Evaluation of a novel urothelial cancer biomarker of lethality

一种新型尿路上皮癌致死性生物标志物的评估

• 批准号: 8228907
• 负责人: Jonathan Eric Rosenberg
• 金额: $ 26.93万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-11 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8228907
• 关键词: 1q23.3; Androgen Receptor; Apoptosis; Biological; Biological Markers; Biological Models; Biology; Breast; Cancer Center; Candidate Disease Gene; Cell Line; Cessation of life; Chromosomal Gain; Chromosomal Loss; Chromosomes; Clinical; Cystectomy; DNA; DNA copy number; Data; Data Set; Disease; Disease Outcome; Distant Metastasis; Early identification; Evaluation; Event; FGFR3 gene; Foundations; Future; Gene Expression; Genes; Genomics; Grant; Greece; Lead; MDM2 gene; Malignant Neoplasms; Messenger RNA; Molecular Profiling; Nature; Neoplasm Metastasis; Oncogenes; Oncology Group; Outcome; PIK3CA gene; PTEN gene; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Positioning Attribute; Primary Neoplasm; Prognostic Factor; Prostate; RNA; Recurrence; Risk; Role; Specimen; Staging; Technology; Terminal Disease; Transcript; Transitional Cell Carcinoma; Tumor Suppressor Genes; Validation; Woman; Work; Xenograft Model; chromosome loss; clinically relevant; cohort; comparative genomic hybridization; effective therapy; gain of function; hazard; improved; in vitro testing; mRNA Expression; nano-string; new therapeutic target; novel; overexpression; prognostic; research clinical testing; therapeutic target; tumor

DESCRIPTION (provided by applicant): Treatment for advanced urothelial carcinoma (UC) has changed little in 20 years. While some potential therapeutic targets have been identified, identification of new clinically relevant therapeutic targets and predictive biomarkers is critical to improve outcomes for this disease. Limited information exists regarding the changes that occur in tumors that ultimately metastasize, the lethal phenotype of UC. For patients with metastatic UC, clinical prognostic variables are able to identify broad risk groups. However, the variability of outcomes within these groups is significant, and the ability to accurately prognosticate is limited. To identify novel biomarkers and therapeutic targets in patients with metastatic UC, a cohort of 94 patients who subsequently developed distant metastases and received uniform treatment were identified and thoroughly clinically annotated. Genomic DNA copy number analysis was performed on primary tumors by array comparative genomic hybridization, an unbiased approach. DNA copy number gains (CNG) and losses were assessed for association with overall survival, controlling for known clinical prognostic factors. CNG of a short region of chromosome 1q23.3 was associated with a very poor median overall survival (7.3 months), compared to 18 months for patients without 1q23.3 CNG (p = 0.007). By confirming the lethality of 1q23.3 CNG in another cohort, and beginning to characterize the underlying biology of 1q23.3 CNG, this grant is expected to facilitate the identification of a critical factor in UC pathogenesis and lethality, and may in fact identify a new therapeutic target in UC. The specific aims for this project include confirmation of chromosome 1q23.3 CNG as a biomarker of lethality in an independent cohort of UC patients using a novel DNA copy number technology (NanoString CNV). Performing external validation in an unrelated cohort of metastatic UC tumors will establish the clinical relevance of the association of 1q23.3 CNG with lethality. In addition, this grant will identify specific genes residing on 1q23.3 that drive lethality in UC. It is predicted that chromosome 1q23.3 CNG will alter expression of candidate genes in that region, and that changes in gene expression will lead to phenotypic changes in model systems such as increased proliferation and invasion, and decreased programmed cell death. We will evaluate mRNA expression of transcripts in and around the region of 1q23.3 CNG in UC tumors with known gain or loss using NanoString mRNA quantification, and characterize phenotypic changes in model systems. This aim will explore the biological underpinnings of 1q23.3 CNG, and serve as preliminary data for future research to determine the exact mechanism of UC lethality. Ultimately, this biomarker could identify patients destined to develop lethal disease while they still have early-stage disease, and direct them towards different and hopefully curative therapy (e.g. early cystectomy for non-invasive UC). This work will provide the foundation for future studies to develop the 1q23.3 biomarker as a potential clinical test, as well as explore the biology of 1q23.3 CNG in xenograft models and in larger clinical datasets. PUBLIC HEALTH RELEVANCE: Urothelial carcinoma (UC) is among the most expensive malignancy to treat due to the invasive nature of surveillance and treatment, and metastatic UC remains a terminal illness with few effective treatment options. Early identification of patients destined to develop lethal UC will allow for more appropriate treatment for those patients, and potentially identify critical biological pathways that drive this disease. This grant will support work to confirm and characterize the biological underpinnings of chromosome 1q23.3 amplification in UC to determine why it is associated with lethal disease.

