It’s not uncommon for police detectives to link a convicted criminal to other crimes. The bad guy often turns out to be more villainous than first thought.
Two researchers at the Aflac Cancer Center and Blood Disorders Service of Children’s Healthcare of Atlanta have linked an already-known genetic bad guy to another crime, in a manner of speaking. By finding that link, Dr. Muxiang Zhou and Dr. Lubing Gu have found a new target in cancer cells. Finding a way to attack that new target could lead to improved treatments for children with leukemia and other cancers.
A gene called TP53 (typically referred to as p53) plays a well-known role in the body’s fight against cancer. Mutations of the p53 gene hobble that cancer-fighting ability of cells. That mutation is found in about half of adult cancer patients.
High levels of a protein called MDM2, encoded by the murine double minute (MDM2) gene, inhibit the ability of p53 to suppress the growth of cancer cells, says Zhou, who is also an associate professor of Pediatrics at Emory University School of Medicine.
As a result, even in patients with normal p53 genes that is found in over 90% pediatric cancers, a high level of MDM2 means “the disease progresses very fast and is resistant to drugs and radiation,” Zhou says.
Research by Zhou and Gu, published earlier this year in the prestigious medical journal Cancer Cell, revealed that not only does MDM2 inhibit the cancer-fighting p53, it boosts production of XIAP, a protein that protects cancer cells, making them resistant to treatment. Zhou and Gu have received generous grants from CURE Childhood Cancer to support this research.
This discovery is totally unexpected and is what most call target discovery. Researchers find a target, and then must find something to do about it.
Gu and Zhou are now hunting for a compound that will break the connection between the MDM2 and XIAP molecules. Think of wrapping black electrical tape around the ends of two wires.
“Inhibition of the interaction between MDM2 and XIAP with small molecules can allow cancer cells to become more sensitive to chemotherapy,” says Gu.
The researchers tested 1,280 FDA-approved drugs in the first phase of laboratory study and found just four that have the potential to treat cancer patients. One of those four drugs – a compound known as MX3 – strongly inhibited production of XIAP in cancer cells with high levels of MDM2.
“This suggests that MX3 could be the best candidate to be developed as a potential new drug,” says Gu, an assistant professor of Pediatrics at Emory University School of Medicine.
A second wave of testing using 2,000 natural products identified a dozen more that may have potential as therapeutic drugs. Continuing research being done in cooperation with Dr. Haian Fu, a professor of pharmacology and the director of the Chemical Biology Discovery Center at Emory University School of Medicine will test the effect of roughly 38,000 chemical compounds on the MDM2-XIAP connection.