Northeastern University



Behavioral Neuroscience, '25

Diffuse Intrinsic Pontine Glioma (DIPG) and Brainstem Tumors in Pediatric Patients

Mentor: Nathalie Agar, Ph.D.

Institution: Brigham and Women's Hospital

With a 100% mortality rate and an average chance of survival of less than one year, diffuse intrinsic pontine glioma (DIPG) is a horrific cancer that happens to be the most common brainstem tumors found in pediatric patients. This disease generally affects children between the ages of 5 to 10 years old and has been found incredibly difficult to treat. Due to the location and “diffuse” quality of the tumor in a critically important area of the brainstem, surgical resection is not a possible option for these patients. Currently, the treatment for DIPG has been focal irradiation, but usually ends in palliation. Some potential therapeutic candidates have been developed, but many challenges have been faced limiting their use. One of the main challenges has been crossing the “super blood brain barrier” specifically found in DIPG that is making it difficult to reach the affected areas. Studies have found a somatic mutation in the activin receptor gene, ACVR1, and researchers are evaluating the therapeutic relevance of targeting this gene as a possible form of treatment. In addition to these findings, there is also evidence suggesting that having patients follow a ketogenic diet, in which they consume a low amount of carbohydrates and high amount of fat, can be used to support cancer therapy in order to suppress secondary tumor formation. The laboratory led by Dr. Nathalie Agar has recently evaluated the activity of TP-0184, a nanomolar brain-penetrant inhibitor of mutant ACVR1, in a patient with this DIPG mutation to assess its therapeutic relevance. Strikingly, the transcriptomic data suggests that metabolic reprogramming might be at the origin of the resistance in DIPG cell line ACVR1 WT. To further explore this, we will first decipher the potential metabolic reprogramming mentioned in vitro (cell line) using biochemistry and molecular biology and in vivo (orthotopic patient-derived xenograft) with mass-spectrometry imaging. Then, another direction we will investigate is the potential impact of the ketogenic diet in vivo using orthotopic PDX mice implanted with human DIPG cell lines and fed with a control or ketogenic diet. Spatial metabolomics experiments will then be performed on sagittal sections of these brains to explore whether this diet helps improve the prognosis of the patient in junction with the treatment. Altogether, the new data collected might be able to provide new insight into the complex disease of DIPG and have a major impact by finally supplying patients options that have been unavailable in the past.

CaNCURE Research Presentation: