MLN8237 treatment in an orthoxenograft murine model for malignant peripheral nerve sheath tumors

Russell Payne, Oliver D. Mrowczynski, Becky Slagle-Webb, Alexandre Bourcier, Christine Mau, Dawit Aregawi, Achuthamangalam B. Madhankumar, Sang Y. Lee, Kimberly Harbaugh, James Connor, Elias B. Rizk

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Abstract

OBJECTIVE Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas arising from peripheral nerves. MPNSTs have increased expression of the oncogene aurora kinase A, leading to enhanced cellular proliferation. This makes them extremely aggressive with high potential for metastasis and a devastating prognosis; 5-year survival estimates range from a dismal 15% to 60%. MPNSTs are currently treated with resection (sometimes requiring limb amputation) in combination with chemoradiation, both of which demonstrate limited effectiveness. The authors present the results of immunohistochemical, in vitro, and in vivo analyses of MLN8237 for the treatment of MPNSTs in an orthoxenograft murine model. METHODS Immunohistochemistry was performed on tumor sections to confirm the increased expression of aurora kinase A. Cytotoxicity analysis was then performed on an MPNST cell line (STS26T) to assess the efficacy of MLN8237 in vitro. A murine orthoxenograft MPNST model transfected to express luciferase was then developed to assess the efficacy of aurora kinase A inhibition in the treatment of MPNSTs in vivo. Mice with confirmed tumor on in vivo imaging were divided into 3 groups: 1) controls, 2) mice treated with MLN8237, and 3) mice treated with doxorubicin/ifosfamide. Treatment was carried out for 32 days, with imaging performed at weekly intervals until postinjection day 42. Average bioluminescence among groups was compared at weekly intervals using 1-way ANOVA. A survival analysis was performed using Kaplan-Meier curves. RESULTS Immunohistochemical analysis showed robust expression of aurora kinase A in tumor cells. Cytotoxicity analysis revealed STS26T susceptibility to MLN8237 in vitro. The group receiving treatment with MLN8237 showed a statistically significant difference in tumor size compared with the control group starting at postinjection day 21 and persisting until the end of the study. The MLN8237 group also showed decreased tumor size compared with the doxorubicin/ifosfamide group at the conclusion of the study (p = 0.036). Survival analysis revealed a significantly increased median survival in the MLN8237 group (83 days) compared with both the control (64 days) and doxorubicin/ifosfamide (67 days) groups. A hazard ratio comparing the 2 treatment groups showed a decreased hazard rate in the MLN8237 group compared with the doxorubicin/ifosfamide group (HR 2.945; p = 0.0134). CONCLUSIONS The results of this study demonstrate that MLN8237 is superior to combination treatment with doxorubicin/ifosfamide in a preclinical orthoxenograft murine model. These data have major implications for the future of MPNST research by providing a robust murine model as well as providing evidence that MLN8237 may be an effective treatment for MPNSTs.

Original languageEnglish (US)
Pages (from-to)465-475
Number of pages11
JournalJournal of neurosurgery
Volume130
Issue number2
DOIs
StatePublished - Feb 2019

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Neurilemmoma
Ifosfamide
Aurora Kinase A
Doxorubicin
Therapeutics
Neoplasms
Survival Analysis
MLN 8237
Control Groups
Tumor Cell Line
Luciferases
Peripheral Nerves
Oncogenes
Amputation
Sarcoma
Analysis of Variance
Extremities
Immunohistochemistry
Cell Proliferation
Neoplasm Metastasis

