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101.1万例新病例，4200例死亡。尽管早期发现增加，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。死亡通常是由于疾病在转移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。这是由于几乎所有患者都会出现耐药性，平均在9个月内出现。导致耐药性的一个主要因素是肿瘤内发现的非同寻常的多样性，这是由肿瘤生长过程中持续的基因突变模式引起的。这意味着一个肿瘤实际上可以由许多子肿瘤（称为“亚克隆”）组成，每个子肿瘤都是不同的。当这些“亚克隆体”中的一些（但不是全部）被摧毁时，治疗通常会失败，而剩下的那些会重新长得更强壮，导致绝症（称为“致命亚克隆体”）。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。这项研究将涉及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”可以被单独观察。随着疾病进展和/或产生耐药性，将从其他器官的肿瘤（转移）、血液/尿液样本以及尸检组织中分析更多的DNA。这将允许在疾病进展/耐药性之前和之后确定“致命亚克隆”。通过确定“致命亚克隆”并在整个疾病过程中跟踪它们，预计可以确定它们的优势和劣势，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成本有效的诊断测试，以检测“致命的亚克隆”，这意味着高风险患者可以提前识别，并考虑更积极的治疗计划。在未来，被称为“免疫疗法”的新一代治疗方法在解决“致命亚克隆”和提高肾癌存活率方面具有重要的临床前景。在其他类型的肿瘤中，如皮肤癌、肺癌和血癌，在过去5年中已经取得了突破性的成果。免疫系统在肾肿瘤中起着积极的作用，白细胞（淋巴细胞）能够渗透到肿瘤中并杀死癌细胞。这个过程可以用于治疗，要么提高白细胞的活性水平，要么引入更多的白细胞来攻击肿瘤。与传统药物相比，这种方法的最大好处是，白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。免疫疗法先前在晚期肾癌患者身上进行了试验，结果好坏参半。一小部分患者表现出显著的结果（10年以上无癌症），但大多数患者未能获得任何益处。其原因尚不清楚，因为我们对免疫系统如何在肾肿瘤内运作的生物学理解有限。该项目的后半段将对肾肿瘤内的免疫系统进行详细研究。上面的DNA分析将被RNA分析和一种称为“多重免疫组织化学”的技术所补充，以绘制不同类型白细胞的位置和活性。这将是迄今为止在肾癌患者中进行的最大的此类研究，旨在揭示免疫系统对肾癌的反应，为支持新免疫疗法的发展提供见解。

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.