Targeting IL-13Ra2 for effective treatment of malignant peripheral nerve sheath tumors in mouse models

Oliver D. Mrowczynski, Russell A. Payne, Alexandre J. Bourcier, Christine Y. Mau, Becky Slagle-Webb, Ganesh Shenoy, Achuthamangalam B. Madhankumar, Stephan B. Abramson, Darren Wolfe, Kimberly S. Harbaugh, Elias B. Rizk, James R. Connor

Research output: Contribution to journalArticle

Abstract

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-13Ra2) 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.

Original languageEnglish (US)
Pages (from-to)1369-1379
Number of pages11
JournalJournal of neurosurgery
Volume131
Issue number5
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

Keywords

  • Interleukin-13 receptor alpha 2
  • Intratumoral treatment
  • MPNST
  • Murine model
  • Oncology
  • Pseudomonas toxin

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

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  • Cite this

    Mrowczynski, O. D., Payne, R. A., Bourcier, A. J., Mau, C. Y., Slagle-Webb, B., Shenoy, G., Madhankumar, A. B., Abramson, S. B., Wolfe, D., Harbaugh, K. S., Rizk, E. B., & Connor, J. R. (2019). Targeting IL-13Ra2 for effective treatment of malignant peripheral nerve sheath tumors in mouse models. Journal of neurosurgery, 131(5), 1369-1379. https://doi.org/10.3171/2018.7.JNS18284