Neuroblastoma is commonly used to refer to a spectrum of neuroblastic tumors, including neuroblastomas, ganglioneuroblastomas, and ganglioneuromas, that arise from primitive sympathetic ganglion cells. The disease is the third most common childhood cancer, after leukemia and brain tumors, and is the most common solid extracranial tumor in children. Each year more than 600 cases are diagnosed in the United States each where it accounts for approximately 15% of all pediatric cancer fatalities.
The disease is frequently associated with the presence of MYCN amplification, a genetic biomarker associated with poor prognosis. Researchers from the Department of Hematology/Oncology at Dana-Farber/Children?s Hospital Cancer Center in Boston, Mass. have determined that tumors containing MYCN amplification are sensitive to a new class of drugs, BET bromodomain inhibitors.
The research team made this discovery in a preclinical study, which was funded in part by a Stand Up To Cancer Innovative Research Grant and was published in Cancer Discovery, a journal of the American Association for Cancer Research.
A new therapeutic option
?BET bromodomain inhibitors are a class of drugs that many researchers are hopeful may offer a new therapeutic option for treating patients with certain cancers,? said Kimberly Stegmaier, M.D., assistant professor of pediatrics in the Department of Hematology/Oncology at Dana-Farber/Children?s Hospital Cancer Center in Boston, Mass. ?The challenge has been identifying biomarkers that can help direct clinical translation of these drugs by pinpointing those patients with the highest likelihood of response.?
To identify genetic biomarkers of responsiveness to BET bromodomain inhibitors, Stegmaier and colleagues screened more than 600 cancer cell lines with known genetic characteristics for sensitivity to a prototypical BET bromodomain inhibitor.Using this high-throughput, cell-based screening process, the researchers found that neuroblastoma cells in which the MYCN gene was amplified were sensitive to BET bromodomain inhibitors.
An elusive drug target
?Neuroblastoma is a devastating childhood cancer, and only a minority of children with high-risk disease will be cured with currently available treatments,? Stegmaier said. ?Prior research has shown that MYCN amplification is common in neuroblastoma, but it has been an elusive drug target.?
Validating the findings
To further validate their findings, the researchers tested a BET bromodomain inhibitor, from the laboratory of James E. Bradner, M.D., at the Dana-Farber Cancer Institute, using cultured MYCN-amplified neuroblastoma cell lines and three animal models of MYCN-amplified neuroblastoma. Together, they found that the drug decreased levels of MYCN protein in cultured cells, and that this led to impaired cell growth and cell death. In each animal model, including a mouse model of neuroblastoma that is known to be resistant to many standard therapies, the drug was shown to have anti-tumor effects and to prolong survival.
?My Stand Up To Cancer grant, which focused on modulating difficult drug targets in childhood cancers, was instrumental to us being able to do this exciting work,? Stegmaier said. ?These types of studies are generally considered high-risk, particularly because they start with unbiased screening, and they are generally less likely to be supported by traditional sources of funding.?
For more information:
– Puissant A, Frumm SM, Alexe G, Bassil CF, Qi J, Chanthery YH, Nekritz EA, et al. Targeting MYCN in Neuroblastoma by BET Bromodomain Inhibition. Cancer Discovery March 2013 3; 308. Published OnlineFirst February 21, 2013; doi: 10.1158/2159-8290.CD-12-0418
– Schnepp RW, Maris JM. Targeting MYCN: A Good BET for Improving Neuroblastoma Therapy? Cancer DiscoveryMarch 2013 3; 255 doi: 10.1158/2159-8290.CD-13-0018.
Copyright ? 2013 InPress Media Group/Sunvalley Communication. All rights reserved. Republication or redistribution of InPress Media Group/Sunvalley Communication content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group/Sunvalley Communication. InPress Media Group/Sunvalley Communication shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Onco’Zine and Oncozine are registered trademarks and trademarks of Sunvalley Communication around the world.