Some of the most common genetic mutations that drive liver cancer are hard to target with drugs. The lack of powerful therapeutics that could significantly prolong patient survival has driven a search for novel mechanisms of tumor progression.
By performing RNA sequencing on tissue samples from 12 patients, scientists at the Icahn School of Medicine at Mount Sinai have pinpointed the MAGEA3 gene as a driver of progression in hepatocellular carcinoma, the most common type of liver cancer.
The findings, published in the journal PLOS Genetics, support considering inhibition of MAGEA3 expression or its upstream signaling as a strategy for developing drugs against liver cancer, the team suggested.
The MAGEA3 gene—and the protein it encodes for—is no stranger to the cancer field. It’s been linked to melanoma and non-small cell lung cancer, among others. But a cancer vaccine made by GlaxoSmithKline targeting MAGE-A3 had previously failed to move the needle in melanoma and lung cancer in late-stage testing.
For the new study, the Icahn team probed multiple regions of individual tumor nodules from 44 biopsies. They profiled genetic expression in an attempt to understand which genes were more highly expressed in aggressive regions of tumors.
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A group of genes called cancer testis antigens (CTAs) were found to have increased expression in aggressive regions. Among the CTAs, MAGEA3 appeared to be a major contributor.
The team created a CTA score based on the sequencing data and grouped tumors from two cohorts of 589 patients into either CTA-high or CTA-low groups. Patients in the CTA-high group had significantly more gene signatures correlating with poor clinical outcomes, the team found. And they had significantly worse overall survival than low CTA expressers did. For one cohort, high MAGEA3 expression alone was associated with a 62% increase in death risk, the team reported.
To confirm MAGEA3’s role, the researchers removed the gene in human liver cancer cell lines. They noted a significant decrease in cell proliferation, plus a 3-fold increase in the number of cells bearing a marker of programmed cell death.
They also dialed up MAGEA3 in a mouse model of liver cancer. Mice with over-expressed MAGEA3 died more quickly, confirming that the gene contributes to liver cancer progression, the team said. Further analysis revealed that MAGEA3 could stabilize levels of Survivin, a regulator that prevents programmed cell death, or apoptosis.
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Scientists have been searching for new ways to tackle liver cancer. A team at the University of Pittsburgh School of Medicine previously found the beta-catenin gene could activate the mTOR protein, which is a known cancer promoter. It found that organ rejection med rapamycin, an mTOR inhibitor, helped shrink liver tumors in mice.
A team at the University of California, San Francisco recently showed cancer cells could change gene expression in regulatory T cells in the liver to suppress cancer-killing T cells. They demonstrated that adding a CTLA-4 inhibitor could enhance the efficacy of PD-1 immune checkpoint inhibition in mice.
The MAGEA family of genes has been implicated in several cancers. The Icahn team’s findings support testing MAGEA3 inhibition in clinical trials for patient with primary liver cancer, Augusto Villanueva, M.D., Ph.D., the current study’s senior author, said in a statement. Future studies could search upstream of CTA regulation for more clues to developing drugs to specifically disrupt MAGEA3 function, the researchers suggested in the study.