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

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Interleukin-13 Receptors
Neurilemmoma
Interleukin-13
Therapeutics
Survival
Neoplasms
Cytotoxins
Tumor Burden
Sarcoma

All Science Journal Classification (ASJC) codes

  • Surgery
  • Clinical Neurology

Cite this

Mrowczynski, O. D., Payne, R. A., Bourcier, A. J., Mau, C. Y., Slagle-Webb, B., Shenoy, G., ... 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
Mrowczynski, Oliver D. ; Payne, Russell A. ; Bourcier, Alexandre J. ; Mau, Christine Y. ; Slagle-Webb, Becky ; Shenoy, Ganesh ; Madhankumar, Achuthamangalam B. ; Abramson, Stephan B. ; Wolfe, Darren ; Harbaugh, Kimberly S. ; Rizk, Elias B. ; Connor, James R. / Targeting IL-13Ra2 for effective treatment of malignant peripheral nerve sheath tumors in mouse models. In: Journal of neurosurgery. 2019 ; Vol. 131, No. 5. pp. 1369-1379.
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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.",
author = "Mrowczynski, {Oliver D.} and Payne, {Russell A.} and Bourcier, {Alexandre J.} and Mau, {Christine Y.} and Becky Slagle-Webb and Ganesh Shenoy and Madhankumar, {Achuthamangalam B.} and Abramson, {Stephan B.} and Darren Wolfe and Harbaugh, {Kimberly S.} and Rizk, {Elias B.} and Connor, {James R.}",
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Mrowczynski, OD, Payne, RA, Bourcier, AJ, Mau, CY, Slagle-Webb, B, Shenoy, G, Madhankumar, AB, Abramson, SB, Wolfe, D, Harbaugh, KS, Rizk, EB & Connor, JR 2019, 'Targeting IL-13Ra2 for effective treatment of malignant peripheral nerve sheath tumors in mouse models', Journal of neurosurgery, vol. 131, no. 5, pp. 1369-1379. https://doi.org/10.3171/2018.7.JNS18284

Targeting IL-13Ra2 for effective treatment of malignant peripheral nerve sheath tumors in mouse models. / Mrowczynski, Oliver D.; Payne, Russell A.; Bourcier, Alexandre J.; Mau, Christine Y.; Slagle-Webb, Becky; Shenoy, Ganesh; Madhankumar, Achuthamangalam B.; Abramson, Stephan B.; Wolfe, Darren; Harbaugh, Kimberly S.; Rizk, Elias B.; Connor, James R.

In: Journal of neurosurgery, Vol. 131, No. 5, 01.01.2019, p. 1369-1379.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Targeting IL-13Ra2 for effective treatment of malignant peripheral nerve sheath tumors in mouse models

AU - Mrowczynski, Oliver D.

AU - Payne, Russell A.

AU - Bourcier, Alexandre J.

AU - Mau, Christine Y.

AU - Slagle-Webb, Becky

AU - Shenoy, Ganesh

AU - Madhankumar, Achuthamangalam B.

AU - Abramson, Stephan B.

AU - Wolfe, Darren

AU - Harbaugh, Kimberly S.

AU - Rizk, Elias B.

AU - Connor, James R.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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Mrowczynski OD, Payne RA, Bourcier AJ, Mau CY, Slagle-Webb B, Shenoy G et al. Targeting IL-13Ra2 for effective treatment of malignant peripheral nerve sheath tumors in mouse models. Journal of neurosurgery. 2019 Jan 1;131(5):1369-1379. https://doi.org/10.3171/2018.7.JNS18284