Targeting IL-13Rα2 for effective treatment of malignant peripheral nerve sheath tumors in mouse models

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OBJECTIVE

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas that harbor a high potential for metastasis and have a devastating prognosis. Combination chemoradiation aids in tumor control and decreases tumor recurrence but causes deleterious side effects and does not extend long-term survival. An effective treatment with limited toxicity and enhanced efficacy is critical for patients suffering from MPNSTs.

METHODS

The authors recently identified that interleukin-13 receptor alpha 2 (IL-13Rα2) is overexpressed on MPNSTs and could serve as a precision-based target for delivery of chemotherapeutic agents. In the work reported here, a recombinant fusion molecule consisting of a mutant human IL-13 targeting moiety and a point mutant variant of Pseudomonas exotoxin A (IL-13.E13 K-PE4E) was utilized to treat MPNST in vitro in cell culture and in an in vivo murine model.

RESULTS

IL-13.E13 K-PE4E had a potent cytotoxic effect on MPNST cells in vitro. Furthermore, intratumoral administration of IL-13.E13 K-PE4E to orthotopically implanted MPNSTs decreased tumor burden 6-fold and 11-fold in late-stage and early-stage MPNST models, respectively. IL-13.E13 K-PE4E treatment also increased survival by 23 days in the early-stage MPNST model.

CONCLUSIONS

The current MPNST treatment paradigm consists of 3 prongs: surgery, chemotherapy, and radiation, none of which, either singly or in combination, are curative or extend survival to a clinically meaningful degree. The results presented here provide the possibility of intratumoral therapy with a potent and highly tumor-specific cytotoxin as a fourth treatment prong with the potential to yield improved outcomes in patients with MPNSTs.

ABBREVIATIONS ALT = alanine transaminase; AST = aspartate transaminase; BUN = blood urea nitrogen; DMEM = Dulbecco’s modified Eagle medium; FBS = fetal bovine serum; H & E = hematoxylin and eosin; hIL-13 = human IL-13; IL-13 = interleukin-13; IL-13Rα2 = IL-13 receptor alpha 2; MPNST = malignant peripheral nerve sheath tumor; NF1 = neurofibromatosis type 1; PBS = phosphate-buffered saline; TCGA = The Cancer Genome Atlas.
Article Information

Contributor Notes

Correspondence Oliver D. Mrowczynski: Penn State Hershey Medical Center, Hershey, PA. omrowczynski@pennstatehealth.psu.edu.INCLUDE WHEN CITING Published online November 30, 2018; DOI: 10.3171/2018.7.JNS18284.Disclosures Drs. Mrowczynski, Madhankumar, and Connor have consulting relationships with Targepeutics, Inc. This work was funded in part by Penn State Neurosurgery and by Targepeutics, Inc.
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