Zotiraciclib and Radiation Combo Shows Promise in Pediatric High-Grade Gliomas

Research study background

Research led by investigators in the Neuro-Oncology Program at Children’s Hospital Colorado reveals a promising approach to increasing effectiveness of radiation therapy against the most aggressive childhood brain tumors. The study, published earlier this year in Nature Communications, was a part of a multidisciplinary collaboration with the University of Colorado School of Medicine and the University of Colorado, Boulder.

Radiotherapy is the only standard of care for all subtypes of pediatric high-grade gliomas (HGGs), which include diffuse intrinsic pontine gliomas (DIPGs) and other histone-mutant diffuse midline gliomas (DMGs). This treatment can ease symptoms and temporarily delay progression but isn’t curative. Outcomes for children with HGG are often poor, as these tumors typically develop resistance to radiation therapy, and most children survive only a few years after diagnosis.

When researchers examined how pediatric HGG model cells responded to therapeutic ionizing radiation, they found Positive Transcription Elongation Factor b (P-TEFb) played a key role. Radiation exposure caused active chromatin to rapidly reorganize and enabled P-TEFb to quickly trigger genes necessary for survival ─ particularly those involved in repairing DNA damage and controlling the cell cycle.

Their discovery prompted investigators to explore a combined therapeutic approach to determine if they could block P-TEFb's function and disrupt the survival response. Investigators simultaneously applied zotiraciclib, an orally available P-TEFb inhibitor, and radiation to HGG model cells. The team observed that the combination impaired these cells from repairing DNA damage or regulating their cycles properly. This led to much higher rates of tumor cell death and extended survival in murine models compared to radiation treatment alone.

Clinical implications

These findings are significant as it suggests a new approach to improve the effectiveness of radiation therapy against gliomas. By blocking P-TEFb, doctors might weaken cancer cells' ability to adapt and survive radiation treatment. This combination therapy could potentially improve outcomes for patients with these challenging and often deadly brain tumors, regardless of the glioma subtype.

Zotiraciclib is currently being tested in clinical trials as a potential treatment for adults with brain tumors such as anaplastic astrocytoma or glioblastoma. As a participating site of the Pediatric Brain Tumor Consortium, study authors are working with a team of collaborators to bring this drug into a new phase 1 clinical trial for children with HGGs.