New Targets, New Treatments

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.

Drs. Muxiang Zhou and Dr. Lubing Gu are pediatric hematology and oncology specialists/researchers at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta. They have linked an already-known genetic bad guy to another crime, in a manner of speaking.

By finding that link, Dr. Zhou and Dr. Gu have discovered a new way to target and kill cancer cells. Finding an effective way to attack the target could lead to improved treatments—with fewer side effects—for children with highly chemo-resistant cancers, such as neuroblastoma.

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 the ability of the body’s cells to fight cancer. In fact, this mutation is found in about half of all adult cancer patients.

According to Dr. Zhou, high levels of a protein called MDM2 (or murine double minute) inhibit the p53 gene’s ability to suppress the growth of cancer cells.

Although normal p53 genes are found in over 90 percent of pediatric cancers, a high level of MDM2 means “the disease progresses very fast and is resistant to drugs and radiation,” says Dr. Zhou, who is also an Associate Professor of Pediatrics at Emory University School of Medicine.

Drs. Zhou and Gu further discovered that not only does MDM2 inhibit the cancer-fighting p53 gene, it also boosts production of XIAP, a protein that protects cancer cells and makes them resistant to treatment. This finding was published in the prestigious medical journal, Cancer Cell.

Called a target discovery, the connection between MDM2 and XIAP was totally unexpected. Target discoveries happen when researchers inadvertently find new pathways to access cancer cells. Once a target discovery is made, researchers look for an effective way to attack the new target and kill the cancer cells. 

Dr. Zhou says, “With this targeted drug discovery screening, we hope to identify drugs that can improve the outcome for children … and save more lives, sooner.”

Drs. Zhou and Gu are now hunting for small-molecule compounds that insulate and therefore break the connections between the MDM2 and XIAP molecules. This is similar to wrapping black electrical tape around the ends of two wires.

This insulating effect disrupts the signals from MDM2 to boost the production of the cancer-resistant XIAP. According to Dr. Gu, “Inhibition of the interaction between MDM2 and XIAP with small molecules can allow cancer cells to become more sensitive to chemotherapy.”

Drs. Zhou and Gu tested 1,280 FDA-approved drugs in the first phase of laboratory study. They found four that have the potential to treat cancer patients. One of the most promising of these four drugs—a compound known as MX3—strongly inhibited the production of XIAP in cancer cells that have high levels of MDM2.

“This suggests that MX3 could be the best candidate to be developed as a potential new [anti-cancer] drug,” says Dr. Gu, who is also an Assistant Professor of Pediatrics at Emory University School of Medicine.

In the second phase of laboratory study, an additional 2,000 natural products were tested on the MDM2-XIAP connection. Twelve were identified as having the potential to treat cancer patients.

Drs. Zhou and Gu have each applied for 2013-2014 CURE grants that will help the progress of their research. The objective of Dr. Zhou's proposal is to find potent and less harmful drugs that will disrupt MDM2 through the novel anthraquinone analog BW-AQ-101.

Dr. Gu's grant proposal focuses on exploring the therapeutic potential of a small-molecule compound designated MX69 to treat childhood neuroblastoma. The grant will also allow Dr. Gu to perform pharmacological studies and any necessary chemical modifications on MX69.

Further research is 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.

Dr. Fu will test the effects of roughly 38,000 additional chemical compounds on the MDM2-XIAP connection. After testing, the compounds that can that can break the connections between the MDM2 and XIAP molecules will be added to the list of 16 other candidate compounds that have been discovered.

So far, Drs. Gu and Zhou have conducted their experiments only in test tubes. The next phase of research will be to apply the candidate compounds to the MDM2-XIAP connection in live test subjects.

They will observe how the candidate compounds impact the MDM2-XIAP connections in the live test subjects, and then compare the results to those of their earlier experiments. When the animal studies are completed, the next step is to recreate these experiments in human tumor tissue samples.

The goal will be to identify candidate compounds that disrupt the MDM2-XIAP connection in actual human tumor tissues just as they did in the test tube experiments and live studies.

Dr. Gu says of their ongoing research, “Because the survival of children with neuroblastoma remains very poor, our studies will help generate knowledge that will increase our understanding of the aggressive growth and drug resistance in these high-risk neuroblastoma patients.”

Dr. Zhou agrees, adding, “We do expect that our research will lead to the discovery of several known and novel drugs that are both specific and efficient as MDM2-targeting therapies to treat patients … who currently do not have good treatment options.”