Improving efficacy of radioiodine treatment of thyroid cancer

提高放射性碘治疗甲状腺癌的疗效

• 批准号: 10375547
• 负责人: JAMES A FAGIN
• 金额: $ 46.2万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375547
• 关键词: Address; Adjuvant; Age; Attenuated; BRAF gene; Biological; Biological Markers; Bispecific Antibodies; Case-Control Studies; Clinical Trials; Combined Modality Therapy; Differentiated Gene; Disease; Disease remission; Drug Targeting; ERBB2 gene; ERBB3 gene; Feedback; Gene Expression; Genes; Genomics; Goals; Immune response; Impairment; Interruption; Iodides; Iodine; Kinetics; Lesion; MAP Kinase Gene; MEKs; Malignant Neoplasms; Malignant neoplasm of thyroid; Metastatic/Recurrent; Mitogen-Activated Protein Kinase Inhibitor; Molecular; Mus; Mutation; Neoplasm Metastasis; Oncoproteins; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Property; Protein Isoforms; Proteins; Radiation Dose Unit; Radioactive Iodine; Refractory; Research Design; Resistance; Schedule; Series; Signal Transduction; T-Lymphocyte; Testing; Therapeutic antibodies; Thyroglobulin; Thyroid Gland; Thyroidectomy; Time; Toxic effect; Treatment Efficacy; Tyrosine; base; cancer cell; cell killing; dimer; exome sequencing; improved; inhibitor; insight; kinase inhibitor; mouse model; mutant; neoplastic cell; novel strategies; novel therapeutics; oxidation; patient population; pilot trial; radioiodine therapy; recruit; responders and non-responders; response; restoration; small molecule; trait; transcriptome; transcriptomics; tumor; tumor heterogeneity; tumor microenvironment; uptake

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.

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信号传导的癌蛋白抑制控制甲状腺分化功能和对RAI应答的基因的表达，这可以在小鼠模型和初步临床试验中用RAF或MEK抑制剂至少部分逆转。这些治疗在BRAFV 600 E突变型癌症中效果较差，我们发现这是由于对RAF或MEK抑制剂的适应性耐药性。在小鼠BrafV 600 E PTC中，严重的MAPK通路阻断增加碘摄取，但不增加碘保留时间。因为这些化合物 缓解增加PI 3 K信号传导的负反馈输入，PI 3 K信号传导损害碘氧化和并入甲状腺球蛋白（TG）所需的基因表达。这可以通过与泛PI 3 K抑制剂的联合治疗来挽救。该提案的目标是在迄今为止取得的进展的基础上，在最有可能受益的甲状腺癌患者中实现更大的再分化治疗效果。我们建议这样做：1。研究选择性PI 3 K亚型或HER激酶抑制剂是否在阻断MAPK的情况下增加碘保留和RAI功效。2.测试RAF抑制剂vemurafenib和pan-PI 3 K抑制剂copanlisib对碘有机化基因表达的影响，以及这与RAI难治性BRAFV 600 E转移性甲状腺癌患者的病灶124 I摄取和保留时间的关系。3.使用病例对照研究设计，确定对常规或MAPK抑制剂增强RAI治疗有特殊结构反应的患者中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，以靶向对MAPK抑制剂的适应性反应。