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Data from NF1 Deletion Generates Multiple Subtypes of Soft-Tissue Sarcoma That Respond to MEK Inhibition
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Data from NF1 Deletion Generates Multiple Subtypes of Soft-Tissue Sarcoma That Respond to MEK Inhibition
Data from NF1 Deletion Generates Multiple Subtypes of Soft-Tissue Sarcoma That Respond to MEK Inhibition
RD
Rebecca D. Dodd
Rebecca D. Dodd
JM
Jeffrey K. Mito
Jeffrey K. Mito
WE
William C. Eward
William C. Eward
RC
Rhea Chitalia
Rhea Chitalia
MS
Mohit Sachdeva
Mohit Sachdeva
YM
Yan Ma
Yan Ma
JB
Jordi Barretina
Jordi Barretina
LD
Leslie Dodd
Leslie Dodd
DK
David G. Kirsch
David G. Kirsch
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3 April 2023
other
Published by
American Association for Cancer Research (AACR)
https://doi.org/10.1158/1535-7163.c.6536521
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 NF1flox/flox; Ink4a/Arfflox/flox 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 VEGFα 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. Mol Cancer Ther; 12(9); 1906–17. ©2013 AACR.
Keywords
MODEL
SARCOMAS
TISSUE
MEK INHIBITORS
SOFT
PD325901
PROTEIN
TREATMENT
NF1
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