A novel targeted therapy could be an effective treatment option for neuroblastoma

A novel targeted therapy could be an effective treatment option for neuroblastoma

New research from VCU Massey Cancer Center -; published Thursday in Cell Reports -; showed that a novel targeted therapy could be an effective treatment option for a deadly pediatric cancer known as neuroblastoma.

Neuroblastoma is a type of cancer that develops in nerve tissue, most commonly in the glands around the kidneys. Despite numerous medical advances that have improved disease outcomes, high-risk neuroblastoma continues to account for most cancer-related deaths in children under five.

Previous research has shown that activation of a specific group of proteins -; MEK/ERK-; Helps neuroblastoma cells survive and grow. However, a class of drugs used to stop the function of these proteins, called MEK inhibitors, have proven ineffective in treating the disease because high doses are associated with significant levels of toxicity.

“Breakthroughs that significantly alter the fate of high-risk neuroblastoma 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 laboratory and his collaborators conducted a high-throughput drug screen using SHP099. This compound is part of a new class of drugs that target and block an enzyme called SHP2, which is in the same genetic pathway as MEK/ERK.

High-throughput screening is an important method in drug discovery and development, allowing researchers to automate thousands to millions of tests on chemical or biological compounds.

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

We found different but consistently beneficial effects in all models of low-NF1, high-risk neuroblastoma, revealing a new drug target in recurrent 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 lead authors Jinyang Cai, Ph.D., and Sheeba Jacob, Ph.D., -; was that SHP2 inhibitors were ineffective at blocking the function of MEK/ERK in healthy cells and therefore were not toxic to them.

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

Since a large number of SHP2 inhibitors are currently in clinical testing, Faber and his colleague John Glod, MD, Ph.D. work together to hopefully advance one of these inhibitors into clinical testing 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 head and neck squamous cell carcinoma (HNSCC). Separate results will be published shortly, and the team plans to further test combination therapy in HNSCC with SHP2 and EGFR inhibitors.

Source:

Virginia Commonwealth University

Reference:

Cai, J., et al. (2022) High-risk neuroblastoma with NF1 loss of function is targeted by SHP2 inhibition. Cell Reports. doi.org/10.1016/j.celrep.2022.111095.