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

描述(申请人提供)：由于前列腺癌是在雄激素的影响下发展的，雄激素剥夺疗法(ADT)在过去的60年里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，ADT仅在耐去势前列腺癌(CRPC)患者复发并死于他们的疾病之前的一段短时间内有效。紫杉烷是唯一能延长转移性CRPC患者生存期的化疗药物，而多西紫杉醇和卡巴西紫杉醇都是FDA批准的这一适应症。尽管紫杉烷在治疗CRPC方面最初有效，但患者最终会因为产生耐药性而失败。紫杉烷治疗的耐药性可归因于几种细胞机制，如细胞内紫杉烷积聚减少，紫杉烷诱导的抗应激激活的凋亡通路缺陷，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，我们已经证明ERG过度表达，这发生在大约50%的前列腺癌患者中，在临床前模型中与紫杉烷抵抗有关。然而，ERG诱导紫杉烷耐药的确切机制尚不清楚。了解ERG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。我们推测ERG至少通过两种机制在紫杉烷耐药中发挥关键作用：1)改变微管动力学；2)直接调节抗应激/凋亡途径。为了测试这些，并确定ERG作为紫杉烷耐药的生物标志物的临床相关性，我们提出如下建议：展示ERG表达对不同的微管动力学参数、微管翻译后修饰和紫杉烷有效的药物靶向接触的影响(目标1)；研究ERG通过直接调节与细胞生存、细胞凋亡和/或微管动力学相关的基因表达在紫杉烷治疗背景下介导紫杉烷耐药的机制(目标2)；以及从被诊断为去势抵抗前列腺癌并接受紫杉烷治疗的男性预期队列中筛选预治疗的组织样本和CTC(目标3)。在这项研究的结论中，我们的发现将为ERG在紫杉烷耐药中的作用提供生物学上的见解。我们研究的数据将为治疗决策提供洞察力和临床理论基础 对于患者的选择适当的治疗，朝着个性化癌症护理迈出了一步。

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.