The James Fagin Lab

The focus of the Fagin lab is to understand the pathogenesis and the biology of thyroid cancers at single cell resolution with the goal of identifying new mechanism-based therapies.  His group has been instrumental in characterizing somatic genetic changes associated with tumor initiation and progression in radiation-induced and sporadic thyroid cancer, and in defining their functional consequences. He showed that selective MEK and RAF kinase inhibitors restored thyroid differentiation and responsiveness to radioactive iodine in GEM models of the disease, which led to the development of innovative clinical trials showing significant promise of this therapeutic strategy. His group also defined novel mechanisms of adaptive resistance of BRAF-mutant thyroid cancers to MAPK pathway inhibitors. The improved efficacy of one of these approaches, the co-targeting of RAF and HER2/HER3 has recently been confirmed in phase II trials. In addition to these studies, the lab is currently working in the following areas:

1. Investigation of the role of the HIPPO pathway as a rheostat regulating adaptive resistance to small molecules targeting the MAPK pathway in thyroid cancer and other cell lineages.
2. Advanced thyroid cancers have increased frequency of mutations of genes encoding chromatin remodeling proteins, including several members of the SWI/SNF chromatin remodelling complex. His group is systematically exploring the impact of individual Swi/Snf and histone methyl transferase disruptions on the chromatin and transcriptional landscape of thyroid cancers in GEMM. Current evidence indicates that they lock thyroid tumor cells into an undifferentiated state that can no longer be reversed by MAPK pathway blockade, while creating new and unanticipated therapeutic vulnerabilities.
3. A hallmark of anaplastic thyroid cancers is their heavy infiltration with T cells and myeloid cells. He is investigating how profound MAPK pathway inhibition reprograms these tumors at single cell resolution. The lab is also investigating how cell autonomous antigen presentation and the tumor microenvironment contribute to promote T cell cytotoxicity. In a related project, his group is collaborating with the Levine lab to investigate whether tumor-infiltrating myeloid cells harboring mutations of Tet2, Dnmt3a or Axsl1, which are hallmarks of clonal hematopoiesis, confer refractoriness to therapy in GEMM with Braf-driven ATC.
4. The Fagin and Nai-Kong Cheung labs are collaborating to develop bispecific antibodies to target unique changes in the membrane proteome of thyroid cancers in response to MAPK pathway blockade.

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