Studies of targeted treatment in RET mutant thyroid cancers

Abstract

The societal burden of thyroid cancer is increasing, with both incidence and mortality on the rise. Mutations in the REarranged during Transfection (RET) gene are found in both the papillary and medullary subtype. There are significant limitations in current targeted treatment regimens of thyroid cancer, including the absence of a prolonged therapeutic response and severe toxicities. The goal of this project was to identify alternative strategies for the development of targeted treatments for this malignancy. This thesis demonstrates that constitutive activation of RET was associated with increased activation of mTOR, which was inhibited with the dual mTOR inhibitor INK128. The tolerability and efficacy of combining a RET kinase inhibitor together with the mTOR inhibitor was demonstrated in a murine model. Treatment of thyroid cancer cell lines with the HSP90 inhibitor AUY922, resulted in increased apoptosis. Tumour associated macrophages (TAMs), found in the microenvironment, were shown to play a pivotal role in thyroid cancer development. Following genetic ablation of TAMs in mouse models, there was profound remodelling of the tumour stroma with less extrathyroidal invasion and tumour cell proliferation. This thesis has identified novel therapeutic mechanisms for treatment of thyroid cancer which may lead to clinical trials, and better patient outcomes.