Pre-doctoral Fellowship Grant Awarded to Akhila Parthasarathy

DIPG/DMG is one of the most aggressive types of pediatric brain tumors, with a dismal median survival of less
than one year. One of the hallmarks of DIPG/DMG is the H3K27M mutation, found in 80% of the patients. This
mutation in the histone proteins, a gateway to access DNA, drives abnormal gene expression. DMG is also
associated with another challenge: its “immune dessert” niche, where tumor-killing immune cells called T cells
are virtually absent within the tumor itself, making immunotherapeutic approaches hardly effective.
Viroimmunotherapy is a promising tool that combines engineering viruses to selectively kill cancer cells and
create a robust influx of antitumor immune cells to the tumor. In a recent phase I clinical trial for pediatric patients
with DIPG, we showed that treatment with our oncolytic adenovirus, Delta-24-RGD, improved median survival
without significant toxicities. In this project, we aim to investigate the effect of the virus on the histone proteins
and its consequent effect on enhancing anti-tumor immunity. Preliminary studies combining Delta-24-RGD and
p300-related histone-modifying drugs show encouraging results in reducing cell viability in human and mouse
DMG cells. The objective of this project is to find the mechanistic link between altered histone proteins and their
subsequent effect in suppressing immune activity in the tumor niche. Our findings will eventually propel testing
the combination of Delta-24-RGD and p300 inhibitors in a clinical trial for patients with DIPG/DMG.