All Science Journal Classification (ASJC) codes

  • Surgery
  • Clinical Neurology

Cite this

Payne, Russell ; Mrowczynski, Oliver D. ; Slagle-Webb, Becky ; Bourcier, Alexandre ; Mau, Christine ; Aregawi, Dawit ; Madhankumar, Achuthamangalam B. ; Lee, Sang Y. ; Harbaugh, Kimberly ; Connor, James ; Rizk, Elias B. / MLN8237 treatment in an orthoxenograft murine model for malignant peripheral nerve sheath tumors. In: Journal of neurosurgery. 2019 ; Vol. 130, No. 2. pp. 465-475.
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abstract = "OBJECTIVE Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas arising from peripheral nerves. MPNSTs have increased expression of the oncogene aurora kinase A, leading to enhanced cellular proliferation. This makes them extremely aggressive with high potential for metastasis and a devastating prognosis; 5-year survival estimates range from a dismal 15{\%} to 60{\%}. MPNSTs are currently treated with resection (sometimes requiring limb amputation) in combination with chemoradiation, both of which demonstrate limited effectiveness. The authors present the results of immunohistochemical, in vitro, and in vivo analyses of MLN8237 for the treatment of MPNSTs in an orthoxenograft murine model. METHODS Immunohistochemistry was performed on tumor sections to confirm the increased expression of aurora kinase A. Cytotoxicity analysis was then performed on an MPNST cell line (STS26T) to assess the efficacy of MLN8237 in vitro. A murine orthoxenograft MPNST model transfected to express luciferase was then developed to assess the efficacy of aurora kinase A inhibition in the treatment of MPNSTs in vivo. Mice with confirmed tumor on in vivo imaging were divided into 3 groups: 1) controls, 2) mice treated with MLN8237, and 3) mice treated with doxorubicin/ifosfamide. Treatment was carried out for 32 days, with imaging performed at weekly intervals until postinjection day 42. Average bioluminescence among groups was compared at weekly intervals using 1-way ANOVA. A survival analysis was performed using Kaplan-Meier curves. RESULTS Immunohistochemical analysis showed robust expression of aurora kinase A in tumor cells. Cytotoxicity analysis revealed STS26T susceptibility to MLN8237 in vitro. The group receiving treatment with MLN8237 showed a statistically significant difference in tumor size compared with the control group starting at postinjection day 21 and persisting until the end of the study. The MLN8237 group also showed decreased tumor size compared with the doxorubicin/ifosfamide group at the conclusion of the study (p = 0.036). Survival analysis revealed a significantly increased median survival in the MLN8237 group (83 days) compared with both the control (64 days) and doxorubicin/ifosfamide (67 days) groups. A hazard ratio comparing the 2 treatment groups showed a decreased hazard rate in the MLN8237 group compared with the doxorubicin/ifosfamide group (HR 2.945; p = 0.0134). CONCLUSIONS The results of this study demonstrate that MLN8237 is superior to combination treatment with doxorubicin/ifosfamide in a preclinical orthoxenograft murine model. These data have major implications for the future of MPNST research by providing a robust murine model as well as providing evidence that MLN8237 may be an effective treatment for MPNSTs.",
author = "Russell Payne and Mrowczynski, {Oliver D.} and Becky Slagle-Webb and Alexandre Bourcier and Christine Mau and Dawit Aregawi and Madhankumar, {Achuthamangalam B.} and Lee, {Sang Y.} and Kimberly Harbaugh and James Connor and Rizk, {Elias B.}",
year = "2019",
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doi = "10.3171/2017.8.JNS17765",
language = "English (US)",
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pages = "465--475",
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MLN8237 treatment in an orthoxenograft murine model for malignant peripheral nerve sheath tumors. / Payne, Russell; Mrowczynski, Oliver D.; Slagle-Webb, Becky; Bourcier, Alexandre; Mau, Christine; Aregawi, Dawit; Madhankumar, Achuthamangalam B.; Lee, Sang Y.; Harbaugh, Kimberly; Connor, James; Rizk, Elias B.

In: Journal of neurosurgery, Vol. 130, No. 2, 02.2019, p. 465-475.

Research output: Contribution to journalArticle

TY - JOUR

T1 - MLN8237 treatment in an orthoxenograft murine model for malignant peripheral nerve sheath tumors

AU - Payne, Russell

AU - Mrowczynski, Oliver D.

AU - Slagle-Webb, Becky

AU - Bourcier, Alexandre

AU - Mau, Christine

AU - Aregawi, Dawit

AU - Madhankumar, Achuthamangalam B.

AU - Lee, Sang Y.

AU - Harbaugh, Kimberly

AU - Connor, James

AU - Rizk, Elias B.

