Malignant peripheral nerve sheath tumors (MPNSTs) are rare, potentially fatal sarcomas which occur in the covering of nerve structures. They are known to be aggressive, and typically occur in conjunction with the neurofibromatosis type 1 condition (NF1), which predisposes the patient to the development of tumors. To many of the MPNST patients, surgery is difficult, chemotherapies are not very much effective, and survival rates are relatively dreary. Indeed, almost 70 percent of MPNSTs are either metastatic or non curable at the time of diagnosis.
A new research study released on August 13, 2025 in Science Advances, however, provides new hope. Scientists at the University of Iowa and Duke University have identified a metabolic vulnerability of MPNST tumors, namely, tumors with CDKN2A gene deletion, the most frequent alteration in this type of cancer.
Depoisoning an Enzyme with CRISPR Technology
The research team deployed a gene editing technology known as CRISPR-Cas9 to recreate development of MPNSTs in mice. They knocked out Nf1, which was the mouse analog of the human Nf1 gene, after which they applied CRISPR to remove either Cdkn2a or Trp53 (mouse analog of P53 or another tumor suppressor). The strategy produced tumors similar to human MPNSTs, providing a model to research the biology of these tumors.
Looking at these tumors through a multiomic lens of gene expression and metabolites, they identified a dramatic trend:
PPP was severely dependent on tumors that lack CDKN2A-a cellular pathway that generates NADPH, which is required to maintain defense against oxidants and DNA precursors.
The vulnerability of the tumors to the PPP interference was related to the dependency.
The Pentose Phosphate Pathway: A Lifeline of Tumor.
The PPP diverges away from normal glucose metabolism and is essential in assisting cells in resisting oxidative stress; a feature of fast-growing cancer cells. The researchers found glucose 6-phosphate dehydrogenase (G6PD) as the expression that fuelled this mechanism in MPNSTs with CDKN2A loss.
When the researchers delivered a knockout to G6PD via CRISPR or used a drug like 6-an to knock G6PD inactive, the outcome was remarkable:
Growth of tumor cells slowed considerably in the test situations.
In mice, tumors have reduced and survival rates have improved.
The ability of G6PD inhibition to sensitize tumors to doxorubicin, a commonly used but ineffective chemotherapy drug against MPNST, is of high importance.
This metabolic targeting combined with chemotherapy has the potential to help the patients who presently lack good choices.
NRF2: The Master Switch Behind Tumor Protection
Probing further, the group found that the increased G6PD activity in such tumors was the work of NRF2, a transcription factor that is linked with antioxidant defenses. By decreasing NRF2, they received the same effects as blocking G6PD tumor growth was lower and the response to chemo was higher.
This was confirmed in patient data
Increased NRF2 and G6PD were also found to correlate with rapid transformation of benign neurofibroma to malignant MPNST in NF1 patients.
In TCGA PanCancer Atlas, higher NRF2/G6PD signatures were associated with an unfavorable disease outcome across various tumors.
This implies not only that the NRF2-PPP axis is unique to MPNSTs but also a major point of weakness in all cancers that bypass the pathways of antioxidant production
Patient and Future Therapeutic Implications
As far as MPNST patients are concerned with the decreased options, this discovery provides a ray of optimistic hope. Clinical trials currently targets MEK inhibitors (where the activation pathway lost by NF1 is also active), but responses showed only modest activity. Combining of MEK inhibitors with PPP or NRF2-directed therapies has a potential to provide higher treatment efficacy.
The challenges are not yet over especially in drug development. G6PD inhibitors do exist, but are too toxic to use systemically. Investigators are now focusing on a more specific delivery process to the tumor and NRF2 inhibitors used in the sarcomas.
According to the lead author Rebecca D. Dodd, the metabolic dependencies might help us develop smarter, less toxic therapy against some of the hardest to treat cancers.
A Step Toward Personalized Cancer Medicine
This paper highlights the significance of cancer metabolism as an aspect to be considered in the design of therapy. By selecting and characterizing patient tumors with the specific vulnerabilities that drew their attention to begin with, researchers can begin to create precision oncology by matching each tumor with a therapy based on its biology.
In the case of a patient with NF1 or MPNST, this may translate to detecting the high risk tumors earlier and open new modalities of treatment which can finally curb this devastating disease.
Reference:
McGivney, G. R., et al. (2025). Somatic CRISPR tumorigenesis and multiomic analysis reveal a pentose phosphate pathway disruption vulnerability in MPNSTs. Science Advances, 11, eadu2906.