Improving efficacy of radioiodine treatment of thyroid cancer

晚期甲状腺癌患者通常对放射性碘 (RAI) 治疗无效。组成性激活 MAPK 信号传导的癌蛋白会抑制控制甲状腺分化功能和对 RAI 反应的基因表达，而在小鼠模型和试点临床试验中，RAF 或 MEK 抑制剂可以至少部分逆转这种情况。这些治疗方法对 BR​​AFV600E 突变型癌症效果较差，我们证明这是由于对 RAF 或 MEK 抑制剂的适应性耐药所致。深度 MAPK 通路阻断可增加小鼠 BrafV600E PTC 中的碘吸收，但不会增加碘保留时间。这是因为这些化合物 缓解增加 PI3K 信号传导的负反馈输入，从而损害碘氧化和掺入甲状腺球蛋白 (TG) 所需的基因表达。这可以通过与泛 PI3K 抑制剂联合治疗来挽救。该提案的目标是在迄今为止取得的进展的基础上，使最有可能受益的甲状腺癌患者获得更大的再分化疗法疗效。我们建议通过以下方式做到这一点： 1. 研究选择性 PI3K 同工型或 HER 激酶抑制剂是否可以在 MAPK 阻断的情况下增加碘保留和 RAI 功效。 2. 测试 RAF 抑制剂 vemurafenib 和泛 PI3K 抑制剂 copanlisib 对碘化物组织基因表达的影响，以及这与 RAI 难治性 BRAFV600E 转移性甲状腺癌患者病灶 124I 摄取和保留时间的关系。 3. 使用病例对照研究设计，确定对传统或 MAPK 抑制剂增强 RAI 治疗有特殊结构反应的患者 RAI 疗效的分子预测因子。 4) 开发新型治疗性双特异性抗体，以重定向多克隆 T 细胞，以针对 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.