New targeted therapy may be an effective treatment option for neuroblastoma

New Research from VCU Massey Cancer Center -; published Thursday in Mobile Reports -; showed that a new targeted therapy could be an effective treatment option for a deadly childhood cancer known as neuroblastoma.

Neuroblastoma is a cancer that develops in nerve tissue, usually in the glands surrounding the kidneys. Despite multiple medical advances that have improved outcomes for the disease, high-risk neuroblastoma remains responsible for the majority of cancer-related deaths in children five years of age and younger.

Previous research has shown that the activation of a specific group of proteins -; MEK/ERK-; helps neuroblastoma cells survive and grow. However, a class of drugs used to inhibit the function of these proteins called MEK inhibitors has not been shown to be effective in treating the disease because high doses are associated with a significant degree of toxicity.

“Breakthroughs that have significantly changed the fate of high-risk neuroblastomas have been elusive,” said study author Anthony Faber, Ph.D., co-leader of the Developmental Therapeutics research program, and Natalie N. and John R. Congdon, Sr. Endowed Chair in Cancer Research at VCU Massey Cancer Center.

To address the lack of effective treatment options for neuroblastoma, Faber’s lab along with his collaborators performed high-throughput drug screening with SHP099. This compound belongs to a new class of drugs that target and block an enzyme called SHP2, which is along the same genetic pathway as MEK/ERK.

High-throughput screening is an important method in drug discovery and design that allows researchers to automate thousands to millions of tests for chemical or biological compounds.

Repeatedly, Faber and his research team found that neuroblastoma tumors in mice were sensitive to SHP099, and the tumors shrank significantly in some models. SHP099 had a particularly effective impact in tumor cells that had limited or no expression of the neurofibromin 1 (NF1) protein. In addition, they found that NF1 expression is much lower in advanced or relapsed neuroblastoma cells, and that the protein is more easily deactivated in high-risk neuroblastoma.

We found variable but consistently positive effects in all models of low NF1, high-risk neuroblastoma, revealing a novel drug target in relapsed disease.”

Anthony Faber, Ph.D., associate professor, Philips Institute for Oral Health Research, VCU School of Dentistry

Faber said one of the key findings in the study -; created by first authors Jinyang Cai, Ph.D., and Sheeba Jacob, Ph.D., -; was that SHP2 inhibitors were not effective in blocking the function of MEK/ERK in healthy cells and therefore were not toxic to them.

“These findings suggest that, unlike MEK inhibitors, SHP2 inhibitors can be dosed high enough to inhibit MEK/ERK signaling in neuroblastoma tumors,” said Faber, who explains the high efficiency and capabilities of the Cancer Mouse Models Core at Massey. for allowing his team to extensively test SHP099.

As a large number of SHP2 inhibitors are now in clinical testing, Faber will work with collaborator John Glod, MD, Ph.D., to hopefully bring one of these inhibitors into clinical trials at the National Cancer Institute. Currently, Faber’s group also plans to test SHP2 inhibitors in combination with anti-GD2 therapy, an approved immunotherapy for neuroblastoma.

In addition to neuroblastoma, Faber’s team also found that SHP099 is effective in squamous cell carcinoma of the head and neck (HNSCC). Separate findings will be published shortly and the team plans further testing of a combination therapy in HNSCC with SHP2 and EGFR inhibitors.