Improving efficacy of radioiodine treatment of thyroid cancer

晚期甲状腺癌患者往往对放射性碘(RAI)治疗无效。激活MAPK信号的原癌蛋白抑制了控制甲状腺分化功能和对RAI反应的基因的表达，在小鼠模型和试点临床试验中，这一点至少可以被RAF或MEK抑制剂部分逆转。这些治疗在BRAFV600E突变的癌症中效果较差，我们发现这是由于对RAF或MEK抑制剂的适应性耐药。深度阻断MAPK通路可增加小鼠BRAFV600E PTCs对碘的摄取，但不增加碘滞留时间。这是因为这些化合物 缓解增加PI3K信号的负反馈输入，PI3K信号会损害碘化物氧化和并入甲状腺球蛋白(TG)所需基因的表达。这可以通过与PAN-PI3K抑制剂的联合治疗来挽救。这项提案的目标是在迄今取得的进展的基础上，为最有可能受益的甲状腺癌患者实现再分化治疗的更大疗效。我们建议通过：1.研究在MAPK阻断的情况下，选择性PI3K异构体或HER激酶抑制剂是否增加了碘的滞留和RAI的有效性。2.检测RAF抑制剂维莫拉非尼和PAN-PI3K抑制剂Copanlisib对RAI难治性BRAFV600E转移性甲状腺癌患者碘有机化基因表达的影响及其与124I摄取和滞留时间的关系。3.采用病例对照研究设计，在对常规或MAPK抑制剂增强型RAI治疗有特殊结构反应的患者中，确定RAI疗效的分子预测因子。4)开发新的治疗性双特异性抗体，以重定向多克隆T细胞以靶向对MAPK抑制剂的适应性反应。

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.