Understanding the biology of taxane response in the context of ETS rearranged pro

描述（由申请人提供）：前列腺癌（PCa）在雄激素类固醇的影响下发生，这就是为什么雄激素剥夺疗法（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治疗。不幸的是，ADT仅在患者复发并死于疾病之前的短暂时间内有效。对于这些ADT耐药的患者，通过后续多西他赛化疗治疗，总生存率仅略有改善。尽管如此，从临床前数据中已经出现了这样的想法，即如果在PCa发展中尽早给予联合化学激素疗法可能特别有效。其基本原理是防止雄激素不敏感克隆的出现，并根除隐匿性转移，以最大限度地减少总转移性肿瘤负荷，从而最大限度地提高治愈的可能性。临床观察表明，一部分患者对ADT和辅助紫杉烷有反应，这表明识别反应者可能导致对PCa治疗的重要临床和生物学见解。我们强烈怀疑，最近描述的ETS重排PCa将以不同的方式响应于基于药物的治疗。这是基于大量数据，即ETS重排的PCa，最常见的是TMPRSS 2-ERG，由三种5'启动子之一驱动（即，TMPRSS 2、SLC 45 A3和NDRG 1）。所有三种启动子都受到雄激素和雌激素的严格调控，这为这些致癌融合转录物如何在正常睾酮（DHT）水平的状态下具有活性提供了强有力的理论基础，但也可以在激素去势后保持活性。事实上，最近在89名去势抵抗性前列腺癌男性中进行的CYP 17抑制剂阿比特龙的I/II期临床试验的最新结果证实了这一点，显示出对ERG重排患者的明显治疗益处。目前尚不清楚ETS融合PCa与非融合PCa对当前紫杉烷类药物治疗的反应是否不同。因此，本提案的总体目标是确定ETS融合基因产物对单独激素治疗与激素治疗和紫杉烷类化疗的反应的影响，并鉴定将靶向融合基因产物的其他分子。两个具体目标如下：在目标1中，我们将使用体外（二维（2D）和3D细胞培养）和体内（异种移植）PCa模型，确定tERG（或NDRG 1-ERG）表达对6种PCa细胞系中紫杉烷敏感性的影响，这些细胞系在雄激素敏感性或雄激素受体表达方面不同。在目标2中，我们将使用一种新的小分子微阵列平台来鉴定与融合基因蛋白产物特异性相互作用的化合物，并且这些化合物可有效地将不期望的致癌状态恢复到更非恶性或药物敏感的状态。在这项研究的结论，我们的研究结果将提供生物学的ETS基因重排在PCa治疗反应中的作用，并将导致更好的靶向治疗和高风险PCa患者的管理。 公共卫生相关性：前列腺癌是美国的主要公共卫生问题，2007年诊断出超过219，000例，死亡人数超过27，000人。雄激素剥夺疗法（ADT）在过去60年中一直被用作诊断患有转移性前列腺癌或局部治疗（如根治性前列腺切除术）后复发的疾病的男性的标准治疗。不幸的是，ADT仅在患者复发并死于疾病之前的短暂时间内有效。总生存率只有轻微改善辅助治疗与紫杉烷为基础的化疗。然而，临床前数据表明，如果在检测到高危前列腺癌后尽早给予化疗-激素联合治疗，可能特别有效。其基本原理是防止雄激素不敏感的肿瘤细胞的出现，并根除隐匿性转移，以最大限度地减少总转移性肿瘤负荷，从而最大限度地提高治愈的可能性。我们强烈怀疑，大约50%的前列腺癌患者携带特定的分子改变，导致高度敏感的雄激素调节基因和肿瘤产生基因的融合，与没有这种基因融合的男性相比，他们对紫杉烷治疗的反应不同。这些所谓的ETS基因重排在雄性激素存在的情况下充当“开关”。这项提案的成功完成应该会让我们更好地理解为什么晚期前列腺癌患者对紫杉烷类化疗和新的治疗药物没有反应，这些药物是专门为更好地治疗这些患者而设计的。

DESCRIPTION (provided by applicant): Prostate cancer (PCa) develops under the influence of androgenic steroids, which is why androgen deprivation therapy (ADT) has been used for the last 60 years as a standard of care for patients diagnosed with metastatic disease or that recur after local treatments. Unfortunately, ADT is only effective for a brief period before patients relapse and die from their disease. For these ADT-resistant patients, overall survival is only slightly improved by subsequent treatment with Docetaxel-based chemotherapy. Nevertheless, the idea has emerged from preclinical data that combined chemo-hormonal therapies could be particularly effective if administrated as early as possible in the PCa development. The rationale for it is to prevent the emergence of androgen-insensitive clones and to eradicate occult metastases in order to minimize the total metastatic tumor burden and hence maximize the possibility of cure. Clinical observations that a subset of patients respond to ADT with adjuvant taxane suggest that identifying responders could lead to important clinical and biological insight into PCa therapy. We strongly suspect that the recently described ETS rearranged PCa will respond differently to hormone-based treatment. This is based on the overwhelming data that ETS rearranged PCa, most commonly TMPRSS2-ERG, are driven by one of three 5' promoters (i.e., TMPRSS2, SLC45A3 and NDRG1). All three promoters are under tight regulation by both androgen and estrogen providing a strong rationale how these oncogenic fusion transcripts are active in states of