October 11, 2019
2 min read

Researchers identify potential therapeutic target for glioblastoma

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Asparagine endopeptidase appeared to promote disease progression among patients with isocitrate dehydrogenase-wild-type glioblastoma by inactivation of p53, according to results of a prospective study published in Journal of the National Cancer Institute.

Researchers noted that asparagine endopeptidase (AEP), also referred to as legumain, may serve as a prognostic and therapeutic target for glioblastoma.

“Mutations that directly inactivate or delete p53 itself are relatively few in [isocitrate dehydrogenase-wild-type glioblastoma],” Yongming Qiu, MD, PhD, clinical oncologist in the department of neurosurgery at Ren Ji Hospital and at Shanghai Jiao Tong University in China, and colleagues wrote. “Though the p53 pathway can be compromised by amplification of MDM2, the mechanisms that suppress p53 functions remain elusive in most [isocitrate dehydrogenase-wild-type glioblastoma]. Therefore, understanding the inhibitory mechanisms targeting wild-type p53 is extremely important for addressing glioblastoma, especially in the [isocitrate dehydrogenase-wild-type] form.”

Qiu and colleagues analyzed serum samples from healthy donors (n = 48) and from patients with glioblastoma (n = 20) through enzyme-linked immunosorbent assays to determine the role of AEP in progression of glioblastoma.

Results showed AEP binds to and cuts wild-type p53, which inhibits the wild-type p53-mediated tumor suppressor function in tumor and stromal cells by extracellular vesicle communication.

Researchers performed immunohistochemical analyses on 99 human glioma specimens. Results showed that overexpression of AEP promoted tumorigenesis and shortened survival among patients. Patients with high AEP levels had shorter median OS than patients with low AEP expression (8 months vs. 26 months; HR = 3.94; 95% CI, 1.87-8.28).

Higher plasma AEP levels also appeared associated with larger tumor sizes in glioblastoma (P = .03). The concentration of AEP in serum decreased in patients after surgery.

Additionally, researchers studied the effects of AEP inhibitors on glioblastoma progression by implanting a subline of U87-NC (negative control), U87-AEP-SH (short hairpin) or U87-AEP-OE (overexpression) cells into murine models. Treatment with an AEP inhibitor significantly slowed tumor progression (P = .002), whereas AEP overexpression significantly increased tumor volume (P < .001).

This potential treatment needs to be studied further, researchers noted.

“Targeting AEP with a vaccine has been found to be effective in the targeted therapy of cancer,” Qiu and colleagues wrote. “Individuals who overexpress AEP with their tumor infiltrating lymphocytes may be more responsive to PD-1- or PD-L1-based immunotherapeutics. Moreover, the strict substrate specificity of AEP combined with its overexpression in various tumors has motivated the exploitation of AEP as a prodrug activator in cancer treatment, such as by adding a cleavable peptide chain to doxorubicin or auristatin.”


Chemical inhibitors of AEP have been under development, and the potential efficacy of targeting MDM2-p53 or MDM4-p53 interactions has already been proven, James J. Manfredi, PhD, professor of oncological sciences at Icahn School of Medicine at Mount Sinai, wrote in an accompanying editorial.

“This further provides support to the idea that AEP inhibitors may be a new addition to the arsenal of therapies that can be used in tumors with impairment of the p53 pathway,” Manfredi wrote. “Appropriate and effective treatments for glioblastoma are an unmet need that may very well be addressed by further study of AEP in this clinically challenging disease.” – by John DeRosier

Disclosures: The study authors report no relevant financial disclosures. Manfredi reports no relevant financial disclosures.