Journal article
NF1 deletion generates multiple subtypes of soft-tissue sarcoma that respond to MEK inhibition
Molecular cancer therapeutics, Vol.12(9), pp.1906-1917
09/2013
DOI: 10.1158/1535-7163.MCT-13-0189
PMCID: PMC3825462
PMID: 23858101
Abstract
Soft-tissue sarcomas are a heterogeneous group of tumors arising from connective tissue. Recently, mutations in the neurofibromin 1 (NF1) tumor suppressor gene were identified in multiple subtypes of human soft-tissue sarcomas. To study the effect of NF1 inactivation in the initiation and progression of distinct sarcoma subtypes, we have developed a novel mouse model of temporally and spatially restricted NF1-deleted sarcoma.
To generate primary sarcomas, we inject adenovirus containing Cre recombinase into NF1
flox/flox
; Ink4a/Arf
flox/flox
mice at two distinct orthotopic sites: intramuscularly or in the sciatic nerve. The mice develop either high-grade myogenic sarcomas or MPNST-like tumors, respectively. These tumors reflect the histological properties and spectrum of sarcomas found in patients. To explore the utility of this model for preclinical studies, we performed a study of MAPK pathway inhibition with the MEK inhibitor PD325901. Treatment with PD325901 delays tumor growth through decreased cyclin D1 mRNA and cell proliferation. We also examined the effects of MEK inhibition on the native tumor stroma and find that PD325901 decreases VEGFα expression in tumor cells with a corresponding decrease in microvessel density. Taken together, our results utilize a primary tumor model to demonstrate that sarcomas can be generated by loss of NF1 and Ink4a/Arf, and that these tumors are sensitive to MEK inhibition by direct effects on tumor cells and the surrounding microenvironment. These studies suggest that MEK inhibitors should be further explored as potential sarcoma therapies in patients with tumors containing NF1 deletion.
Details
- Title: Subtitle
- NF1 deletion generates multiple subtypes of soft-tissue sarcoma that respond to MEK inhibition
- Creators
- Rebecca D Dodd - Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USAJeffrey K Mito - Department Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USAWilliam C Eward - Department of Orthopaedic Surgery, Duke University Medical Center, Durham, North Carolina 27710, USARhea Chitalia - Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USAMohit Sachdeva - Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USAYan Ma - Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USAJordi Barretina - The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USALeslie Dodd - Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USADavid G Kirsch - Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA
- Resource Type
- Journal article
- Publication Details
- Molecular cancer therapeutics, Vol.12(9), pp.1906-1917
- DOI
- 10.1158/1535-7163.MCT-13-0189
- PMID
- 23858101
- PMCID
- PMC3825462
- NLM abbreviation
- Mol Cancer Ther
- ISSN
- 1535-7163
- eISSN
- 1538-8514
- Grant note
- K02 AI093866 || AI / National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
- Language
- English
- Date published
- 09/2013
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094389602771
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