Brendan Price, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Pediatric high-grade gliomas (pHGG) have few treatment options and most children diagnosed only survive for 1-2 years. Identifying new treatments is therefore of the highest priority. Work in the lab is focused on understanding how these brain tumors arise, with the aim of developing new treatments.
Pediatric gliomas frequently have mutations in one of the proteins which package the DNA in the cell. This protein, called histone H3.3, plays a very important role in controlling how DNA functions. In pediatric brain tumors, we have found that mutation of a single amino-acid (glycine 34) in H3.3 (called H3.3G34R) blocks one of the cell’s DNA repair pathways. This loss of DNA repair has a cascade effect, leading to further genetic changes which ultimately lead to tumor development. However, this makes H3.3G34R pediatric gliomas dependent on other DNA repair pathways to survive. This dependence on a sub-set of DNA repair pathways represents an “achilles heel” which we can exploit to develop new targeted therapies for this disease.
One of the challenges in our work is that there are few cell lines available which we can use to study this disease. Funding from the Child Brain Tumor Foundation has allowed us to create cell lines expressing tumor derived mutations in histone H3.3. To achieve this, we have used the new genome engineering method, called CRISPR, to insert point mutations in histone H3.3 which are the same as those found in pediatric patients. This has allowed us to generate paired cell lines which are either normal or mutated for histone H3.3. We are using these cell lines to identify the key DNA repair pathway which is inactivated in pHGG with the H3.3G34R mutation.
With support from The Childhood Brain Tumor Foundation, we are
carrying a small screen for potential new drugs which can specifically
kill these tumor cells. By understanding how these mutations contribute
to altered DNA repair in pHGG, we can develop new approaches to treat
this intractable disease.