Novel target for high-risk neuroblastoma identified in pre-clinical research


Carol J. Thiele, Ph.D., integrated the results of both genetic and chemical-based screens in neuroblastoma cell lines. The screens identified SETD8, an enzyme that in humans is encoded by the SETD8 gene, as a druggable neuroblastoma target that was later shown to improve survival in mice with neuroblastoma tumors.

Neuroblastoma is a cancer of the adrenal gland, neck, chest, and spinal cord. It accounts for 15 percent of all cancer deaths in children. Despite intense treatment, current therapy for neuroblastoma is still inadequate for 50 percent of high-risk patients and causes significant toxicities. There are limited targeted drugs for this type of cancer, so identifying molecular inhibitors to block tumor growth is an important goal for cancer researchers. Pre-clinical research by investigators at the Center for Cancer Research and their colleagues have identified a number of novel epigenetic targets for high-risk neuroblastoma and validated a promising new targeted inhibitor in pre-clinical models. The results of this study appear in Cancer Cell.

To identify targets in the pharmaceutical drug development pipeline, Carol J. Thiele, Ph.D., Senior Investigator, Pediatric Oncology Branch, and her colleagues integrated the results of both genetic and chemical-based screens in neuroblastoma cell lines. The siRNA screen identified 53 genes whose loss of expression led to a decrease in neuroblastoma cell growth and 16 genes that also induced differentiation, which is where a cell changes type. The screens identified SETD8, an enzyme that in humans is encoded by the SETD8 gene, as a druggable neuroblastoma target that was later shown to improve survival in mice with neuroblastoma tumors. They also found that genetic or pharmacological inhibition of SETD8 activity resulted in activation of the tumor-suppressing p53 pathway in neuroblastoma, which provides a new strategy for treating this high-risk cancer in children.

Summary Posted: 01/2017