Preclinical assessments of the MEK inhibitor PD-0325901 in a mouse model of Neurofibromatosis type 1

Edwin Jousma, Tilat A. Rizvi, Jianqiang Wu, David Janhofer, Eva Dombi, Richard S. Dunn, Mi Ok Kim, Andrea R. Masters, David R. Jones, Timothy P. Cripe, Nancy Ratner

Research output: Contribution to journalArticle

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Abstract

Background: Neurofibromatosis type 1 (NF1) is a genetic disorder that predisposes affected individuals to formation of benign neurofibromas, peripheral nerve tumors that can be associated with significant morbidity. Loss of the NF1 Ras-GAP protein causes increased Ras-GTP, and we previously found that inhibiting MEK signaling downstream of Ras can shrink established neurofibromas in a genetically engineered murine model. Procedures: We studied effects of MEK inhibition using 1.5mg/kg/day PD-0325901 prior to neurofibroma onset in the Nf1 <sup>flox/flox</sup>; Dhh-Cre mouse model. We also treated mice with established tumors at 0.5 and 1.5mg/kg/day doses of PD-0325901. We monitored tumor volumes using MRI and volumetric measurements, and measured pharmacokinetic and pharmacodynamic endpoints. Results: Early administration significantly delayed neurofibroma development as compared to vehicle controls. When treatment was discontinued neurofibromas grew, but no rebound effect was observed and neurofibromas remained significantly smaller than controls. Low dose treatment of mice with PD-0325901 resulted in neurofibroma shrinkage equivalent to that observed at higher doses. Tumor cell proliferation decreased, although less than at higher doses with drug. Tumor blood vessels per area correlated with tumor shrinkage. Conclusions: Neurofibroma development was not prevented by MEK inhibition, beginning at 1 month of age, but tumor size was controlled by early treatment. Moreover, treatment with PD-0325901 at very low doses may shrink neurofibromas while minimizing toxicity. These studies highlight how genetically engineered mouse models can guide clinical trial design. Pediatr Blood Cancer 2015;62:1709-1716.

Original languageEnglish (US)
Pages (from-to)1709-1716
Number of pages8
JournalPediatric Blood and Cancer
Volume62
Issue number10
DOIs
StatePublished - Oct 1 2015

Fingerprint

Neurofibroma
Neurofibromatosis 1
Mitogen-Activated Protein Kinase Kinases
Neoplasms
Peripheral Nervous System Neoplasms
ras GTPase-Activating Proteins
Neurofibromin 1
Vascular Tissue Neoplasms
GTPase-Activating Proteins
PD 0325901
ras Proteins
Inborn Genetic Diseases
Guanosine Triphosphate
Tumor Burden
Pharmacokinetics
Cell Proliferation
Clinical Trials
Morbidity

Keywords

  • MEK
  • Nerve
  • Neurofibroma
  • NF1
  • Therapy

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology

Cite this

Jousma, E., Rizvi, T. A., Wu, J., Janhofer, D., Dombi, E., Dunn, R. S., ... Ratner, N. (2015). Preclinical assessments of the MEK inhibitor PD-0325901 in a mouse model of Neurofibromatosis type 1. Pediatric Blood and Cancer, 62(10), 1709-1716. https://doi.org/10.1002/pbc.25546

Preclinical assessments of the MEK inhibitor PD-0325901 in a mouse model of Neurofibromatosis type 1. / Jousma, Edwin; Rizvi, Tilat A.; Wu, Jianqiang; Janhofer, David; Dombi, Eva; Dunn, Richard S.; Kim, Mi Ok; Masters, Andrea R.; Jones, David R.; Cripe, Timothy P.; Ratner, Nancy.

In: Pediatric Blood and Cancer, Vol. 62, No. 10, 01.10.2015, p. 1709-1716.

Research output: Contribution to journalArticle

Jousma, E, Rizvi, TA, Wu, J, Janhofer, D, Dombi, E, Dunn, RS, Kim, MO, Masters, AR, Jones, DR, Cripe, TP & Ratner, N 2015, 'Preclinical assessments of the MEK inhibitor PD-0325901 in a mouse model of Neurofibromatosis type 1', Pediatric Blood and Cancer, vol. 62, no. 10, pp. 1709-1716. https://doi.org/10.1002/pbc.25546
Jousma, Edwin ; Rizvi, Tilat A. ; Wu, Jianqiang ; Janhofer, David ; Dombi, Eva ; Dunn, Richard S. ; Kim, Mi Ok ; Masters, Andrea R. ; Jones, David R. ; Cripe, Timothy P. ; Ratner, Nancy. / Preclinical assessments of the MEK inhibitor PD-0325901 in a mouse model of Neurofibromatosis type 1. In: Pediatric Blood and Cancer. 2015 ; Vol. 62, No. 10. pp. 1709-1716.
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abstract = "Background: Neurofibromatosis type 1 (NF1) is a genetic disorder that predisposes affected individuals to formation of benign neurofibromas, peripheral nerve tumors that can be associated with significant morbidity. Loss of the NF1 Ras-GAP protein causes increased Ras-GTP, and we previously found that inhibiting MEK signaling downstream of Ras can shrink established neurofibromas in a genetically engineered murine model. Procedures: We studied effects of MEK inhibition using 1.5mg/kg/day PD-0325901 prior to neurofibroma onset in the Nf1 flox/flox; Dhh-Cre mouse model. We also treated mice with established tumors at 0.5 and 1.5mg/kg/day doses of PD-0325901. We monitored tumor volumes using MRI and volumetric measurements, and measured pharmacokinetic and pharmacodynamic endpoints. Results: Early administration significantly delayed neurofibroma development as compared to vehicle controls. When treatment was discontinued neurofibromas grew, but no rebound effect was observed and neurofibromas remained significantly smaller than controls. Low dose treatment of mice with PD-0325901 resulted in neurofibroma shrinkage equivalent to that observed at higher doses. Tumor cell proliferation decreased, although less than at higher doses with drug. Tumor blood vessels per area correlated with tumor shrinkage. Conclusions: Neurofibroma development was not prevented by MEK inhibition, beginning at 1 month of age, but tumor size was controlled by early treatment. Moreover, treatment with PD-0325901 at very low doses may shrink neurofibromas while minimizing toxicity. These studies highlight how genetically engineered mouse models can guide clinical trial design. Pediatr Blood Cancer 2015;62:1709-1716.",
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