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

在 ETS 重新安排的背景下了解紫杉烷反应的生物学

• 批准号: 8080857
• 负责人: David S. Rickman
• 金额: $ 14.26万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8080857
• 关键词: ABL1 gene; Adjuvant; Affect; Algorithms; Anchorage-Independent Growth; Androgen Receptor; Androgens; Antibodies; Benign; Binding; Biological; Biological Assay; Biology; CYP17A1 gene; Cancer Model; Cancer Patient; Castration; Cell Culture Techniques; Cell Line; Cell Survival; Cells; Cessation of life; Characteristics; Chimeric Proteins; Clinical; Clinical Trials; Collaborations; DNA Binding; DNA Sequence Rearrangement; DU145; Dana-Farber Cancer Institute; Data; Detection; Development; Diagnosis; Disease; Drug-sensitive; Epithelial Cells; Epitopes; Estrogens; Family member; Gene Fusion; Gene Proteins; Gene Rearrangement; Genes; Genomics; Goals; Growth; Hormones; In Vitro; Institutes; LNCaP; Label; LacZ Genes; Lead; Luciferases; Malignant neoplasm of prostate; Measures; Mediating; Medical Oncologist; Metastatic Prostate Cancer; Modeling; Molecular; Molecular Profiling; NDRG1 gene; Natural History; Neoplasm Metastasis; Neoplastic Cell Transformation; Non-Malignant; Oncogenic; PC3 cell line; Patients; Phase; Prostate; Prostate Cancer therapy; Prostatic Diseases; Proteins; Protocols documentation; Public Health; Radical Prostatectomy; Regulation; Relapse; Reporter; Resistance; Role; Screening procedure; Signal Pathway; Steroids; Surface Plasmon Resonance; TMPRSS2 gene; Taxane Compound; Technology; Testing; Testosterone; Therapeutic Agents; Time; Transcript; Translating; Tumor Burden; United States; Universities; VCaP; Work; Xenograft Model; Xenograft procedure; abiraterone; base; cancer cell; cancer therapy; cell motility; chemotherapy; chromatin immunoprecipitation; cohort; cytotoxicity; deprivation; docetaxel; fusion gene; high risk; hormone therapy; human data; improved; in vitro Assay; in vivo; inhibitor/antagonist; insight; knock-down; male; medical schools; men; migration; neoplastic cell; novel; novel therapeutics; pre-clinical; prevent; promoter; protein expression; public health relevance; receptor expression; research study; response; small molecule; standard of care; taxane; therapeutic target; therapy resistant; treatment response; tumor; tumor xenograft; two-dimensional

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.

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展，这就是为什么雄激素剥夺疗法 (ADT) 在过去 60 年来一直被用作诊断患有转移性疾病或患有转移性疾病的患者的标准治疗方法局部治疗后复发。不幸的是，ADT 仅在患者复发并死于疾病之前的短时间内有效。对于这些 ADT 耐药患者，通过随后基于多西紫杉醇的化疗治疗，总生存期仅略有改善。尽管如此，临床前数据得出的想法是，如果在前列腺癌的发展过程中尽早进行联合化疗和激素疗法，可能会特别有效。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，从而最大限度地减少总转移性肿瘤负担，从而最大限度地提高治愈的可能性。部分患者对紫杉烷辅助 ADT 产生反应的临床观察表明，识别反应者可能会对 PCa 治疗产生重要的临床和生物学见解。我们强烈怀疑最近描述的 ETS 重排 PCa 对基于激素的治疗​​会有不同的反应。这是基于 ETS 重排 PCa（最常见的是 TMPRSS2-ERG）的压倒性数据，由三个 5' 启动子之一（即 TMPRSS2、SLC45A3 和 NDRG1）驱动。所有三个启动子均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) 水平的状态下保持活跃，但在激素去势后也能保持活跃提供了强有力的理论依据。事实上，CYP17 抑制剂阿比特龙最近在 89 名患有去势抵抗性前列腺癌的男性中进行的 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 对当前紫杉烷类疗法的反应是否与非融合 PCa 不同。因此，该提案的总体目标是确定 ETS 融合基因产物对单独激素疗法与激素疗法和基于紫杉烷的化疗的反应的影响，并确定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，我们将使用体外测定 tERG（或 NDRG1-ERG）表达对 6 个 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有所不同（2三维（2D）和 3D 细胞培养）和体内（异种移植）PCa 模型。在目标 2 中，我们将使用新型小分子微阵列平台来识别与融合基因蛋白产物特异性相互作用的化合物，并有效地将不期望的致癌状态恢复为更非恶性或药物敏感状态。在这项研究结束时，我们的研究结果将为 ETS 基因重排在 PCa 治疗反应中的作用提供生物学见解，并将为高风险 PCa 患者提供更好的针对性治疗和管理。 公共健康相关性：前列腺癌是美国的一个主要公共健康问题，2007 年确诊病例超过 219,000 例，死亡人数超过 27,000 例。过去 60 年来，雄激素剥夺疗法 (ADT) 一直被用作诊断男性的标准治疗方法患有转移性前列腺癌或局部治疗（例如根治性前列腺切除术）后复发的疾病。不幸的是，ADT 仅在患者复发并死于疾病之前的短时间内有效。基于紫杉烷的化疗辅助治疗仅略微改善总生存率。然而，临床前数据表明，如果在检测到高危前列腺癌后尽早进行联合化疗激素疗法，可能会特别有效。其基本原理是防止雄激素不敏感肿瘤细胞的出现并根除隐匿性转移，从而最大限度地减少总转移性肿瘤负担，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融合，对紫杉烷类治疗的反应与没有这种基因融合的男性不同。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”。该提案的成功完成应该有助于更好地理解为什么患有晚期 PCa 的男性无法对基于紫杉烷的化疗以及专门为更好地治疗这些男性而设计的新治疗药物产生反应。