The Role of BRAF Mutation in Thyroid Cancer Invasion

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DESCRIPTION (provided by applicant): Role of BRAF mutation in thyroid cancer invasion: Thyroid cancer is a common malignancy associated with substantial morbidity. Well-differentiated thyroid cancer is the most common endocrine malignancy and ranks as the seventh most common cancer diagnosed in women. Increasing incidence of thyroid cancer over the past few decades is reflected by the projected 37,000 new cases in 2009. While the majority of patients with well-differentiated thyroid cancer presents with limited disease and become disease-free after initial treatment, 20% of patients with thyroid cancer have local or regional recurrent disease, and 5% develop distant metastases. Prior studies have identified the BRAF gene as the most commonly mutated in papillary thyroid cancer, activation of this pathway leads to ERK translocation and downstream transcriptional dysregulation. This mutation is implicated in the initiation and progression of aggressive subtypes such as tall cell, and in those with extra-thyroidal extension, lymph nodal and distant metastases. Moreover, it is associated with both loss of radioiodine avidity and cancer recurrence. The mechanisms by which this mutation induces invasion and distant spread are not fully understood. We have recently carried out a detailed Gene Set Enrichment Analysis to analyze the genomic signature of papillary thyroid cancer patients with or without this BRAF mutation. We have found that BRAFV600E mutation results in the alteration of several cell adhesion molecules including Thrombospondin-1, integrins and other stromally active proteases, such as matrix metalloproteases. Here we posit that BRAF mutation and changes in these adhesion molecules plays a crucial role in the invasion and metastasis of the most aggressive and non-curable forms of papillary thyroid cancer. In addition, we postulate that selective BRAF inhibitors that are currently being validated in several forms of cancer could be utilized in the treatment of the thyroid cancers harbouring BRAF mutation. Our goal is to characterize the role of BRAF V600E mutation, as well as BRAF induced expression of TSP-1, matrix metalloproteases and other ECM molecules in thyroid cancer cell lines, as well as a novel preclinical mouse model of thyroid cancer. We also plan to test the efficacy of BRAFV600E specific inhibitors and to determine whether TSP-1, and MMPs could be utilized as a diagnostic biomarker for detection of the aggressive forms of thyroid cancer as well as therapeutic biomarkers to evaluate the response to BRAF inhibitors.