RE-ENGINEERING RADIOIODINE THERAPY FOR THE 21ST CENTURY

重新设计 21 世纪的放射性碘治疗

• 批准号: MR/P000509/1
• 负责人: Christopher McCabe
• 金额: $ 84.53万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP000509%2F1
• 关键词: RE; ENGINEERING; RADIOIODINE; THERAPY; 21ST

The newest data available show us that nearly a third of a million new cases of thyroid cancer are reported worldwide per year. In general terms, patient outcome is good, but around a quarter of patients do not respond well to the main therapy, which involves the intake of a radioactive isotope (radioiodine 131I). For these patients, life expectancy is significantly reduced. Importantly, around 38,000 people die from thyroid cancer per annum. Radioiodine is a safe and effective treatment which has been in clinical use for 73 years. However, its utilisation has remained largely unchanged since 1942. It is our assertion that new breakthroughs and technologies could transform radioiodine treatment, making it more effective for all patients, but with further significant benefits to those thyroid cancer patients who do not respond well to the therapy.The radioisotope 131I works by destroying thyroid cells. It is taken up into cells by a transporter protein called the sodium iodide symporter (NIS). This remains a poorly understood protein. For instance, the processes which govern its activity are not completely understood. Our project aims to change this through an ambitious series of high level experiments, calling on our existing data, and via the generation of new insight. We will use cutting edge cell and animal experiments to isolate the utterly best way of improving the function of NIS, and hence the efficiency of thyroid cancer treatment.Through our existing long term commitment to this project, we have already found a way of increasing 131I uptake into cells by at least 70%. Now, we need to discover whether we have reached the maximum possible improvement in the therapy, or whether new technologies can transform this effect and make the treatment even more effective and applicable. To do this we will establish new models which bridge the gap between assays based on 'classical' cell culture (mainly isolated cells in monolayer), and biological validation in whole animals such as rodents. We will engage with drug companies and world leading scientists to carry out an ambitious joined up and intensive period of research with the overall goal of finally making 131I uptake a viable and effective treatment for all patients with thyroid cancer.

可获得的最新数据显示，全世界每年报告的甲状腺癌新病例中有近三分之一。总的来说，患者的结果是好的，但大约四分之一的患者对主要治疗反应不佳，主要治疗包括摄取放射性同位素(放射性碘131I)。对于这些患者来说，预期寿命显著缩短。重要的是，每年约有38,000人死于甲状腺癌。放射性碘是一种安全有效的治疗方法，临床应用已有73年之久。然而，自1942年以来，它的使用基本保持不变。我们断言，新的突破和技术可能会改变放射性碘治疗，使其对所有患者更有效，但对那些对治疗反应不佳的甲状腺癌患者有更大的好处。放射性同位素131I通过破坏甲状腺细胞发挥作用。它被一种被称为钠碘转运体(NIS)的转运蛋白吸收到细胞中。这仍然是一种知之甚少的蛋白质。例如，管理其活动的过程并没有完全被理解。我们的项目旨在通过一系列雄心勃勃的高水平实验，调用我们现有的数据，并通过产生新的见解来改变这一点。我们将使用尖端细胞和动物实验来分离出改善NIS功能的最好方法，从而提高甲状腺癌治疗的效率。通过我们现有的长期致力于这个项目，我们已经找到了一种方法，将~(131)I在细胞中的摄取增加至少70%。现在，我们需要发现我们是否已经达到了治疗的最大可能改进，或者新技术是否可以改变这种效果，使治疗更加有效和适用。为了做到这一点，我们将建立新的模型，以弥合基于经典细胞培养(主要是单层分离细胞)的分析和整个动物(如啮齿动物)的生物学验证之间的差距。我们将与制药公司和世界领先的科学家合作，开展雄心勃勃的联合密集研究，总的目标是最终使131I摄取成为所有甲状腺癌患者可行和有效的治疗方法。

项目成果

Functional consequences of the first reported mutations of the proto-oncogene PTTG1IP/PBF.

• DOI: 10.1530/erc-16-0340
• 发表时间: 2017-09
• 期刊: Endocrine-related cancer
• 影响因子: 3.9
• 作者: Imruetaicharoenchoke W;Fletcher A;Lu W;Watkins RJ;Modasia B;Poole VL;Nieto HR;Thompson RJ;Boelaert K;Read ML;Smith VE;McCabe CJ
• 通讯作者: McCabe CJ

Targeting non-canonical pathways as a strategy to modulate the sodium iodide symporter.

• DOI: 10.1016/j.chembiol.2021.07.016
• 发表时间: 2022-03-17
• 期刊: Cell chemical biology
• 影响因子: 8.6
• 作者: Read ML;Brookes K;Thornton CEM;Fletcher A;Nieto HR;Alshahrani M;Khan R;Borges de Souza P;Zha L;Webster JRM;Alderwick LJ;Campbell MJ;Boelaert K;Smith VE;McCabe CJ
• 通讯作者: McCabe CJ

Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer.

• DOI: 10.1038/onc.2017.154
• 发表时间: 2017-09-14
• 期刊: Oncogene
• 影响因子: 8
• 作者: Read ML;Fong JC;Modasia B;Fletcher A;Imruetaicharoenchoke W;Thompson RJ;Nieto H;Reynolds JJ;Bacon A;Mallick U;Hackshaw A;Watkinson JC;Boelaert K;Turnell AS;Smith VE;McCabe CJ
• 通讯作者: McCabe CJ

PTTG and PBF Functionally Interact with p53 and Predict Overall Survival in Head and Neck Cancer.

• DOI: 10.1158/0008-5472.can-18-0855
• 发表时间: 2018-10-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Read ML;Modasia B;Fletcher A;Thompson RJ;Brookes K;Rae PC;Nieto HR;Poole VL;Roberts S;Campbell MJ;Boelaert K;Turnell AS;Smith VE;Mehanna H;McCabe CJ
• 通讯作者: McCabe CJ

Dimerization of the Sodium/Iodide Symporter.

钠/碘同向转运体的二聚化。

• DOI: 10.1089/thy.2019.0034
• 发表时间: 2019
• 期刊: official journal of the American Thyroid Association
• 作者: Thompson RJ