Research Team Identifies GATA4 Loss-of-Function as Oncogenic in Hepatocellular Carcinoma

Opens new avenues for pharmacologic development

By Yogen Saunthararajah, MD

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Cleveland Clinic Cancer Center and the National Cancer Center of Singapore have identified a genetic alteration that plays a central role in the development of liver cancer and may lead to effective new treatments. Our findings appear in the Journal of Clinical Investigation

Over the past decade, rates of hepatocellular carcinoma (HCC) have been steadily rising and the prognosis has remained poor. It is the second leading cause of cancer death worldwide with a five-year U.S. survival rate of 17.6 percent. Risk factors for HCC include hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, diabetes, obesity and alcohol abuse.

Progress in developing new treatments has been slow. The FDA recently approved the first new medication in a decade, the kinase inhibitor regorafenib, the second drug to be exclusively approved for liver cancer, which is in the same class as the only other approved drug, sorafenib. A lack of understanding of the mechanisms that cause the disease has stymied drug development.

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Narrowing the gene pool

Recent advances in genomic research technologies have enabled major progress in probing the genetic mutations present in HCC cells, increasing the prospects for understanding the molecular mechanisms of HCC-genesis. One major discovery was made in the eighth pair of chromosomes (8p) of HCC cells. One of this pair of chromosomes consistently loses about 500 of its genes, a deletion of the short arm of the chromosome found in about 60 percent of liver cancers. This 8p deletion is also found in many other cancers, including lung, colon, breast, bladder, brain, ovary and prostate.

Of the 500 genes on this chromosome arm, none are mutated at a high rate, the usual way that we identify a gene central to oncogenesis. The discovery of some liver cancer patients with smaller deletions of chromosome 8 narrowed this search, allowing us to target tens instead of hundreds of genes. By careful analysis of this shorter list of genes, our research team identified GATA4 as the key gene, since it is a major transcription factor driver of hepatocyte epithelial lineage-fate.

When a hepatocyte is missing one copy of GATA4, it begins to develop but fails hepatocyte epithelial-differentiation. This is because GATA4 loss-of-function favors enzymes that silence rather than activate the genes that are needed for differentiation. So the precursor cell continues to replicate, in a vain attempt to produce fully formed hepatocytes, resulting in tumorigenesis.

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GATA4 a way forward

This discovery has major significance for treating liver cancer. Most oncology drugs aim to induce apoptosis. Unfortunately, p53, the master mediator of apoptosis and target for upregulation with such treatments, and its key cofactors, are absent/nonfunctional in HCC.

This new discovery regarding GATA4 indicates that we can use therapies that inhibit the enzymes that silence rather than activate genes (corepressors like DNA methyltransferases), so that the hepatocyte development process can be completed and produce epithelial cells that focus on specialized functions rather than replication. Our research team is testing new treatments that work this way in mice, including new versions of DNA methyltransferase-inhibiting drugs decitabine and 5-azacytidine that can distribute into the liver and into liver cancers. We are hoping to move to clinical trials in about a year.

Dr. Saunthararajah co-leads the Developmental Therapeutics Program of the Case Comprehensive Cancer Center and is staff in the Department of Hematologic Oncology and Blood Disorders at Cleveland Clinic Cancer Center.