BAG-1: A novel strategy for targeting the androgen receptor splice variants in castrate resistant prostate cancer.

研究的科学/医学背景？前列腺癌是最常见的男性癌症（2010年诊断出41，000例），也是英国男性癌症死亡的第二常见原因（2010年死亡10，700例）。在英国，每小时就有一名男子死于前列腺癌。前列腺的生长依赖于激素（雄激素）。激素是身体的化学信使，通过结合其受体（雄激素受体）刺激细胞生长。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。如果诊断为早期前列腺癌，可以通过手术和/或放射治疗治愈。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）疾病。降低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（激素初治前列腺癌）。不幸的是，随着时间的推移，几乎所有的病例都会发展成致命的疾病，不再对这种治疗有反应（去势抵抗性前列腺癌）。导致去势抵抗的一种机制是雄激素受体结构改变（剪接变体）。这些是永久活性的，不结合雄激素，使目前的治疗无效。目前没有临床上可用的治疗策略靶向雄激素受体剪接变体，这是一个未满足的研究和临床需求的关键领域。BAG-1是一种蛋白质，与未接受激素治疗的前列腺癌相比，在去势抵抗性前列腺癌中的水平增加。BAG-1激活前列腺癌中的雄激素受体和雄激素受体剪接变体。降低BAG-1蛋白水平的技术抑制前列腺癌细胞的生长。BAG-1为抑制雄激素受体剪接变异体提供了一个新的治疗靶点，并影响去势抵抗性前列腺癌患者的生存。研究试图达到什么目的？该研究将确定患者活检组织中的BAG-1蛋白水平，并将其与患者生存和治疗反应相关联，以确定BAG-1作为去势抵抗性前列腺癌的预后生物标志物（生存和治疗反应的预测因子）。它将确定BAG-1作为雄激素受体和雄激素受体剪接变体信号传导的关键调节剂，驱动前列腺癌的去势抵抗和治疗抵抗。该研究将确定BAG-1作为一种新的治疗靶点，用于去势抵抗性前列腺癌的抗癌药物发现工作。在去势抵抗性前列腺癌中，尚无临床上可用的靶向雄激素受体剪接变体的疗法。靶向BAG-1提供了一种克服去势抵抗和治疗抵抗的策略，改善了这种常见疾病的患者生存率。谁在进行这项研究？亚当·夏普博士是伦敦皇家马斯登医院肿瘤内科的一名专科注册医生。在接受医学培训之前，他完成了理学学士（生物化学和药理学）和哲学博士（癌症科学）。他的职业抱负是成为一名学术医学肿瘤学家，拥有一个专注于癌症治疗领域转化研究的实验室。该奖学金将在Johann de Bono教授和Paul Workman教授的监督下进行，他们是药物发现，药物开发，伴侣蛋白和前列腺癌药物领域的关键意见领袖。夏普博士将在癌症研究所的癌症治疗部门工作，该部门是全球最受好评的学术药物发现部门。该奖学金将发起一个由BAG-1，雄激素受体，伴侣蛋白，药物发现和前列腺癌医学领域的国际领导人组成的财团（赞助商和合作者），以确保该奖学金的最大科学和临床影响。

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 hormones (androgens). Hormones are the body's chemical messengers that stimulate cell growth through binding their receptors (androgen receptor). 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 androgen levels provide robust responses in 90% of cases (hormone naive prostate cancer). Unfortunately, in time, nearly all cases progress to fatal disease that no longer responds to such therapies (castrate resistant prostate cancer). One mechanism driving castrate resistance is the identification of structurally altered androgen receptors (splice variants). These are permanently active and do not bind androgens rendering current therapies ineffective. There are currently no clinically available treatment strategies that target the androgen receptor splice variants and this is a critical area of unmet research and clinical need. BAG-1 is a protein found at increased levels in castrate resistant prostate cancer compared to hormone naive prostate cancer. BAG-1 activates both the androgen receptor and androgen receptor splice variants in prostate cancer. Techniques lowering BAG-1 protein levels inhibit the growth of prostate cancer cells. BAG-1 provides a novel therapeutic target to inhibit the androgen receptor splice variants and impact on the survival of patients with castrate resistant prostate cancer. What is the research trying to achieve?This fellowship will determine BAG-1 protein levels in patient biopsies and correlate this with patient survival and treatment responses to identify BAG-1 as a prognostic biomarker (predictor of survival and treatment response) in castrate resistant prostate cancer. It will identify BAG-1 as a critical regulator of androgen receptor and androgen receptor splice variant signalling driving castrate resistance and therapeutic resistance in prostate cancer. The fellowship will identify BAG-1 as a novel therapeutic target for anticancer drug discovery efforts in castrate resistant prostate cancer.Why is this important?There are no clinically available therapies that target androgen receptor splice variants in castrate resistant prostate cancer. Targeting BAG-1 provides a strategy to overcome castrate resistance and therapeutic resistance improving patient survival in this common disease. Who is carrying out the research?Dr Adam Sharp is a specialist registrar in medical oncology at the Royal Marsden Hospital in London. He completed his Bachelor of Science (Biochemistry and Pharmacology) and Doctor of Philosophy (Cancer Sciences) before undertaking his medical training. His career ambition is to be an academic medical oncologist with a laboratory focused on translational research within the field of cancer therapeutics. This fellowship will be carried out under the supervision of Professors Johann de Bono and Paul Workman who are key opinion leaders within the fields of drug discovery, drug development, chaperone proteins and prostate cancer medicine. Dr Sharp will be based in the Cancer Therapeutics Unit at the Institute of Cancer Research, the top rated academic drug discovery unit worldwide. The fellowship will initiate a consortium (sponsors and collaborators) of international leaders within the fields of BAG-1, androgen receptor, chaperone proteins, drug discovery and prostate cancer medicine to ensure the greatest scientific and clinical impact of this fellowship.