Patients with advanced thyroid cancer are frequently refractory to radioiodine (RAI) therapy. Oncoproteins that constitutively activate MAPK signaling suppress expression of genes that control thyroid differentiated function and response to RAI, which can be reversed, at least in part, with RAF or MEK inhibitors in mouse models and in pilot clinical trials. These treatments are less effective in BRAFV600E-mutant cancers, which we showed to be due to adaptive resistance to RAF or MEK inhibitors. Profound MAPK pathway blockade increases iodide uptake but does not increase iodine retention time in mouse BrafV600E PTCs. This is because these compounds relieve negative feedback inputs that increase PI3K signaling, which impairs expression of genes required for iodide oxidation and incorporation into thyroglobulin (TG). This can be rescued by combined treatment with a pan-PI3K inhibitor. The goal of this proposal is to build on the progress so far to attain greater efficacy of redifferentiation therapies in patients with thyroid cancer who are most likely to benefit. We propose to do this by: 1. Investigating whether selective PI3K isoform or HER kinase inhibitors increase iodide retention and RAI efficacy in the context of MAPK blockade. 2. Test the effects of the RAF inhibitor vemurafenib and the pan-PI3K inhibitor copanlisib on expression of iodide organification genes and how this relates to lesional 124I uptake and retention time in patients with RAI-refractory BRAFV600E metastatic thyroid cancer. 3. Identify molecular predictors of RAI efficacy in patients who had exceptional structural responses to conventional or MAPK-inhibitor enhanced RAI treatment using a case-control study design. 4) Develop novel therapeutic bispecific antibodies to redirect polyclonal T cells to target adaptive responses to MAPK inhibitors.