Research Grant Update: Therapeutic Blockade of Metabolic Dependencies in Diffuse Intrinsic Pontine Glioma
The research grant proposal “Therapeutic Blockade of Metabolic Dependencies in Diffuse Intrinsic Pontine Glioma” was funded in December 2019 by TeamConnor Childhood Cancer Foundation for the 2020 research year. Despite significant challenges, Dr. Diplab Dasgupta and his team at Cincinnati Children’s Hospital worked through the pandemic. They were supported by the generous funding from TeamConnor research grant; they were able to generate exciting data and submitted an NIH (National Institute of Health) R01 proposal. Reviewers at the NIH understood the importance of the study; however they asked for key additional data, both mechanistic and in vivo. The grant did not get funded, and they are planning to submit a revised application as soon as we generate the required data. Leveraging previous funding from the TeamConnor grant, they generated the first comprehensive gene -metabolite interaction maps and identified two novel druggable targets in this lethal brain tumor. Both targets were part of the de novo purine synthesis and one carbon metabolism pathways. This funding allowed them to move the project forward and perform preclinical studies. Based on our novel findings we filed a provisional patent application for the use of a small molecule to treat DIPG.
They found that DIPG patient mutations directly regulate at least one of these genes. This target that they are currently pursuing is a gene called ATIC which is a key enzyme in the metabolic pathway that makes the building blocks for DNA and RNA. A small molecule ATIC inhibitor was highly specific in killing DIPG cells leaving normal human neural cells (astrocytes, neurons and neural stem cells) unaffected. They also found that this small molecule penetrates the blood brain barrier and shrinks tumor volume or maintains stable disease and in some cases eradicates the tumor significantly increasing survival in their preclinical mouse models of DIPG. They are currently pursuing in-depth molecular and mechanistic studies to better understand the full impact of ATIC inhibition in tumors.
TeamConnor Childhood Cancer Foundation is thankful to the support and generosity of donors who have given the gifts to fund our important mission for childhood cancer research. Thank you to Dr. Dasgupta and his amazing team at Cincinnati Children’s Hospital for overseeing the important research for children fighting the brave battle of childhood cancer.