Children’s, Pitt Researchers Explain Cancer Gene Role in Growth of Pediatric Liver Tumors

Researchers at the University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh of UPMC have uncovered how a key cancer gene works to accelerate cell growth in a mouse model of pediatric liver tumors. The results provide a better understanding of how inhibition of this gene can be used to combat the disease, and also suggest that doing so may be associated with fewer side effects than originally assumed. The findings were published in the Journal of Biological Chemistry, and selected as one of the journal’s “Papers of the Week.”

The new research focuses on one of cancer’s key genetic players, a gene called Myc.

“Understanding how Myc leads to tumor growth can provide valuable insight we can use to treat the disease, since at least 50 percent of all cancers overexpress Myc in some way,” explained lead study investigator Edward Prochownik, M.D., Ph.D., director of oncology research, Children’s Hospital, and the Paul C. Gaffney Professor of Microbiology and Molecular Genetics at Pitt’s School of Medicine.

Dr. Prochownik’s research concentrates on the role of Myc in liver tumors. His team previously showed that although Myc plays a variety of roles in healthy dividing cells, it is not important for normal liver cell growth and regeneration. In fact, the Myc gene can be completely deleted from normal liver cells without affecting their long-term regenerative potential, as Dr. Prochownik and his colleagues reported in other work earlier this year.

In the current study, researchers studied the gene’s role in a mouse model of hepatoblastoma, a form of liver cancer that occurs in children, typically under the age of 3. Using genetic engineering techniques, the team induced hepatoblastoma tumors in mice that either did or did not have Myc in their liver cells. They found that mice lacking Myc in their liver cells generated tumors more slowly and survived longer than expected.

“Mice lacking liver Myc still developed tumors, but the tumors grew more slowly, suggesting that tumor growth, but not initiation, is dependent on Myc,” explained Dr. Prochownik.

Subsequent experiments showed that Myc promotes tumor growth by turning up the cell’s thermostat, raising its rate of metabolism so it can supply all of the metabolic building blocks and energy needed for rapid tumor growth. Prochownik and his colleagues believe that the different needs for Myc in normal versus tumor growth may be due to the fact that, in the latter case, this “metabolic thermostat” is turned up higher and therefore is more Myc-dependent. The more controlled conditions that exist with normal liver regeneration are therefore much less Myc-dependent.

Given that Myc plays such an important role in many cancers, a drug that inhibits it is an attractive therapeutic, explained Dr. Prochownik. However, because Myc is expressed in normal cells as well as cancerous ones, there have been concerns in the field that inhibiting the gene would produce too many detrimental side effects.

“Our research strongly suggests that this is not the case. Normal cells are not dependent on Myc the way that tumor cells are, so a Myc inhibitor could selectively target cancer cells while sparing healthy cells,” he added.

Over the past several years the team has developed several Myc inhibitors and they are now working to improve the drugs’ efficacy in cell culture and animal models of cancer. So far, they are proving to be effective in models of multiple myeloma and neuroblastoma, Dr. Prochownik said.

“Although they are not quite ready to give to patients yet, these compounds are a very exciting approach to treating a variety of cancers,” he added.

This research was supported by National Institutes of Health grants 5RO1 CA174713, 1R01 CA204586, and 1R01 DK100287.

Additional co-authors of the new paper include Huabo Wang, Ph.D., Jie Lu, B.S., Lia R. Edmunds, Ph.D, Sucheta Kulkarni, Ph.D., James Dolezal, B.A., Junyan Tao, Ph.D., Sarangarajan Ranganathan, M.D., Laura Jackson, M.D., Marc Fromherz, B.A., Donna Beer Stolz, Ph.D., Radha Uppala, B.S., Sivakama Bharathi, Ph.D., Satdarshan P. Monga, M.D., and Eric S. Goetzman, Ph.D., all of the University of Pittsburgh.