Leveraging circulating tumour DNA (ctDNA) to dissect the evolutionary genomic dynamics of drug resistance in prostate cancer.

利用循环肿瘤 DNA (ctDNA) 剖析前列腺癌耐药性的基因组进化动力学。

• 批准号: MR/P002072/2
• 负责人: Anuradha Jayaram
• 金额: $ 18.2万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP002072%2F2
• 关键词: Leveraging; circulating; tumour; DNA; ctDNA

1. Scientific/medical context of research?Prostate cancer is the commonest male cancer (41,000 diagnosed in 2010) and the second commonest (10,700 died in 2010) cause of male cancer death in the UK. One man dies of prostate cancer every hour in the UK. The growth of the prostate is dependent on male hormones (androgens). Prostate cancer develops when prostate cells grow uncontrollably. This is initially dependent on androgens. If diagnosed early prostate cancer can be cured by surgery and/or radiotherapy. However, 30% of cases will relapse and more than 20% of cases will present with widespread (metastatic) disease that is incurable. Initial treatment strategies to lower hormone (androgen) levels provide robust responses in 90% of cases (hormone naïve prostate cancer). However, with time, cancers develop other mechanisms of resistance despite low (castrate) levels of testosterone - known as castration resistant prostate cancer (CRPC). Unfortunately, this advanced form of prostate cancer is currently incurable. Over the last two years, two novel treatments have become available as treatment options for CRPC along with chemotherapy. These agents are Abiraterone acetate and Enzalutamide. These agents have been proven to prolong survival in patients with CRPC. Eventually, prostate cancer progresses despite these new drugs and chemotherapy: a proportion of patients respond for a number of years and others progress very rapidly.2. What is the research trying to achieve?Understanding why these agents stop working or drug resistance requires an understanding of DNA changes (genomic) and identifying these changes over time. Treatments for prostate cancer can influence the growth of prostate cancer and understanding this would require analysis of multiple cancer biopsies. This is an impractical solution as performing multiple biopsies is difficult and more importantly uncomfortable to the patient. This proposal will aim to identify these abnormalities with a simple blood test that can be done regularly. This blood test will be able to serially/sequentially monitor tumour gene changes and identify abnormalities in the androgen receptor and other genomic changes that associate with resistance. 3. Why is the research important?Better drugs and management strategies are urgently required. Understanding and identifying causes of resistance at different time points throughout the disease course will allow us to institute early treatment changes and therefore improve patient outcome. Additionally new drugs can be developed to target these mechanisms and also implement a personalised treatment approach for the patients using a non-invasive technique and identify the right treatment for the right patient groups and reduce unnecessary side-effects with ineffective treatments. 4. Who is carrying out the research?Dr Anuradha Jayaram is a clinical research fellow in the Prostate Cancer Targeted Therapy group at the Royal Marsden Hospital in London. She completed her medical degree and specialist oncology training in Ireland. Her career ambition is to be an academic medical oncologist with a laboratory focused on translational research within the field of prostate cancer. This fellowship will be carried out under the supervision of Professors Mel Greaves, Dr Gerhardt Attard and Professor Ros Eeles who are key opinion leaders within the fields of cancer evolution, prostate cancer targeted therapy and prostate cancer genetics. Dr Sharp will be based in the Centre for Cancer and evolution at the Institute of Cancer Research, the top rated academic unit worldwide. The fellowship will initiate a consortium (sponsors and collaborators) of international leaders within the fields of circulating biomarkers and molecular characterisation in prostate cancer medicine to ensure the greatest scientific and clinical impact of this fellowship.

