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NF1 deletion generates multiple subtypes of soft-tissue sarcoma that respond to mek inhibition

Dodd, RD and Mito, JK and Eward, WC and Chitalia, R and Sachdeva, M and Ma, Y and Barretina, J and Dodd, L and Kirsch, DG (2013) NF1 deletion generates multiple subtypes of soft-tissue sarcoma that respond to mek inhibition. MOLECULAR CANCER THERAPEUTICS. pp. 1906-1917.

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 <sup>flox/flox</sup>; Ink4a/Arf<sup>flox/flox</sup> mice at two distinct orthotopic sites: intramuscularly or in the sciatic nerve. The mice develop either high-grade myogenic sarcomas or malignant peripheral nerve sheath tumor (MPNST)-like tumors, respectively. These tumors reflect the histologic properties and spectrum of sarcomas found in patients. To explore the use of this model for preclinical studies, we conducted a study of mitogen-activated protein kinase (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 VEGFalpha expression in tumor cells with a corresponding decrease in microvessel density. Taken together, our results use a primary tumor model to show 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. 2013 American Association for Cancer Research

Item Type: Article
Additional Information: pubid: 161 nvp_institute: NIBR contributor_address: (Dodd, Chitalia, Sachdeva, Ma, Kirsch) Departments of Radiation Oncology, Duke University Medical Center, Box 91006, Durham, NC 27708, United States (Mito, Kirsch) Departments of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, United States (Eward) Departments of Orthopaedic Surgery, Duke University Medical Center, Durham, NC, United States (Dodd) Departments of Pathology, Duke University Medical Center, Durham, NC, United States (Barretina) Broad Institute of Harvard and MIT, Cambridge, United States (Barretina) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States (Barretina) Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States (Barretina) Novartis Institutes for Biomedical Research, Cambridge, MA 02139, United States (Barretina) Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/21991

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