Understanding Clonal Origins of MPNSTs

One of the clinical hurdles we are trying to mitigate is understanding how the intrinsic tumor biology effects the ability of the tumor to spread. This will help us with how we think about metastasis and treatment of metastasis in patients. We are using patient genomic information to assess what changes occur in the tumor cells that might be passed on from primary to metastatic tumors.

Patient Derived Xenografts

Despite advances in our understanding of the pathobiology of these tumors and the identification of seemingly-promising therapeutic targets using a single mouse MPNST model system (NPCis mice and derivative cell lines), no investigational agents have demonstrated efficacy following translation to human clinical trials. To optimize clinical translation, one aim of the Hirbe Lab is to develop a collection of MPNST Patient Derived Xenografts (MPNST-PDXs) for the NF community, which more fully represent the spectrum of genetic heterogeneity seen in the human condition. To date, we have generated 5 clinically annotated NF1-MPNST PDX lines that we have histologically and genomically characterized and are now available for pre-clinical testing. Future work will continue to expand this collection. 

In an effort to make a more comprehensive set, the Hirbe Lab is collaborating with the Pratilas Lab at Johns Hopkins University using their NF1 Biospecimen Repository. For more information about their repository, please click here. 

SPTBN2: Diagnostic Marker

 Recent findings in the lab have made us very excited about this target. More work is needed to understand what is happening to cause this difference and whether that pathway can be targeted therapeutically. Stay tuned!


Prior work from our laboratory has demonstrated that β-III-spectrin is highly expressed in MPNSTs, but not plexiform neurofibromas suggesting that β-III-spectrin could play an important role in the progression and diagnostics of these tumors. Knockdown of β-III-spectrin significantly increased cell death in vitro and in vivo in a subcutaneous tumor model.  Additionally, in the metastasis model, knockdown of β-III-spectrin led to a decreased tumor burden and increased overall survival.  Knockdown of β-III-spectrin was also associated with mis-localization of the mGluR1 glutamate receptor, a G-protein coupled receptor that can affect cell survival.   Additionally, β-III-spectrin –deficient cells had decreased levels of EAAT4, a glutamate transporter.

 Using RNA sequencing from the original patient and the xenograft we are exploring similarities and differences. 

ATRX: Prognostic Marker

Previous work in our lab had identified ATRX chromatin remodeler (ATRX), previously termed, Alpha Thalassemia/Mental Retardation Syndrome X Linked, as a gene mutated in a subset of MPNSTs. Given the great need for novel biomarkers and therapeutic targets for MPNSTs, we sought to determine the expression of ATRX in a larger subset of sporadic and NF1 associated MPNSTs (NF1-MPNSTs). We performed immunohistochemistry (IHC) on MPNSTs (NF1-associated and sporadic), plexiform neurofibromas, and atypical neurofibromas. We demonstrated that ATRX is aberrantly expressed in the majority of NF1-MPNSTs, but not plexiform or atypical neurofibromas. Additionally, aberrant ATRX expression is associated with decreased overall survival in NF1-MPNST, but not sporadic MPNST and may serve as a prognostic marker for patients with NF1-MPNST.

TYK2: Therapeutic Target

Leveraging advanced genomic sequencing methods, our lab previously identified TYK2 as a frequently mutated gene in NF1-associated MPNSTs, and showed that this gene is critical for MPNST cell survival both in MPNST cells grown in the laboratory and in mice. We believethat TYK2 drives MPNST growth by protecting them from cell death and thus may serve as a biomarker for poor prognosis as well as a druggable target. We are currently working to define the molecular mechanism of TYK2 in MPNST development and growth using engineered primary MPNST cell lines in vitro and complementary patient derived tumor lines in vivo. We are also assessing the utility of TYK2 expression as a biological marker for MPNST and progression and evaluating the utility of therapeutic targeting of TYK2 using small molecule inhibitors.  These experiments have the potential to lead to a therapeutic option which is desperately needed for these aggressive sarcomas.