1. 研究的科学/医学背景？前列腺癌是英国最常见的男性癌症（2010年诊断出41,000例）和第二大男性癌症死亡原因（2010年死亡10,700例）。在英国，每小时就有一人死于前列腺癌。前列腺的生长依赖于雄性激素（雄激素）。当前列腺细胞不受控制地生长时，就会发生前列腺癌。这最初依赖于雄激素。如果诊断出早期前列腺癌，可以通过手术和/或放疗治愈。然而，30%的病例会复发，超过20%的病例会出现无法治愈的广泛（转移性）疾病。降低激素（雄激素）水平的初始治疗策略在90%的病例中提供了强有力的反应（激素naïve前列腺癌）。然而，随着时间的推移，尽管睾丸激素水平较低，癌症仍会发展出其他抵抗机制——即所谓的去势抵抗性前列腺癌（CRPC）。不幸的是，这种晚期前列腺癌目前是无法治愈的。在过去的两年中，两种新的治疗方法与化疗一起成为CRPC的治疗选择。这些药物是醋酸阿比特龙和恩杂鲁胺。这些药物已被证明可以延长CRPC患者的生存期。最终，尽管有这些新药和化疗，前列腺癌仍会恶化：一部分患者的反应持续数年，而另一些患者的进展非常迅速。这项研究想要达到什么目的？要了解这些药物停止工作或耐药性的原因，需要了解DNA（基因组）的变化，并确定这些变化随时间的变化。前列腺癌的治疗可以影响前列腺癌的生长，了解这一点需要对多次癌症活检进行分析。这是一个不切实际的解决方案，因为进行多次活检是困难的，更重要的是不舒服的病人。这项建议旨在通过一种简单的血液检查来识别这些异常，这种检查可以定期进行。这种血液检测将能够连续/顺序地监测肿瘤基因的变化，并识别雄激素受体的异常和与耐药性相关的其他基因组变化。3. 为什么这项研究很重要？迫切需要更好的药物和管理策略。了解和确定在整个疾病过程中不同时间点的耐药原因将使我们能够制定早期治疗方案，从而改善患者的预后。此外，可以开发针对这些机制的新药，也可以使用非侵入性技术为患者实施个性化治疗方法，并为正确的患者群体确定正确的治疗方法，减少无效治疗带来的不必要的副作用。4. 谁在进行这项研究？Anuradha Jayaram博士是伦敦皇家马斯登医院前列腺癌靶向治疗小组的临床研究员。她在爱尔兰完成了医学学位和专科肿瘤学培训。她的职业抱负是成为一名学术医学肿瘤学家，拥有一个专注于前列腺癌领域转化研究的实验室。该奖学金将在Mel Greaves教授、Gerhardt Attard博士和Ros Eeles教授的指导下进行，他们是癌症进化、前列腺癌靶向治疗和前列腺癌遗传学领域的关键意见领袖。夏普博士将在癌症研究所的癌症与进化中心工作，这是全球最受好评的学术单位。该奖学金将发起一个由前列腺癌医学循环生物标志物和分子表征领域的国际领导者组成的联盟（赞助商和合作者），以确保该奖学金的最大科学和临床影响。

项目成果

Leveraging circulating tumour DNA to dissect the evolutionary genomic dynamics of drug resistance in prostate cancer

利用循环肿瘤 DNA 剖析前列腺癌耐药性的基因组进化动力学

• 发表时间: 2021
• 作者: Jayaram Anuradha Krishna

Phase II pilot study of the prednisone to dexamethasone switch in metastatic castration-resistant prostate cancer (mCRPC) patients with limited progression on abiraterone plus prednisone (SWITCH study).

• DOI: 10.1038/s41416-018-0123-9
• 发表时间: 2018-10
• 期刊: British journal of cancer
• 影响因子: 8.8
• 作者: Romero-Laorden N;Lozano R;Jayaram A;López-Campos F;Saez MI;Montesa A;Gutierrez-Pecharoman A;Villatoro R;Herrera B;Correa R;Rosero A;Pacheco MI;Garcés T;Cendón Y;Nombela MP;Van de Poll F;Grau G;Rivera L;López PP;Cruz JJ;Lorente D;Attard G;Castro E;Olmos D
• 通讯作者: Olmos D

Circulating tumor DNA in advanced prostate cancer: transitioning from discovery to a clinically implemented test.

晚期前列腺癌中循环肿瘤DNA：从发现过渡到临床实施的测试。

• DOI: 10.1038/s41391-018-0098-x
• 发表时间: 2019-05
• 期刊: Prostate cancer and prostatic diseases
• 影响因子: 4.8
• 作者: González-Billalabeitia E;Conteduca V;Wetterskog D;Jayaram A;Attard G
• 通讯作者: Attard G

Assessment of the Validity of Nuclear-Localized Androgen Receptor Splice Variant 7 in Circulating Tumor Cells as a Predictive Biomarker for Castration-Resistant Prostate Cancer.

• DOI: 10.1001/jamaoncol.2018.1621
• 发表时间: 2018-09-01
• 期刊: JAMA oncology
• 影响因子: 28.4
• 作者: Scher HI;Graf RP;Schreiber NA;Jayaram A;Winquist E;McLaughlin B;Lu D;Fleisher M;Orr S;Lowes L;Anderson A;Wang Y;Dittamore R;Allan AL;Attard G;Heller G
• 通讯作者: Heller G

Plasma DNA and Metastatic Castration-Resistant Prostate Cancer: The Odyssey to a Clinical Biomarker Test.

• DOI: 10.1158/2159-8290.cd-18-0124
• 发表时间: 2018-04
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: A. Jayaram;D. Wetterskog;G. Attard