Lethal renal cell carcinoma sub-clones: Defining mechanisms of tumour evolution, treatment resistance and immune escape.

在过去的40年里，肾癌在英国翻了一番，每年有超过11，000例新发病例和超过4，200例死亡。尽管早期发现率增加，但5年生存率仍然很低，为56%，晚期疾病的平均生存期仅为18个月。死亡通常是由疾病在称为转移的过程中扩散到远端器官引起的。虽然已经引入了治疗晚期转移性疾病的新药，但它们主要用作姑息治疗选择，以延迟而不是预防死亡。这是由于耐药性，几乎所有患者平均在9个月内发生。导致耐药性的一个主要因素是肿瘤内发现的异常多样性，这是由肿瘤生长过程中连续的基因突变模式引起的。这意味着肿瘤实际上可以由许多亚肿瘤（称为“亚克隆”）组成，每个亚肿瘤都是不同的。当这些“亚克隆”中的一部分（但不是全部）被摧毁时，治疗通常会失败，而剩下的那些又会长得更强，导致晚期疾病（称为“致命亚克隆”）。这项研究将研究“致命亚克隆”如何生长，它们如何在体内扩散以及它们如何抵抗药物。该研究将涉及320名肾癌患者，从药物治疗前开始，并将分析他们原发性肾脏肿瘤的DNA，这些肿瘤将被物理切割成一系列独立的子区域（平均每个患者7个）。这使得不同的“子克隆”可以单独查看。随着疾病进展和/或变得耐药，将从其他器官中的肿瘤（转移）、血液/尿液样本以及尸检组织中分析额外的DNA。这将允许在疾病进展/耐药性之前和之后精确定位“致命亚克隆”。通过查明“致命的亚克隆”并在整个病程中跟踪它们，预计可以确定它们的长处和短处，从而产生基本的生物学知识，以支持开发新的治疗方案。该项目的另一个目标是开发一种新的具有成本效益的诊断测试来检测“致命亚克隆”，这意味着可以提前识别高风险患者并考虑更积极的治疗计划。在未来，称为“免疫疗法”的新一代治疗方法具有解决“致命亚克隆”和提高肾癌生存率的重大临床前景。在其他类型的肿瘤，如皮肤癌、肺癌和血癌方面，过去5年已经取得了突破性成果。免疫系统在肾肿瘤中起着积极的作用，白色血细胞（淋巴细胞）能够渗透到肿瘤中并杀死癌细胞。这一过程可以通过提高白色血细胞的活性水平或引入更多的白细胞来攻击肿瘤来进行治疗。与传统药物相比，这种方法的最大好处是白色血细胞是一种活的治疗方法，可以适应并跟上不断变化的癌细胞。免疫疗法以前曾在晚期肾癌患者中进行过测试，结果喜忧参半。一小部分患者显示出显著的结果（10年以上无癌症），但大多数患者未能获得任何益处。原因尚不清楚，因为我们对免疫系统在肾脏肿瘤内如何运作的生物学理解有限。该项目的后半部分将对肾脏肿瘤中的免疫系统进行详细研究。上述DNA分析将通过RNA分析和称为“多重免疫组织化学”的技术进行补充，以绘制不同类型白色血细胞的位置和活性。这将是迄今为止在肾癌患者中进行的最大规模的研究，旨在揭示免疫系统如何对肾癌做出反应，为支持新免疫疗法的开发提供见解。

Kidney cancers have doubled in the UK over last 40 years, with >11,000 new cases annually and >4,200 deaths. Despite increased early detection the 5-year survival rates remain poor at 56%, with average survival of only ~18 months for advanced disease. Death is typically caused by disease spread to distal organs in a process called metastasis. While new drugs have been introduced to treat advanced metastatic disease, they are mainly used as palliative treatment options to delay rather than prevent mortality. This is due to drug resistance, which occurs in almost all patients, on average within 9 months. A major factor contributing to drug resistance is the extraordinary diversity found within tumours, caused by a pattern of continuous genetic mutation as the tumour grows. This means a tumour can actually be made up of many sub-tumours (called "subclones"), each of which is different. Treatment typically fails when some but not all of these "subclones" can be destroyed, and the ones left then grow back stronger causing terminal disease (called "lethal subclones").This research will study how "lethal subclones" grow, how they spread across the body and how they resist drugs. The study will involve 320 kidney cancer patients, starting before drug treatment and will analyse DNA from their primary kidney tumour, which will be physically cut into a series of separate subregions (on average 7 per patient). This allows the different "subclones" to be looked at individually. As disease progresses and/or becomes treatment resistant, additional DNA will be analysed from tumours in other organs (metastases), from blood/urine samples as well as from autopsy tissue. This will allow the "lethal subclones" to be pinpointed, both before and after disease progression/drug resistance. By pinpointing the "lethal sub-clones" and tracking them through the disease course, it is anticipated that their strengths and weaknesses can be identified, generating fundamental biological knowledge to support the development of new treatment options. Another aim of this project is to develop a new cost effective diagnostic test to detect "lethal subclones", meaning high risk patients can be identified upfront and more aggressive treatment plans considered.In the future a new generation of treatments called "immunotherapies" hold significant clinical promise to tackle "lethal subclones" and increase survival rates for kidney cancer. In other tumour types, such as skin, lung and blood cancers, breakthrough results have already been achieved in the last 5 years. The immune system plays an active role in kidney tumours, with white blood cells (lymphocytes) able to penetrate into the tumour and kill cancer cells. This process can be exploited therapeutically, either by raising the activity level of white blood cells or introducing more of them to attack the tumour. The great benefit of this approach, as compared to traditional drugs, is that the white blood cells are a living treatment that can adapt and keep up with the changing cancer cells. Immunotherapies have been previously tested in advanced kidney cancer patients with mixed results. A modest fraction of patients showed remarkable results (10+ years cancer free) however the majority failed to derive any benefit. The reasons for this are unclear, due to our limited biological understanding of how the immune system operates inside kidney tumours. The second half of this project will conduct a detailed study of the immune system within kidney tumours. The DNA analysis from above will be complimented by RNA analysis and a technique called "multiplex immunohistochemistry", to map the location and activity of different types of white blood cell. This will be the biggest study of its kind in kidney cancer patients to date and aims to reveal how the immune system behaves in response to kidney cancer, providing insights to support the development of new immunotherapies.