The role of Wnt signaling in aggressive thyroid carcinoma

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PROJECT SUMMARY: Thyroid cancer is rapidly increasing in the U.S. and is expected to be the 4th leading cancer diagnosis by 2030, surpassing colorectal cancer. While most patients are cured of their thyroid cancer following initial treatment, a significant portion of patients develop recurrent and aggressive disease. In fact, some well-differentiated thyroid cancers develop into anaplastic thyroid carcinoma (ATC), a highly lethal and treatment-resistant disease with an abysmal 4-month survival. While these ATCs usually carry common driver-mutations such as BRAFV600E, studies suggest that the majority also acquire activating mutations in the Wnt pathway. In addition, BRAF inhibitors have shown limited efficacy in treating these aggressive thyroid tumors. Research in other cancers suggests that Wnt signaling may play a role in the failure of BRAF inhibitor therapy. There is compelling evidence that thyroid carcinomas are dependent on Wnt signaling, particularly poorly differentiated and aggressive disease. The goal of this proposal is to discover the role of Wnt signaling in metastatic, recurrent, and treatment-resistant thyroid cancer. My preliminary data on BRAFV600E-mutant thyroid cancer demonstrate alterations in Wnt/β-catenin signaling following BRAF inhibition. My studies also create a unique thyroid cancer organoid system to study primary patient-derived thyroid cancers across a heterogeneous landscape of genetic alterations. Finally, I create a humanized patient-derived xenograft mouse model for thyroid cancer, with loss of murine MHCII and MHCI that can serve to study the in vivo biology of thyroid cancer and to test new therapeutics (including anti- Wnt drugs) against thyroid cancers resistant to standard-of-care therapy. In this proposal I will test the hypothesis that Wnt signaling causes the increased invasive and metastatic potential of aggressive thyroid cancer. In Aim 1, I will define the in vivo effect of Wnt inhibition on the malignant phenotype of aggressive thyroid cancer. In Aim 2, I will discover the role of Wnt signaling in the resistance mechanism of BRAF-mutant thyroid cancer following BRAF inhibitor therapy. In Aim 3, I will use sequential patient samples to determine the drivers of Wnt signaling upregulation in ATC. Through completion of these studies, I will define the role of Wnt signaling, a major oncogenic pathway, in thyroid carcinoma. I anticipate that these pre-clinical studies will lead to clinical trials of Wnt inhibitors for anaplastic thyroid cancer and dramatically improve detection and treatment of the most aggressive forms of thyroid cancer. In addition, these studies will form the foundation of a strong research program for a promising junior investigator. Through this K08 grant and the guidance by accomplished mentors, I will gain the knowledge and experience needed to become an independently funded and successful physician- scientist.