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New targeted therapy may be effective treatment option for deadly childhood cancer – ScienceDaily


New research from the VCU Massey Cancer Center was published Thursday in the Cell reports – demonstrated that a new targeted therapy could be an effective treatment option for a deadly childhood cancer known as neuroblastoma.

Neuroblastoma is a type of cancer that develops in nerve tissue, most commonly in the glands around the kidneys. Despite the many medical advances that have improved disease outcomes, high-risk neuroblastoma remains the cause of most cancer deaths in children five years of age and younger.

Previous studies have shown that activation of a specific group of proteins – MEK/ERK – helps neuroblastoma cells survive and grow. However, a class of drugs used to block these proteins from functioning, called MEK inhibitors, has proven ineffective in treating the disease, as high doses are associated with significant levels of toxicity.

“Breakthroughs that significantly change the fate of high-risk neuroblastoma have been elusive,” said study author Anthony Faber, Ph.D., co-director of the Developmental Therapeutics Research Program, and Natalie N. and John R. Congdon, senior chair. in cancer research at VCU Massey Cancer Center.

To address the lack of effective treatment options for neuroblastoma, Faber’s lab and colleagues conducted a high-throughput drug screening using SHP099. This compound belongs to 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 of drug discovery and development that allows researchers to automate thousands and millions of tests of chemical and 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 against tumor cells that had limited or no expression of the neurofibromin 1 (NF1) protein. In addition, they determined that NF1 expression is significantly lower in progressive or relapsed neuroblastoma cells, and that the protein is more easily deactivated in high-risk neuroblastoma.

“We found different but consistent positive effects across models of low- and high-risk NF1 neuroblastoma, which opens up a new drug target for disease relapse,” said Faber, who is also an assistant professor at VCU’s Philips Institute for Oral Health Research. School of Dentistry.

Faber said one of the most important findings in the study, by first authors Jinyan Tsai, PhD, and Shiba Jacob, PhD, was that SHP2 inhibitors were ineffective at blocking MEK/ERK function in healthy cells and therefore were not toxic to them. .

“These findings suggest that, unlike MEK inhibitors, SHP2 inhibitors can be dosed at high enough doses to inhibit MEK/ERK signaling in neuroblastoma tumors,” said Faber, who acknowledged the high efficacy and potential of the Cancer Mouse Models Core at Massey, which allowed his team to comprehensively test SHP099.

Because there are a number of SHP2 inhibitors currently in clinical trials, Faber will work with collaborator John Glode, MD, to hopefully advance one of these inhibitors into clinical trials at the National Cancer Institute. Faber’s group is also currently planning to test SHP2 inhibitors in combination with anti-GD2 therapy, an approved neuroblastoma immunotherapy.

In addition to neuroblastoma, Faber’s team also found SHP099 to be effective in head and neck squamous cell carcinoma (HNSCC). Individual results will be published soon, and the team plans to further test HNSCC combination therapy with SHP2 and EGFR inhibitors.

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Materials is provided Virginia Commonwealth University. Originally written by Blake Belden. Note: Content can be edited for style and length.

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