normal testosterone (DHT) levels but can also remain active following hormone castration. Indeed, recent findings from a recent phase I/II clinical trial of the CYP17 inhibitor, abiraterone, in 89 men with castrate resistant prostate cancer confirm this by showing a clear treatment benefit in patients harboring ERG rearrangement. It is unknown if ETS fusion PCa respond differently to current taxane-based therapies than non-fusion PCa. Therefore, the overarching goal of this proposal is to determine the influence ETS fusion gene products to the response of hormonal therapy alone versus hormonal therapy and taxane-based chemotherapy and to identify other molecules that will target fusion gene products. The two specific aims are the following: In Aim 1, we will determine the effect of tERG (or NDRG1-ERG) expression on taxane sensitivity in 6 PCa cell lines that differ in terms of androgen sensitivity or androgen receptor expression using in vitro (2-dimensional (2D) and 3D cell culture) and in vivo (xenograft) PCa models. In Aim 2 we will use a novel small-molecule microarray platform to identify compounds that interact specifically with fusion gene protein products and that are effective in reverting the undesired oncogenic state to more nonmalignant or drug-sensitive states. At the conclusion of this study our findings will provide biological insight into the role of ETS gene rearrangement in PCa treatment response and will lead to better targeted therapeutics and management of high risk PCa patients. PUBLIC HEALTH RELEVANCE: Prostate cancer is a major public health problem in the United States with over 219,000 cases diagnosed and over 27,000 deaths in 2007. Androgen deprivation therapy (ADT) has been used for the last 60 years as a standard of care for men diagnosed with metastatic prostate cancer or disease that recurs after local treatment such as radical prostatectomy. Unfortunately, ADT is only effective for a brief period before patients relapse and die from their disease. Overall survival is only slightly improved by adjuvant treatment with taxane-based chemotherapy. Nevertheless, preclinical data suggests that combined chemo-hormonal therapies could be particularly effective if administrated as early as possible after the detection of high-risk prostate cancer. The rationale is to prevent the emergence of androgen-insensitive tumor cells and to eradicate occult metastases in order to minimize the total metastatic tumor burden and hence maximize the possibility of cure. We strongly suspect that the approximately 50% of prostate cancer patients who harbor a specific molecular alteration leading to the fusion of highly sensitive androgen regulated gene and a tumor producing gene will respond differently to taxane-based treatment than men without this gene fusion. These so-called ETS gene rearrangements act as an "on switch" in the presence of the male hormone androgen. The successful completion of this proposal should lead to a better understanding of why men with advanced PCa fail to respond to taxane-based chemotherapies and to new therapeutic agents that are tailored to better treat these men.