There is mounting experimental support for a central role of mutations leading to constitutive activation of effectors signaling along the MAP kinase pathway in the pathogenesis of papillary thyroid carcinomas. Thus, there is practically no overlap between PTC with RET/PTC, NTRK, RAS or BRAF mutations, which altogether are found in >70% of cases. The lack of concordance for these mutations provides compelling genetic evidence for the requirement of this signaling system for transformation to PTC. This represents a unique paradigm of human tumorigenesis through mutation of multiple effectors lying in tandem. This is also of significance for development of novel therapies because if confirmed, selective kinase inhibitors acting distally in the pathway may prove to be efficacious for the majority of PTCs. Therefore, the core hypothesis of this proposal is that unregulated activation of MAP-kinase components is required for thyroid cell transformation to PTC, and that BRAF is a central node in the pathway. We will also test the hypothesis that continued BRAF activation is required for tumor maintenance. The following specific aims will be pursued: 1) Establish requirement of BRAF for RET/PTC-mediated transformation in vivo. 2) Determine whether continued expression of oncogenic BRAF is required for tumor maintenance. 3) Determine the role of the specific ERK phosphatases MKP-3 and DUSP5 in ERK activation and thyroid cell transformation after expression of RET or BRAF oncoproteins. 4) Determine the expression profile of thyroid PCCL3 cells after conditional expression of RET/PTC, BRAFV600E, or RET/PTC with BRAF-RNAi. The goal of this final aim is to identify common gene sets regulated similarly by RET/PTC and BRAF, as well as those that are distinct and may point to mechanisms accounting for phenotypic differences between PTCs associated with each of these oncoproteins.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA050706-21
Application #
7766286
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Mietz, Judy
Project Start
1989-08-01
Project End
2011-11-30
Budget Start
2010-03-01
Budget End
2011-11-30
Support Year
21
Fiscal Year
2010
Total Cost
$390,958
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Xing, Mingzhao; Alzahrani, Ali S; Carson, Kathryn A et al. (2015) Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. J Clin Oncol 33:42-50
Garcia-Rendueles, Maria E R; Ricarte-Filho, Julio C; Untch, Brian R et al. (2015) NF2 Loss Promotes Oncogenic RAS-Induced Thyroid Cancers via YAP-Dependent Transactivation of RAS Proteins and Sensitizes Them to MEK Inhibition. Cancer Discov 5:1178-93
Dunn, Lara; Fagin, James A (2015) Therapy: Lenvatinib and radioiodine-refractory thyroid cancers. Nat Rev Endocrinol 11:325-7

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