描述(申请人提供)：20年来，晚期尿路上皮癌(UC)的治疗几乎没有变化。虽然已经确定了一些潜在的治疗靶点，但识别新的临床相关治疗靶点和预测性生物标记物对于改善这种疾病的预后至关重要。关于最终转移的肿瘤中发生的变化，即UC的致命表型，存在有限的信息。对于转移性UC患者，临床预后变量能够识别广泛的危险组。然而，这些组内的结果差异很大，准确预测的能力是有限的。为了确定转移性UC患者的新生物标志物和治疗靶点，对94名随后发生远处转移并接受统一治疗的患者进行了鉴定和彻底的临床注释。用阵列比较基因组杂交法对原发肿瘤进行基因组DNA拷贝数分析，这是一种无偏见的方法。评估DNA拷贝数增加(CNG)和丢失与总存活率的关系，并控制已知的临床预后因素。染色体1q23.3短区域CNG患者的中位总生存期(7.3月)非常低，而无1q23.3 CNG患者的中位生存期为18个月(p=0.007)。通过在另一个队列中确认1q23.3 CNG的致命性，并开始描述1q23.3 CNG的潜在生物学特征，这项拨款有望促进UC发病和致命性的关键因素的识别，并实际上可能确定UC的新治疗靶点。该项目的具体目标包括使用一种新的DNA拷贝数技术(纳米串CNV)确认染色体1q23.3 CNG作为UC患者独立队列中致死性的生物标志物。在一组无关的UC转移性肿瘤队列中进行外部验证将确定1q23.3 CNG与致死率之间的临床相关性。此外，这项拨款将确定位于1q23.3上的特定基因，这些基因可以驱动UC的致命性。据预测，染色体1q23.3 CNG将改变该区域候选基因的表达，基因表达的变化将导致模型系统的表型变化，如增加增殖和侵袭，减少细胞程序性死亡。我们将使用纳米串mRNA定量技术评估已知得失的UC肿瘤中1q23.3 CNG区域及其周围转录产物的mRNA表达，并在模型系统中表征表型变化。这一目标将探索1q23.3 CNG的生物学基础，并作为未来研究的初步数据，以确定UC致死的确切机制。最终，这个生物标记物可以在患者仍有早期疾病时识别出他们注定要发展为致命疾病的患者，并指导他们进行不同的、有望治愈的治疗(例如，非侵入性UC的早期膀胱切除术)。这项工作将为未来开发1q23.3生物标志物作为潜在的临床试验以及在异种移植模型和更大的临床数据集中探索1q23.3 CNG的生物学奠定基础。 公共卫生相关性：由于监测和治疗的侵袭性，尿路上皮癌(UC)是治疗费用最高的恶性肿瘤之一，转移性UC仍然是一种晚期疾病，几乎没有有效的治疗选择。及早识别将发展为致命性UC的患者将允许对这些患者进行更适当的治疗，并有可能确定导致这种疾病的关键生物学途径。这笔赠款将支持确认和表征UC中染色体1q23.3扩增的生物学基础的工作，以确定为什么它与致命疾病有关。