Northwestern University’s Dr. Chen Shen Takes a Closer Look at How ATRX Mutation Affects DIPG.
The ChadTough Foundation and Michael Mosier Defeat DIPG Foundation have partnered to fund more than $3.3 million in Diffuse Intrinsic Pontine Glioma (DIPG) research grants. Their first round of grants was announced in 2017 and included a fellowship grant awarded to Dr. Chen Shen, a research fellow at Northwestern University. Her study is entitled “Dissection of ATRX in Diffuse Intrinsic Pontine Glioma.”
Under the direction of Dr. Oren Becher at Northwestern University Feinberg School of Medicine, Dr. Shen’s project focuses on the ATRX protein and its role in driving DIPG tumor growth. Dr. Becher’s laboratory is unique because they study DIPG exclusively and do so through genetically engineered mouse models. Because DIPG is a heterogeneous disease, they can develop mouse models to control for specific mutations to understand how each mutation may contribute to DIPG.
The first step of Dr. Shen’s project was to develop a new mouse model that also deleted ATRX in addition to the histone mutation to study how ATRX contributes to DIPG formation. While the histone mutation is commonly seen in human DIPG tumors, ATRX has been found to be deleted in a subset of only 10-30% of human DIPG tumors. When ATRX deletions do occur in human DIPG tumors, they co-occur with the more commonly seen histone mutations. This model will be used to look at what happens when you add the deletion of ATRX on top of the histone mutation. Dr. Becher reports that the new mouse model has been developed and work is ongoing to evaluate how ATRX deletion changes genes that are turned on in tumor cells. Final results are expected at the end of this year. Interestingly, they were also able to obtain additional information on some other genes that appear to be regulated by ATRX loss with this model, and are currently validating these genes that are differentially expressed between the tumors with and without ATRX. “Once we validate these genes that appear to be regulated by ATRX, this will be important knowledge for the field because it has not been well described what genes are regulated by ATRX in DIPG cells specifically with the histone mutation,” said Dr. Becher.
Additionally, Dr. Shen will test some of the ATRX mutant mouse cell lines with and without ATRX loss to see how ATRX affects response to radiation. Radiation is the current standard of treatment for DIPG used to temporarily improve clinical symptoms, and can increase survival by about 3-6 months. Dr. Becher notes that not all children with DIPG respond to radiation in the same way. “There are some kids that we treat with radiation and they don’t benefit at all and some that have a dramatic response,” said Dr. Becher. Because of these differences in response, they would like to explore if this response can be linked to ATRX loss.
Dr. Becher’s lab will continue this project after the fellowship grant work ends as they have some new angles to explore once the target genes that appear to be regulated by ATRX have been validated. This work is planned to begin soon.
-Written by Ellen Klepack, a ChadTough Volunteer Writer