Memorial Hospital Research Laboratories // Human Oncology & Pathogenesis Program

James A. Fagin, MD

The focus of our work is to understand the pathogenesis and the biology of thyroid cancers with the goal of identifying new molecular-based therapies. Thyroid cancer is the most common endocrine malignancy. Exposure to radiation during childhood confers increased predisposition to this disease. Our lab has been instrumental in characterizing many of the somatic genetic changes associated with thyroid tumor initiation and progression in both radiation-induced and sporadic thyroid cancer, and in defining the functional consequences using in vitro and in vivo experimental models.

We have focused in particular on the role of MAP kinase effectors in thyroid tumor initiation in sporadic and radiation-induced thyroid cancers, because these tumors are associated with a high prevalence of non-overlapping activating mutations of at least six genes encoding effectors in the pathway: the tyrosine kinase receptors RET and NTRK, the three RAS genes and BRAF. More recently, we have begun to explore the role of PI3K activation as a transitional event required for tumor progression.

Our present effort is in the following areas:

Development and refinement of animal models of thyroid cancer to further probe the signaling pathways required for transformation. We have developed mouse models that recapitulate the genetic changes in thyroid cancer in a physiologically appropriate manner, by using conditional gene knock-in and deletion approaches, and are using them to determine the role of oncoprotein signal intensification in the development of oncogene addiction, and to establish the key pathways required for tumor viability.
Identification of expression targets of oncogenic RET, RAS and BRAF that may account for critical phenotypic changes associated with cancers harboring the respective mutant genes.
Exploring the role of innate immune cells in modulating thyroid cancer behavior in mouse models of the disease.
Characterization of small molecule kinase inhibitors with potential therapeutic potential.

Publications

Montero-Conde C, Ruiz-Llorente S, Dominguez JM, Knauf JA, Viale AJ, Sherman EJ, Ryder M, Ghossein RA, Rosen N, Fagin JA. Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF mutant thyroid carcinomas. Cancer Discovery 2013, May;3(5):520-33.

Ho AL, Grewal RK, Leboeuf R, Sherman EJ, Pfister DG, Deandreis D, Pentlow KS, Zanzonico PB, Haque S, Gavane S, Ghossein RA, Ricarte-Filho JC, Dominguez JM, Shen R, Tuttle RM, Larson SM, Fagin JA. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. Engl J Med 2013; Feb 14;368(7):623-32.

Chakravarty D, Santos E, Ryder M, Knauf J, Liao XH, West B, Bollag G, Kolesnick R, Thin T, Rosen N, Zanzonico P, Larson S, Refetoff S, Ghossein R, Fagin JA. Small-molecule MAPK inhibitors restore RAI incorporation in murine thyroid cancers with conditional BRAF activation. J Clin Invest. 2011 121(12):4700-11.

Franco AT, Malaguarnera R, Refetoff S, Liao XH, Lundsmith E, Kimura S, Pritchard C, Marais R, Davies TF, Weinstein LS, Chen M, Rosen N, Ghossein R, Knauf JA, Fagin JA. Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumor initiation in mice. Proc Natl Acad Sci U S A. 2011 Jan 10 108(4):1615-20.

Chen X, Mitsutake N, LaPerle K, Akeno N, Zanzonico P, Longo V, Mitsutake S, Kimura E, Geiger H, Santos E, Wendel HG, Franco A, Knauf JA, Fagin JA. Endogenous Expression Of HrasG12V Induces Developmental Defects and Neoplasms with Copy Number Imbalances Of The Oncogene. Proc. Natl Acad Sci USA, 2009 12;106(19):7979-84.