Nucleic Acid-Based Strategy Targeting Fusion Oncogenes in CNS Tumors
Nearly 40% of all childhood cancers contain abnormal gene fusions, yet targeted therapies exist for only a subset of these alterations. Fusions, formed when two separate genes are joined together, promote tumor growth and often drive disease, making them attractive therapeutic targets. However, the complicated structure of fusion proteins often impedes small molecule inhibitor development, and when drugs are available, resistance to therapy inevitably develops. Furthermore, the diversity of rare fusion partners hinders traditional drug development mechanisms. This project aims to develop a personalized medicine approach using nucleotide-based therapies. Nucleotide-based therapies consist of DNA and RNA molecules engineered to bind directly to target fusions and deplete their expression, bypassing the traditional challenges that exist with small molecule inhibition. In this project, I will use nucleotide therapies engineered against specific fusion transcripts in pediatric gliomas, a group of aggressive, relentless brain tumors. I hypothesize that oncofusions can be directly targeted using this approach to offer a new treatment strategy for children with low-grade and high-grade glioma.
Project Goals
Children with recurrent gliomas lack standard-of-care therapies, and they remain extremely difficult-to-treat. My overarching goal is to change this narrative by developing targeted therapies directed at one of the most pervasive molecular alterations identified in childhood cancers: oncogenic fusions. Our team has designed nucleotide therapies that decrease fusion expression in multiple cancer types. Using constructs designed specifically for pediatric low-grade glioma and high-grade glioma, I will test their ability to decrease cell growth in cell culture and patient-derived organoid models. I will characterize the mechanistic impact of fusion depletion by performing advanced RNA-sequencing analysis. Using mouse models, I will test the ability of nucleotide therapies to reach deep brain tissues by direct injection into the cerebrospinal fluid, leveraging the blood brain barrier to retain therapies in the central nervous system. Using neurosurgical placement of a catheter that imitates delivery in patients, I will deliver nucleotide therapies and evaluate how they impact tumor growth and how they are distributed across the body. This work will provide critical data necessary to open a clinical trial evaluating this personalized medicine approach for children with brain tumors
