Mechanistic Insights Underlying ERG-induced Taxane Resistance in Castration-Resis

描述（由申请人提供）：由于前列腺癌在雄激素类固醇的影响下发展，雄激素剥夺疗法（ADT）在过去60年中一直被用作诊断为转移性疾病或局部治疗后复发的患者的标准护理。不幸的是，在去势抵抗性前列腺癌（CRPC）患者复发和死亡之前，ADT仅在短时间内有效。紫杉烷是唯一一种能够延长转移性CRPC患者生存期的化疗药物，多西他赛和卡巴他赛都已获得FDA批准用于这一适应症。尽管紫杉烷类药物治疗CRPC有初步疗效，但由于耐药性的发展，患者最终失败。对紫杉烷治疗的抗性归因于几种细胞机制，如细胞紫杉烷积累减少，紫杉烷诱导的抗应激激活导致凋亡通路缺陷，以及促进存活或微管动力学改变的抗凋亡机制。根据初步结果，我们已经表明ERG过表达（发生在大约50%的前列腺癌患者中）与临床前模型中的紫杉烷耐药有关。然而，erg诱导的紫杉烷对紫杉烷抗性的确切机制仍有待研究。了解ergg诱导的紫杉烷耐药性对于制定规避这种耐药性的策略至关重要。我们假设ERG至少通过两种机制在紫杉烷抗性中起关键作用：1)改变微管动力学和2)直接调节抗应激/凋亡途径。为了测试这些并确定ERG作为紫杉烷耐药生物标志物的临床相关性，我们提出以下建议：证明ERG表达对微管动力学、微管翻译后修饰和紫杉烷有效药物靶标结合的不同参数的影响（目的1）；在紫杉烷治疗的背景下，研究ERG通过直接调节与细胞存活、凋亡和/或微管动力学相关的基因表达介导紫杉烷耐药性的机制（目的2）；从诊断为去势抵抗性前列腺癌并接受过紫杉烷治疗的男性前瞻性队列中筛选预处理组织样本和ctc（目的3）。在本研究的结论中，我们的发现将为ERG在紫杉烷抗性中的作用提供生物学见解。我们的研究数据将为治疗决策提供见解和临床依据

DESCRIPTION (provided by applicant): Because prostate cancer develops under the influence of androgenic steroids, androgen deprivation therapy (ADT) has been used for the last 60 years as a standard of care for patients diagnosed with metastatic disease or disease that recurs after local treatment. Unfortunately, ADT is only effective for a brief period before patiens relapse with castration-resistant prostate cancer (CRPC) and die from their disease. Taxanes are the only chemotherapies shown to prolong survival for patients with metastatic CRPC, and both docetaxel and cabazitaxel are FDA approved for this indication. Despite the initial efficacy of taxanes in treating CRPC, patients ultimately fail due to the development of drug resistance. Resistance to taxane therapy has been attributed to several cellular mechanisms such as decreased cellular taxane accumulation, defects in apoptotic pathways by taxane induced activation of anti-stress and anti-apoptotic mechanisms that promote survival or alterations in microtubule dynamics. Based on preliminary results we have shown that ERG over-expression, which occurs in roughly 50% of prostate cancer patients, is associated with taxane resistance in pre-clinical models. However, the precise mechanism of ERG-induced taxane resistance to taxanes remains to be characterized. Understanding ERG-induced taxane resistance is essential for developing strategies to circumvent this resistance. We hypothesize that ERG plays a critical role in taxane resistance through at least two mechanisms: 1) alteration of microtubule dynamics and 2) direct regulation of anti-stress/apoptosis pathways. To test these and determine the clinical relevance of ERG as a biomarker for taxane resistance we propose the following: to demonstrate the effects of ERG expression on distinct parameters of microtubule dynamics, microtubule post-translational modifications, and effective drug-target engagement by taxanes (Aim 1); to investigate the mechanism by which ERG mediates resistance to taxanes through directly regulating gene expression related to cell survival, apoptosis and/or microtubule dynamics in the context of taxane treatment (Aim 2); and to screen pre-treated tissue samples and CTCs from a prospective cohort of men diagnosed with castration-resistant prostate cancer and that have been treated with taxanes (Aim 3). At the conclusion of this study, our findings will provide biological insight into the role ERG in taxane resistance. Data from our study will provide insight and clinical rationale for treatment decisions and for patient selection for appropriate therapies, a step towards personalized cancer care.