Improving efficacy of radioiodine treatment of thyroid cancer

提高放射性碘治疗甲状腺癌的疗效

基本信息

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
项目类别：
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

项目摘要

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.

晚期甲状腺癌的患者经常对放射碘（RAI）治疗难治性。组成性激活MAPK信号传导抑制甲状腺分化功能和对RAI的反应的基因表达的癌蛋白，至少部分地在小鼠模型中，在小鼠模型和试验临床试验中可以逆转。这些治疗方法在BRAFV600E突变癌中的有效性较低，我们证明这是由于对RAF或MEK抑制剂的适应性抗性。深刻的MAPK途径阻滞增加了碘化物的摄取，但不会增加小鼠BRAFV600E PTC中的碘保留时间。这是因为这些化合物减轻了增加PI3K信号传导的负反馈输入，这会损害碘化物氧化所需的基因表达，并掺入甲状腺球蛋白（TG）中。这可以通过将处理与PAN-PI3K抑制剂联合处理来挽救。该提案的目的是建立迄今为止的进展，以在最有可能受益的甲状腺癌患者中重新分辨疗法的更大疗效。我们建议通过：1。研究选择性PI3K同工型或她的激酶抑制剂是否在MAPK封锁的背景下会增加碘化物的保留和RAI疗效。 2。测试RAF抑制剂vemurafenib和Pan-PI3K抑制剂Copanlisib对碘化物有机化基因表达的影响，以及这与患有RAI-RAI-CRAFRAFCORY BRAFV600E转移性甲状腺甲状腺癌症患者的病变124I摄取和保留时间有关。 3.通过病例对照研究设计，确定对常规或MAPK抑制剂增强RAI治疗的患者RAI功效的分子预测指标。 4）开发针对重定向多克隆T细胞的新型双特异性抗体，以靶向对MAPK抑制剂的适应性反应。