$1.4m NCI grant will help develop promising new treatment for aggressive childhood cancer
VCU Massey Cancer Center researchers have been awarded a grant totaling more than $1.4 million over four years from the National Cancer Institute (NCI) to drive the development of a new treatment for MYCN-amplified neuroblastoma, an aggressive subset of pediatric nervous system cancer marked by overexpression of the MYCN gene. There are limited treatments currently available for MYCN-amplified neuroblastoma, and it is among the deadliest of the pediatric cancers.
The grant (1R01CA249219-01) will fund experiments led by Anthony Faber, Ph.D., who has focused much of his research on this aggressive pediatric cancer. He and his team have discovered that the MYCN gene drives the expression of the DNMT1 gene and creates a feedback loop that contributes to aggressive tumor growth. They are hopeful that blocking the gene DNMT1 will interrupt this process and offer an effective treatment for MYCN-amplified neuroblastoma.
“While there are no available drugs that target the MYCN gene, several exist to inhibit DNMT1,” says Faber, Natalie N. and John R. Congdon Chair in Cancer Research and co-leader of the Developmental Therapeutics research program at Massey Cancer Center as well as associate professor at the VCU Phillips Institute in the School of Dentistry. “We will be conducting experiments with cell lines and mouse models in hopes of establishing the evidence needed to support a clinical trial led by our collaborator at the NCI Pediatric Oncology Branch.”
The researchers will focus their efforts on two drugs: decitabine and guadecitabine. Decitabine is approved to treat the blood disorder myelodysplastic syndrome, and guadecitabine is an experimental drug currently being investigated in a clinical led trial by Faber’s collaborator John Glod, M.D., Ph.D., clinical director at the NCI Pediatric Oncology Branch. Both drugs have been shown to inhibit the DNMT1 gene, and the researchers hypothesize that they may complement two drugs currently used as maintenance therapies for MYCN-amplified neuroblastoma: dinutuximab and retinoic acid.
The team, led by VCU Philips Institute graduate student Krista Powell, will conduct experiments with cell lines of MYCN-amplified neuroblastoma to further understand the processes by which MYCN and DNMT1 interact to drive tumor growth and the effects of DNMT1 inhibition on cell survival. Various mouse models of the disease will help determine the effectiveness of each drug combined with dinutuximab and retinoic acid. Other investigators involved in this work include Jennifer Koblinski, Ph.D., director of Massey’s Cancer Mouse Models Core, member of the Cancer Molecular Genetics research program at Massey and assistant professor of in the Department of Pathology at the VCU School of Medicine; Masoud Manjili, Ph.D., member of the Developmental Therapeutics research program at Massey and professor in the Department of Microbiology and Immunology at the VCU School of Medicine; Lisa Shock, Ph.D. member of the Cancer Molecular Genetics research program at Massey and assistant professor in the VCU Department of Immunology and Microbiology; and Mikhail Dozmorov, Ph.D., member of the Cancer Molecular Genetics research program at Massey and assistant professor in the Department of Biostatistics at the VCU School of Medicine.
“This grant is a good example of the inter- and intra-collaborative efforts within the different programs of our cancer center. Without the efforts and expertise of these other investigators at Massey and with Dr. Glod at the NCI, this research would simply not be possible. I’m reminded how fortunate I am to work at a cancer center that values and understands the fruits of collaboration and teamwork,” says Faber. “We’re very thankful for this funding, and we’re excited to pursue these therapies desperately needed for children suffering from this insidious disease,” says Faber.