PY - 2019/2

Y1 - 2019/2

N2 - OBJECTIVE Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas arising from peripheral nerves. MPNSTs have increased expression of the oncogene aurora kinase A, leading to enhanced cellular proliferation. This makes them extremely aggressive with high potential for metastasis and a devastating prognosis; 5-year survival estimates range from a dismal 15% to 60%. MPNSTs are currently treated with resection (sometimes requiring limb amputation) in combination with chemoradiation, both of which demonstrate limited effectiveness. The authors present the results of immunohistochemical, in vitro, and in vivo analyses of MLN8237 for the treatment of MPNSTs in an orthoxenograft murine model. METHODS Immunohistochemistry was performed on tumor sections to confirm the increased expression of aurora kinase A. Cytotoxicity analysis was then performed on an MPNST cell line (STS26T) to assess the efficacy of MLN8237 in vitro. A murine orthoxenograft MPNST model transfected to express luciferase was then developed to assess the efficacy of aurora kinase A inhibition in the treatment of MPNSTs in vivo. Mice with confirmed tumor on in vivo imaging were divided into 3 groups: 1) controls, 2) mice treated with MLN8237, and 3) mice treated with doxorubicin/ifosfamide. Treatment was carried out for 32 days, with imaging performed at weekly intervals until postinjection day 42. Average bioluminescence among groups was compared at weekly intervals using 1-way ANOVA. A survival analysis was performed using Kaplan-Meier curves. RESULTS Immunohistochemical analysis showed robust expression of aurora kinase A in tumor cells. Cytotoxicity analysis revealed STS26T susceptibility to MLN8237 in vitro. The group receiving treatment with MLN8237 showed a statistically significant difference in tumor size compared with the control group starting at postinjection day 21 and persisting until the end of the study. The MLN8237 group also showed decreased tumor size compared with the doxorubicin/ifosfamide group at the conclusion of the study (p = 0.036). Survival analysis revealed a significantly increased median survival in the MLN8237 group (83 days) compared with both the control (64 days) and doxorubicin/ifosfamide (67 days) groups. A hazard ratio comparing the 2 treatment groups showed a decreased hazard rate in the MLN8237 group compared with the doxorubicin/ifosfamide group (HR 2.945; p = 0.0134). CONCLUSIONS The results of this study demonstrate that MLN8237 is superior to combination treatment with doxorubicin/ifosfamide in a preclinical orthoxenograft murine model. These data have major implications for the future of MPNST research by providing a robust murine model as well as providing evidence that MLN8237 may be an effective treatment for MPNSTs.

AB - OBJECTIVE Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas arising from peripheral nerves. MPNSTs have increased expression of the oncogene aurora kinase A, leading to enhanced cellular proliferation. This makes them extremely aggressive with high potential for metastasis and a devastating prognosis; 5-year survival estimates range from a dismal 15% to 60%. MPNSTs are currently treated with resection (sometimes requiring limb amputation) in combination with chemoradiation, both of which demonstrate limited effectiveness. The authors present the results of immunohistochemical, in vitro, and in vivo analyses of MLN8237 for the treatment of MPNSTs in an orthoxenograft murine model. METHODS Immunohistochemistry was performed on tumor sections to confirm the increased expression of aurora kinase A. Cytotoxicity analysis was then performed on an MPNST cell line (STS26T) to assess the efficacy of MLN8237 in vitro. A murine orthoxenograft MPNST model transfected to express luciferase was then developed to assess the efficacy of aurora kinase A inhibition in the treatment of MPNSTs in vivo. Mice with confirmed tumor on in vivo imaging were divided into 3 groups: 1) controls, 2) mice treated with MLN8237, and 3) mice treated with doxorubicin/ifosfamide. Treatment was carried out for 32 days, with imaging performed at weekly intervals until postinjection day 42. Average bioluminescence among groups was compared at weekly intervals using 1-way ANOVA. A survival analysis was performed using Kaplan-Meier curves. RESULTS Immunohistochemical analysis showed robust expression of aurora kinase A in tumor cells. Cytotoxicity analysis revealed STS26T susceptibility to MLN8237 in vitro. The group receiving treatment with MLN8237 showed a statistically significant difference in tumor size compared with the control group starting at postinjection day 21 and persisting until the end of the study. The MLN8237 group also showed decreased tumor size compared with the doxorubicin/ifosfamide group at the conclusion of the study (p = 0.036). Survival analysis revealed a significantly increased median survival in the MLN8237 group (83 days) compared with both the control (64 days) and doxorubicin/ifosfamide (67 days) groups. A hazard ratio comparing the 2 treatment groups showed a decreased hazard rate in the MLN8237 group compared with the doxorubicin/ifosfamide group (HR 2.945; p = 0.0134). CONCLUSIONS The results of this study demonstrate that MLN8237 is superior to combination treatment with doxorubicin/ifosfamide in a preclinical orthoxenograft murine model. These data have major implications for the future of MPNST research by providing a robust murine model as well as providing evidence that MLN8237 may be an effective treatment for MPNSTs.

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