a new study published in PLOS Genetics revealed. This includes decreasing cell proliferation and colony formation, as well as increasing cell apoptosis.

HCC is the most common type of primary liver cancer and one of the leading causes of cancer-related death worldwide.

“The aim of this study is to perform a comprehensive profile of CTA deregulation in HCC and experimentally evaluate the role of MAGEA3 as a driver of HCC progression,” the authors wrote.

The investigators administered RNA sequencing to 44 multiregional tumor biopsies from 12 patients with HCC—each of whom had a median 4 regions—to observe the rate of gene expression in high-grade and low grade-regions of the same tumor nodule. Cell viability was assessed via the MTS assay, and the Incucyte S3 live cell imager evaluated cell apoptosis.

Sequencing revealed that cancer testis antigens (CTAs) were consistently overexpressed in the most aggressive regions. CTAs have historically been investigated as targets of immunotherapy due to their selective expression by tumor cells.

Further, the investigators found that high rates of CTA expression, especially MAGEA3, were linked to worse overall survival and other indicators of poor prognosis for patients with HCC.

When they blocked the expression of MAGEA3 in HCC cells, the cells were no longer able to proliferate, and they died. In contrast, when MAGE3 was overexpressed in isolated liver cells of mice prone to HCC, the mice succumbed to cancer more quickly. These findings support the overall conclusion that MAGEA3 is an effective novel therapeutic target and is important for HCC progression.

“The study uncovered the role of cancer testis antigens, specifically MAGEA3, in liver cancer progression,” said Augusto Villanueva, MD, PhD, of the Icahn School of Medicine at Mount Sinai and lead author, in a statement. “It demonstrates how selective inhibition of MAGEA3 has antitumoral effects on experimental models of this disease. Overall, the study provides the proof-of-principle to test MAGEA3 inhibition in early phase clinical trials for patients with primary liver cancer.”

Further research is required in larger patient pools as to whether downstream targets are more effective to target therapeutically than MAGEA3.

Reference

Craig AJ, Garcia-Lezana T, Ruiz de Galarreta M, et al. Transcriptomic characterization of cancer-testis antigens identifies MAGEA3 as a driver of tumor progression in hepatocellular carcinoma. PLoS Genet. Published online June 24, 2021. doi:10.1371/journal.pgen.1009589