Locations:
Search IconSearch
July 31, 2017/Cancer/Research

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

Opens new avenues for pharmacologic development

Yogen_650x450

By Yogen Saunthararajah, MD

Advertisement

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy

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.

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.

Advertisement

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.

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.

Advertisement

Related Articles

Image showing Dr. Gupta
June 20, 2024/Cancer/Research
Trailblazing Urothelial Cancer Treatments (Podcast)

Platinum-eligible phase 3 trial of enfortumab vedotin and pembrolizumab yields ‘unprecedented data’

Lung cancer cells
June 5, 2024/Cancer/Research
Impact of Tumor Burden on Survival for Patients with EGFR-Mutant NSCLC Treated with Osimertinib

Extent of baseline burden impacts progression-free and overall survival

cancer cells
June 4, 2024/Cancer/Research
Researchers Identify Tumor Microbiome Differences in Early- vs. Average-Onset Pancreatic Adenocarcinoma

Further study warranted to better understand the clinical implications of these findings

car T-cells
June 3, 2024/Cancer/Research
CAR T-Cell Treatment Offers Hope for Richter Transformation

Real-world study shows high response rates that are durable with commercial lisocabtagene maraleucel

Blood clot
May 17, 2024/Cancer/Research
Managing the Risks of Venous Thromboembolisms in Patients with Cancer

Oral anticoagulants may be beneficial but need to be balanced against bleeding risks

Doctors working on MGUS screening study
March 18, 2024/Cancer/Research
Pilot Study Aims for Early Identification of Multiple Myeloma Precursor Among Black Patients

First-of-its-kind research investigates the viability of standard screening to reduce the burden of late-stage cancer diagnoses

Physician with patient
March 6, 2024/Cancer/Research
Targeting Uncontrolled Erythrocytosis in Polycythemia Vera with Rusfertide

Study demonstrates ability to reduce patients’ reliance on phlebotomies to stabilize hematocrit levels

Doctor measuring patient's waist size
February 26, 2024/Cancer/Research
Impact of Obesity on GVHD & Transplant Outcomes in Hematologic Malignancies

Findings highlight an association between obesity and an increased incidence of moderate-severe disease

Ad