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: 7991206
• 负责人: David S. Rickman
• 金额: $ 25.73万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991206
• 关键词: Adjuvant; Affect; Algorithms; Anchorage-Independent Growth; Androgen Receptor; Androgen Therapy; Androgens; Antibodies; Benign; Binding; Biological; Biological Assay; Biology; CWR22Rv1; 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 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; 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，这就是为什么在过去60年中使用雄激素剥夺治疗（ADT）作为诊断出患有转移性疾病的患者或局部治疗后重复出现的患者的标准。不幸的是，ADT仅在患者复发并死于疾病之前有效。对于这些耐ADT患者，仅通过基于多西他赛的化学疗法进行治疗，总体生存率仅略有改善。然而，如果在PCA开发中尽早管理，将化学荷尔蒙疗法组合在一起的临床前数据已经出现了这个想法。其理由是防止雄激素不敏感的克隆的出现并消除隐匿转移，以最大程度地减少转移性肿瘤负担，从而最大程度地减少治愈的可能性。临床观察结果表明，一部分患者对ADT的辅助紫杉烷反应表明，识别响应者可能会导致对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重新排列的PCA对基于激素的治疗​​的反应会有所不同。这是基于大量的数据，即ET重新排列PCA，最常见的是TMPRSS2-ERG，是由三个5'启动子之一（即TMPRSS2，SLC45A3和NDRG1）驱动的。这三个启动子都受雄激素和雌激素的严格调节，提供了强有力的基本原理，这些致癌融合转录本如何在正常睾丸激素（DHT）水平的状态下活跃，但在激素cast割后也可以保持活跃。实际上，CYP17抑制剂Abiraterone的最近一项I/II期临床试验的最新发现，对89名castrate抗性前列腺癌的男性在具有ERG重排的患者中表现出明显的治疗益处，证实了这一点。 ETS Fusion PCA对当前基于紫杉烷的疗法的反应与非融合PCA是未知的。因此，该提案的总体目标是确定ETS融合基因产物对单独的激素治疗与激素治疗和基于紫杉烷的化学疗法的反应的影响，并鉴定其他将靶向融合基因产物的分子。这两个具体目的是：在AIM 1中，我们将确定Terg（或NDRG1-ERG）表达对6个PCA细胞系中紫杉烷敏感性的影响，在6个PCA细胞系中，使用体外（二维（2D）（2D）和3D细胞培养）和iNVO（Xenogroftaft）PCA模型在雄激素敏感性或雄激素受体表达方面有所不同。在AIM 2中，我们将使用一种新型的小分子微阵列平台来识别与融合基因蛋白产品特别相互作用的化合物，并有效地将不希望的致癌态恢复到更非态度或药物敏感的状态。在这项研究的结论中，我们的发现将为ETS基因重排在PCA治疗反应中的作用提供生物学见解，并将导致更好的靶向疗法和高风险PCA患者的管理。 公共卫生相关性：前列腺癌是美国的一个主要公共卫生问题，2007年被诊断出219,000例病例，死亡超过27,000例。在过去的60年中，雄激素剥夺治疗（ADT）已被用作诊断为转移性前列腺癌或疾病的男性的标准，这些男性是局部治疗，例如在局部治疗，例如诸如自然的前列腺切除术。不幸的是，ADT仅在患者复发并死于疾病之前有效。通过基于紫杉烷的化学疗法的辅助治疗，总体生存仅略有改善。然而，临床前数据表明，如果在发现高风险前列腺癌后尽早给药，合并的化学荷尔蒙疗法可能特别有效。基本原理是为了防止雄激素不敏感的肿瘤细胞的出现并消除隐匿性转移，以​​最大程度地减少转移性肿瘤负担，从而最大程度地减轻治愈的可能性。我们强烈怀疑，约有50％的前列腺癌患者具有特定的分子改变，导致高度敏感的雄激素调节基因和产生肿瘤基因的融合对基于紫杉烷的治疗的反应与没有这种基因融合的男性的反应不同。这些所谓的ETS基因重排在雄性激素雄激素的情况下充当“开关”。该提案的成功完成应该可以更好地理解为什么患有高级PCA的男性未能对基于紫杉烷的化学疗法和新的治疗剂做出反应，以量身定制来更好地治疗这些人。