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

描述（由申请方提供）：由于前列腺癌是在雄激素类固醇的影响下发生的，因此在过去60年中，雄激素剥夺疗法（ADT）一直被用作诊断为转移性疾病或局部治疗后复发疾病的患者的标准治疗。不幸的是，ADT仅在患者复发去势抵抗性前列腺癌（CRPC）并死于疾病之前的短暂时间内有效。紫杉烷类是唯一显示出延长转移性CRPC患者生存期的化疗药物，多西他赛和卡巴他赛均被FDA批准用于该适应症。尽管紫杉烷类药物在治疗CRPC方面具有初步疗效，但患者最终由于耐药性的发展而失败。对紫杉烷治疗的抗性归因于几种细胞机制，例如细胞紫杉烷积累减少、由紫杉烷诱导的抗应激和抗凋亡机制的激活引起的凋亡途径缺陷，所述抗应激和抗凋亡机制促进存活或微管动力学的改变。基于初步结果，我们已经表明，ERG过度表达，这发生在大约50%的前列腺癌患者，与紫杉烷耐药的临床前模型。然而，ERG诱导的紫杉烷类耐药的确切机制仍有待进一步研究。了解ERG诱导的紫杉烷类耐药对于制定规避这种耐药的策略至关重要。我们假设ERG通过至少两种机制在紫杉烷抗性中起关键作用：1）微管动力学的改变和2）抗应激/凋亡途径的直接调节。为了测试这些并确定ERG作为紫杉烷抗性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-靶点接合的不同参数的影响（目的1）;为了研究ERG通过直接调节与细胞存活相关的基因表达介导紫杉烷类耐药性的机制，紫杉烷治疗背景下的细胞凋亡和/或微管动力学（目标2）;以及从被诊断患有去势抵抗性前列腺癌并且已经用紫杉烷治疗的男性的前瞻性队列中筛选预处理的组织样品和CTC（目标3）。在这项研究的结论，我们的研究结果将提供生物学洞察的作用，视网膜电图在紫杉烷耐药。我们的研究数据将为治疗决策提供见解和临床依据 并为患者选择合适的治疗方法，这是迈向个性化癌症护理的一步。

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.