SBIR FY25 CONCEPT AWARD: TARGETING DYSFUNCTIONAL CHROMATIN NETWORKS IN DIPG

Patients with diffuse pontine intrinsic glioma (DIPG), an aggressive pediatric brain cancer, desperately need effective treatments. Once diagnosed, these children quickly lose their motor functions and succumb to the tumor with an average life-expectancy of 8-11 months and a 5-year survival of less than 1%. While some therapies are starting to show promise in clinical trials, they are still either short-lived or ineffective for most patients. Despite understanding that DIPG is driven by a well-defined chromatin mutation, there has been no way to drug this defect directly. In this proposal, a novel targeted biochemical approach is utilized to directly target the aberrant interactions caused by the mutation in DIPG. Screening using this method has yielded small molecule hits that specifically disrupt DIPG aberrant chromatin in a test tube and show corresponding destabilization of the DIPG chromatin in patient-derived cells. The goals of this proposal are to identify mechanisms of the small molecule hits, and through medicinal chemistry obtain molecules that show efficacy in DIPG mouse models. The work is expected to provide a new class of lead molecules that can be further developed into novel therapies for DIPG with commercial extensions to larger cancer markets in the future.