Predictive biomarkers of response to DNA repair targeting agents in sporadic prostate cancer

前列腺癌是男性中最常见的癌症，但尽管近年来新药获得批准，但缺乏针对每位患者单独选择最佳治疗方法的测试。在日常临床实践中，我们观察到一些前列腺癌患者的病程非常缓慢，而另一些患者的癌症可能非常严重，对标准治疗没有反应。我们的研究旨在提供一种工具，通过评估肿瘤细胞在受损后如何修复其完整性，来早期识别可能患有预后最差的疾病并可能需要不同治疗的患者。一组蛋白质（每一组由一个基因编码）参与细胞对某些类型损伤的反应，这一过程被称为“DNA修复”。我们现在知道，一部分晚期前列腺癌患者在参与DNA修复系统的不同基因中会有一个或多个基因开关。PARP抑制剂是目前正在开发的一类治疗癌症患者的药物；迄今为止，最大的成功发生在治疗DNA修复基因BRCA1/2中具有特定遗传开关的患者。有这种BRCA突变的人更有可能患上野兽，卵巢或前列腺肿瘤，以及其他癌症，研究表明，这些人会患上一种非常具有攻击性的前列腺癌亚型，发展速度更快，结果也更糟糕。实验室的一些研究表明，当一个细胞在参与DNA修复系统的其他基因中有一个或多个缺陷时，它也可能对PARP抑制产生同样的反应。事实上，有临床证据表明，在没有BRCA1/2遗传突变的卵巢癌患者中，PARP抑制有一定的益处。在癌症研究所，与皇家马斯登NHS信托基金一起，我们目前正在对没有遗传BRCA突变的晚期前列腺癌患者进行PARP抑制剂的临床试验。我们提出的研究项目旨在：a)确定散发性（非遗传性）前列腺癌中参与DNA修复的基因中缺陷的频率，并确定这些缺陷在决定患者预后或对标准治疗作出反应的可能性方面的相关性。b)分析从PARP抑制剂中获益的散发性前列腺癌患者与对这些药物没有反应的患者的基因组图谱的差异。b)在实验室细胞模型中评估这些基因开关如何影响细胞修复DNA损伤的能力，以及它们如何决定对不同处理的敏感性。d)建立一个可以在任何前列腺癌患者中进行的实验室测试，以预测他们的特定疾病是否可能对PARP抑制剂敏感。这些测试将用于优化招募晚期前列腺癌患者进行PARP抑制剂的大型临床试验。

Prostate cancer is the commonest cancer in men, but despite recent advances with new drugs approved over the last few years, there is a lack of tests to select individually the best treatment for each patient. We observe in the daily clinical practice how some patients with prostate cancer have a very indolent course of disease whereas others may have a very aggressive type of cancer and may not respond to standard therapies. Our research aims to provide a tool to identify early who are the patients who may have a disease with worst prognosis and may need a different treatment, by assessing how the tumour cells repairs its integrity after damages.A group of proteins (each of them codified by one gene) is involved in the response of the cell to some types of damage, in a process called "DNA repair". We now know that a proportion of patients with advanced prostate cancer would have one or more genetic switches in the different genes involved in this DNA repair system. PARP inhibitors are a class of drugs in current development to treat cancer in patients; the biggest success so far has occurred in treating patients with particular inherited switches in the DNA repair genes BRCA1/2. People with this BRCA mutations are more likely to develop beast, ovarian or prostate tumours, among other cancers and it has been shown that these people develop a very aggressive subtype of prostate cancer, with quicker progression and worst outcome. Some studies in the laboratory have shown that when a cell has one or more defects in other genes involved in the DNA repair system, it could also become equally responsive to PARP inhibition. Indeed, there is clinical evidence of some benefit of PARP inhibition in ovarian cancer in patients without BRCA1/2 inherited mutations. At the Institute of Cancer Research, together with The Royal Marsden NHS Trust, we are currently running clinical trials of PARP inhibitors for patients with advanced prostate cancer without an inherited BRCA mutation.The research project we present aims to:a) Determine the frequency of defects in the genes involved in DNA repair in sporadic (non-hereditary) prostate cancers and to determine how relevant are these defects in terms of determining the prognosis of the patient or the likelihood of responding to standard treatments.b) Analyse the differences in the genomic profile from the patients with sporadic prostate cancer who have benefited from PARP inhibitors to those who have not responded to these drugs.b) Evaluate in laboratory cell models how these genetic switches impact in the capacity of the cells to repair DNA damage and how these determine the sensitivity to different treatments.d) Set up a laboratory test that can be performed in any patient with prostate cancer to predict if their particular disease is likely to be sensitive to PARP inhibitors. These test will be used to optimise the recruitment of advanced prostate cancer patients for large clinical trials with PARP inhibitors.