Combination Therapy Shows Potential in Neuroblastoma

Investigational drug MLN8237 aids ABT-199 in killing neuroblastoma tumors in advanced mouse models.

A combination therapy has been developed with the potential to use the gene MYCN to attack and kill cancer instead of aiding its growth in patients with neuroblastoma.

Researchers from the VCU Massey Cancer Center and the VCU Philips Institute for Oral Health Research demonstrated the gene MYCN, which is associated with the amplification of neuroblastoma cells, had a high sensitivity to ABT-199, an investigational drug currently in clinical trials.

Research published in Cancer Cell explored other drugs that could be used in combination with ABT-199 to help elevate its effectiveness.

The investigational drug MLN8237 was found to complement and aid ABT-199 in killing neuroblastoma tumors in advanced mouse models and other laboratory experiments.

“The positive preclinical activity and safety profile of this targeted therapy combination will hopefully set the stage for clinical trials in a subset of neuroblastoma patients who urgently need new, more effective therapies,” said study author Anthony Faber, PhD.

It was discovered that when ABT-199 kills neuroblastoma cells, it only did so when amplified MYCN were present. This was because of paradoxical upregulation of the pro-apoptotic protein NOXA found in this particular type of cancer.

Since amplified MYCN is the cause for the development and growth of high-risk tumors and tend to not promote cell death, researchers wanted to have the MYCN “turn against itself” by finding vulnerabilities such as MYCN-upregulated NOXA that are specific to neuroblastoma.

“Fortunately, our primary collaborator, Yael Mossé at the Children's Hospital of Philadelphia (CHOP), treats a high volume of these patients and has been a trailblazer for developing targeted therapies, including MLN8237, in neuroblastoma,” Faber said. “We also have a good relationship with the drug maker, AbbVie, which produces ABT-199; therefore, we believe we are in a good position to hopefully bring the ABT-199/MLN8237 combination into the clinic at CHOP.

“In addition, we are also exploring ABT-199 as a chemosensitizer (makes cells more sensitive to chemotherapy) in MYCN-amplified neuroblastomas with Dr. Mosse's team. Overall, it seems there may be a place for BCL-2 specific inhibitors in the future care of these patients, and we are excited about that.”

Dr. Faber will also be partnering with researchers who conducted prior research that demonstrated the importance between NOXA and BCL-2 inhibitors exploited in the current study.

“Drs. Harada and Krystal have made important advances in the biology of NOXA and its relationship with BCL-2 inhibitors in tumors,” Faber said. “Indeed, their previously published work helped guide us in the right direction.”