Targeting Purine Pathway in DIPG
Principle Investigator: Biplab DasGupta, PhD
Division of Oncology
Diffuse intrinsic pontine glioma (DIPG) is a rare, infiltrative, and incurable brainstem malignancy in children resulting in death within one year from diagnosis. DIPG represents up to 85% of brainstem tumors and has the worst prognosis of all childhood cancers with a five-year overall survival of < 1%. These tumors are inoperable and surgical biopsies are not common. Being a rare disease (about 300-400 new cases in the United States each year), resources and funding are scarce. Lack of surgical options confers particularly poor prognosis and a challenge to study the disease. Genomic studies have identified a recurrent mutation in histone H3 genes that leads to a K27M substitution in the protein and is present in nearly 80% of DIPG. The dominant negative effect of the K27M mutation causes global loss of H3K27me3 methylation, interference with the polycomb repressive complex, releasing genes from their repressed state. This is thought to be a major driver for these tumors classifying H3K27M as an oncohistone. These key studies have substantially contributed to our understanding of the genetic and epigenetic drivers of DIPG. Several clinical trials extrapolated from adult glioma studies have failed to improve survival, and new rationally derived approaches based on our understanding of the disease biology are urgently needed.
We recently generated a transcriptomic-metabolic profile for DIPG elucidating key differentially altered pathways in this tumor. To identify novel molecular targets, we performed the first combined genomic and metabolomic analysis of DIPG. Our studies uncovered the de novo purine biosynthesis pathway as a novel metabolic vulnerability in DIPG. Our strong preliminary data showed that the purine pathway gene ATIC is a previously unknown therapeutic target in DIPG. A commercially available ATIC inhibitor (with potential patentable applications), as well as genetic studies, demonstrated that while ATIC inhibition has little effect on normal glial or neuronal cells of the brain, it killed multiple DIPG lines in vitro and either eradicated established tumors or led to stable disease in vivo. Our preliminary pharmacological data showed that the inhibitor that penetrates the blood-brain barrier, and the therapeutic dose is nontoxic in mice. We are investigating the mechanisms of action of target inhibition using the ATIC inhibitor, as well as genetic tools in DIPG cell lines and two mouse models of DIPG. Our laboratory has over 10 years of experience in studying brain tumor metabolism. Tumor metabolism has been an effective chemotherapeutic target for many years and the success of these therapies validates that a therapeutic window may exist to target malignant metabolism in DIPG. We also have a very strong team of collaborators that includes a pharmacologist and a drug design expert. We are using our preclinical in vitro and in vivo models to achieve a clinically relevant outcome. Our long-term goal is to significantly improve the overall survival of children with DIPG by identifying novel therapeutically amenable targets.