Nov, 2021 - By WMR
A research team has discovered a small-molecule regulator which was able to decrease tumor development in lab animals of this tumor, bringing fresh opportunities for pediatric patients.
While significant progress has been achieved against some kinds of pediatric cancer, increased gliomas remain untreatable. Mutations in the H3F3A gene are seen in 30-60% of these pediatric brain tumors. This gene encodes the blueprint for histone H3.3, a protein that plays a key function in chromatin organization. Scientists have named one of these mutations H3.3G34R/V, which means the amino acid glycine has been replaced by either an arginine or a valine at position 34.
Such tumors develop in little older kids than some of the other well-known kinds of childhood glioma—between the age of 10 – 18 years. Due to a scarcity of viable therapies, the outlook remains poor.
The team, led by Stefan Sweha, lead author and a neuroscience graduate student, focused on epigenetic changes in tumors—that is, changes that aren't permanent alterations in the DNA but impact the way cells access and interpret DNA sequences. Eventually, they discovered changes that resulted in increased production of a protein called LIF, which stands for leukemia inhibitory factor. LIF then stimulates the STAT3 signaling pathway, which has been linked to a variety of different cancers. A small-molecule inhibitor of STAT3 named WP1066 was demonstrated to decrease tumor development and extend the lives of mice with H3.3G34R/V glioma in lab animals.
The drug molecule is presently being evaluated in clinical trials for glioblastoma in adult patients and has the key characteristic of being able to penetrate the blood-brain membrane, which is important for developing brain cancer therapies.
The objective is to get the compound into pediatric clinical trials, said senior study author Sriram Veneti, M.D., Ph.D., the Al and Robert Glick Family Research Professor of Pediatrics in the Department of Pathology at Michigan Medicine.