Elucidating the Role of ATRX in NF1-Associated High-Grade Glioma Formation
Abstract
NF1 patients develop an array of both benign and malignant tumors. Of these, malignant peripheral nerve sheath tumors (MPNST) and high-grade gliomas (HGGs) have the most dismal prognosis. About 15-20% of neurofibromatosis type I (NF1) patients develop brain tumors; a third of these occur outside of the optic nervous tract. Importantly, these non-optic pathway gliomas are more likely to progress to malignancy, especially in adults. Even though the frequency of HGG is low they have a disproportional effect on the morbidity of NF1 patients. Recent studies have identified additional mutations that might be involved in NF1 HGG formation. Unfortunately, accurate mouse models for NF1 associated HGGs that incorporate this data do not exist, hampering our ability to really understand what drives these NF1 associated HGG and to test potential therapies. It is exactly this mechanistic understanding that will allow us to develop rational therapies. Additionally, if we want to evaluate the efficacy of immunotherapies, we will need to generate brain tumor models in mice with an intact immune system. Excitingly, we have developed these mouse models and will use them to test therapies and elucidate what drives these NF HGGs. Besides mutations in NF1, a large proportion of NF1-associated HGGs have mutations in a tumor suppressor called ATRX. Unfortunately, functional studies and studies that investigate how mutations in ATRX contribute to HGG formation are lacking. Our goal is to (1) elucidate how ATRX drives NF1 HGG formation, (2) determine whether these HGGs are sensitive to a promising combination immunotherapy that is going into clinical trial for MPNST, and (c) investigate whether ATRX loss confers a therapeutic sensitivity to other, more early-stage therapies. ATRX is a large gene and is involved in multiple processes in the cell. Our preliminary data suggest that one of these processes specifically contributes to HGG formation. Excitingly, we have evidence that NF1 HGGs are sensitive to different therapies; one of these is a combination immunotherapy in late-stage clinical trial development for MPNST (MEK+BRD4+PD1 checkpoint blockade). This trial was inspired by my previous unpublished work on MPNSTs in the laboratory of Dr. Karen Cichowski. If our current study confirms that NF1-associated HGGs are sensitive to this combination immunotherapy as well, a new clinical trial can be set up relatively quickly, especially if the MPNST trials show little toxicities, and hopefully improve the lives of NF1 patients with HGGs. Importantly, our tractable models, together with my unique expertise in dissecting complex mechanisms of tumor formation and preclinical testing form a powerful combination to better understand, therapeutically target, and help patients with NF1-associated HGGs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010124
Entities
People
- Thomas De Raedt
Organizations
- United States Army