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Investigating the role of the Notch atypical ligand delta-like homologue 1 (DLK1) in adrenocortical carcinoma

研究 Notch 非典型配体 δ 样同源物 1 (DLK1) 在肾上腺皮质癌中的作用

基本信息

批准号：
MR/S022155/1
负责人：
James Pittaway
金额：
$ 35.31万
依托单位：
Queen Mary University of London
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FS022155%2F1
关键词：
Investigating role Notch atypical ligand

项目摘要

Adrenocortical carcinoma (ACC) is a rare, aggressive tumour occurring in the adrenal cortex, the steroid-producing outer layer of the adrenal gland. Early diagnosis and surgical resection is crucial to long-term survival. In many cases, the cancer has spread by the time of diagnosis and the prognosis is bleak, with five-year survival rate in advanced disease under 15%. The only approved medical treatment is the drug mitotane but it is poorly tolerated and often fails to prevent disease progression. It is important to correctly identify ACC to ensure its prompt management. Current practice revolves around prediction of malignancy based upon clinical, biochemical and radiological features. Once a mass has been removed, histological diagnosis is based upon properties of the tumour and a further prediction of malignant potential. This is often complex especially in borderline cases. Therefore it is important to identify new biological markers that can aid in the diagnosis, prognosis and monitoring of disease. It is not known which cells are involved in the development of ACC, nor is it known which cells within an established tumour confer resistance to chemotherapeutic drugs and may be responsible for tumour relapse. We have recently identified a novel population of cells in the adrenal gland, which we believe might be the precursor of adrenal cancer. These cells express a protein called delta-like homologue 1 (DLK1). DLK1 is not normally found in most healthy human tissues. However, expression has been reported in other malignancies and in some of these increased DLK1 expression is associated with a worse prognosis. This makes it an attractive option for further investigation not only as a novel biomarker in ACC but also as a player in the development of this malignancy and as such a potential target for novel therapeutic intervention.In this project I will be investigating the role of DLK1 in adrenocortical carcinoma on two fronts. First, I will be studying its role as a potential novel biomarker in this condition. I will be doing this by looking at expression of DLK1 in collected tumour samples and in blood and seeing if there is a relationship with survival rates as well as clinical and biochemical presentation of disease. In addition, I will also be looking at DLK1+ adrenocortical carcinoma cells and characterising how they differ from other cells in the cancer.To carry out this project, I have developed collaborations with one of the largest groups investigating this condition from Germany (Prof. Fassnacht, University of Würzburg) and also my local pathology department to gain access to over 100 tissue sections of ACC along with the clinical records to assess details of presentation and long-term outcomes.I am collecting ACC tumour samples from four surgical centres across London. From our local hospital I am also collecting normal adrenal tissue from patients having surgery for other non-cancerous pathologies. In addition, I will be performing experiments using two new patient derived adrenocortical carcinoma cells lines through a collaboration developed with University of Colorado Denver in addition the commercially available, H295R cell line.This project combines cellular biological investigation with a clinical focus. It has the promise to identify and characterise a new molecular biomarker for diagnosis and prognosis of ACC, to deliver new biology defining a cell population in this malignancy and to identify targets which may be amenable to novel therapeutic intervention.

肾上腺皮质癌（ACC）是一种罕见的，侵袭性肿瘤发生在肾上腺皮质，类固醇生产肾上腺的外层。早期诊断和手术切除对长期生存至关重要。在许多情况下，癌症在诊断时已经扩散，预后很差，晚期疾病的五年生存率低于15%。唯一批准的药物治疗是药物米托坦，但它的耐受性差，往往不能防止疾病的进展。必须正确识别ACC，以确保其及时管理。目前的实践围绕基于临床、生化和放射学特征的恶性肿瘤预测。一旦肿块被切除，组织学诊断是基于肿瘤的性质和进一步预测恶性潜力。这往往是复杂的，特别是在边界案件。因此，重要的是要确定新的生物标志物，可以帮助疾病的诊断，预后和监测。目前还不知道哪些细胞参与ACC的发展，也不知道已建立的肿瘤中的哪些细胞赋予对化疗药物的抗性，并可能导致肿瘤复发。我们最近在肾上腺中发现了一种新的细胞群，我们认为这可能是肾上腺癌的前兆。这些细胞表达一种称为δ样同源物1（DLK1）的蛋白质。DLK1通常不存在于大多数健康的人体组织中。然而，在其他恶性肿瘤中也有表达的报道，其中一些DLK1表达增加与预后不良相关。这使得它成为一个有吸引力的选择，不仅作为一种新的生物标志物在ACC的进一步调查，但也作为一个球员在这种恶性肿瘤的发展，并作为这样一个潜在的目标，新的治疗intervention.In这个项目中，我将调查DLK1在肾上腺皮质癌的作用在两个方面。首先，我将研究它在这种情况下作为一种潜在的新型生物标志物的作用。我将通过观察DLK1在收集的肿瘤样本和血液中的表达来做到这一点，看看是否与生存率以及疾病的临床和生化表现有关。此外，我还将观察DLK 1+肾上腺皮质癌细胞，并描述它们与癌症中其他细胞的差异。为了实施该项目，我与德国最大的研究该疾病的团队之一合作（Fassnacht教授，维尔茨堡大学）以及我当地的病理部门，以获得超过100个ACC的组织切片，沿着临床记录，以评估表现和长期的细节，我从伦敦的四个外科中心收集ACC肿瘤样本。从我们当地的医院，我也收集正常的肾上腺组织从病人有手术的其他非癌性病变。此外，我将通过与科罗拉多丹佛大学合作开发的两种新的患者来源的肾上腺皮质癌细胞系以及市售的H295 R细胞系进行实验。该项目将细胞生物学研究与临床重点相结合。它有希望识别和鉴定用于ACC诊断和预后的新分子生物标志物，提供定义这种恶性肿瘤中细胞群的新生物学，并识别可能适合新治疗干预的靶点。