Game Changer Grant Awarded to Peter Dirks and Cynthia Hawkins

The origins and steps of progression from a normal brain cell to cancerous brain cell of DIPG is poorly understood and is a critical missing piece that could help identify new treatments. By the time of clinical presentation, these tumors are well-advanced and are highly heterogeneous from a genetic and cellular perspective, features that contribute to escape from therapy. We hypothesize that better treatments for DIPG will involve earlier treatment when the disease is simpler. Defining the key molecular and cellular characteristics of the “pre-malignant” DIPG cell populations and early tumor populations, in addition to the identities of noncancerous populations that comprise the tumor, may lead to earlier diagnosis and to the development of strategies to intercept full development of the DIPG cancer. We will utilize clinically relevant genetically engineered mouse models of DIPG, incorporating serial magnetic resonance imaging (MRI) and “lineage tracing” to study DIPG development from inception. Lineage tracing enables marking individual cells that we engineer with DIPG mutations in brainstem precursor cells, and following the subsequent daughter cells over time. We can use this approach to map tumor development from first initiated cells to clinically apparent disease. We will define how the normal precursor cells in the brainstem are corrupted by DIPG mutations, how they remodel the surrounding brain, and then develop into fully malignant DIPG. In addition to bringing to light new knowledge of DIPG initiation and progression, we predict that we will identify early biomarkers of disease that will enable early diagnosis and will then test strategies that block the progression of the early diseased cells that later become full blown untreatable DIPG. Although early diagnosis of DIPG in humans is very challenging, we predict this work will lead to new concepts for DIPG origins, growth, diagnosis, prevention, and treatment.