Identification of Melanoma Brain Metastasis Tumor Biomarkers

黑色素瘤脑转移肿瘤生物标志物的鉴定

• 批准号: 8451855
• 负责人: Dave S B Hoon
• 金额: $ 38.24万
• 依托单位: SAINT JOHN'S CANCER INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8451855
• 关键词: Adult; Affinity; American Joint Committee on Cancer; Biological Assay; Biological Markers; Brain; Candidate Disease Gene; Cerebrum; Characteristics; Clinical; Clinical Trials; Copy Number Polymorphism; Coupled; Cutaneous Melanoma; Development; Disease; Early treatment; Enrollment; Excision; Freezing; Frequencies; Gene Expression Profile; Genes; Genomics; Health Care Costs; Healthcare; Immunotherapy; Incidence; Individual; Link; Malignant Neoplasms; Metastatic Melanoma; Metastatic malignant neoplasm to brain; Methylation; Molecular; Molecular Profiling; Morbidity - disease rate; Neoplasm Metastasis; Operative Surgical Procedures; Paraffin Embedding; Patients; Pharmaceutical Preparations; Phase; Promoter Regions; Protocols documentation; Quality of life; Radiosurgery; Resources; Screening Result; Single Nucleotide Polymorphism; Site; Specimen; Staging; Subgroup; Systemic Therapy; Testing; Tissue Banking; Tissue Banks; Tissues; Treatment Protocols; Tumor Burden; base; burden of illness; epigenomics; follow-up; high risk; improved; malignant breast neoplasm; melanoma; promoter; public health relevance; therapeutic target; tissue resource; tumor

DESCRIPTION (provided by applicant): Due to the escalating incidence rate of melanoma in the USA and its high frequency to metastasize to the brain, melanoma brain metastasis (MBM) poses an increasingly significant clinical problem. In the absence of predictive biomarkers for MBM, early recognition and effective management of MBM remain inadequate to the detriment of the nation's healthcare economy and patients' quality of life. We will identify genomic and epigenomic aberrations that are signatures of MBM. We will then develop and verify these molecular aberrations as predictive molecular MBM biomarker signature(s) of stage III and IV melanomas for high-risk of MBM occurrence. Our main hypothesis is that specific genomic and epigenomic biomarkers can be identified as signatures of MBM and utilized for stage III and early stage IV melanoma metastasis for MBM occurrence. The specific Aims are based on our strong preliminary studies on genomic and epigenomic aberrations identified in MBM. The Specific Aims are as follows: Aim I. Identify and develop a signature panel of MBM genomic biomarkers that can be used as predictive biomarkers in stage III and IV melanoma for MBM occurrence. Single-nucleotide polymorphism (SNP) will be used to identify copy number variations (CNV) for losses and gains as predictive biomarkers using customized quantitative PCR assays. Prioritized MBM genomic biomarkers will then be assessed as predictors of MBM occurrence. Aim II. Identify and develop a signature panel of epigenomic MBM biomarkers that can be used as predictive biomarkers in stage III and early stage IV for MBM occurrence. Methylation array and quantitative methylation-specific PCR assays have been used to screen and identify biomarker signatures of MBM. These predictive MBM epigenomic biomarkers will then be developed and analyzed by optimized quantitative methylation-specific PCR assays. Prioritized MBM epigenomic biomarkers will then be assessed as predictors of MBM occurrence. Aim III. Verify a MBM predictive signature(s) of genomic and/or epigenomic MBM biomarkers for stage III and IV metastasis. The optimal MBM biomarker signature panel identified in Aims I and II will be tested in patients with stage III and IV metastases, respectivey, for their ability to predict MBM occurrence using phase III multicenter clinical trial patients who have undergone surgical resection to be rendered disease-free. The studies will verify high-risk stage III and IV patients' melanoma subtypes developing into MBM, identification of new targets for therapy, and identification of MBM molecular signatures.

描述（由申请人提供）：由于黑色素瘤在美国的发病率不断上升，并且其转移到脑的频率很高，黑色素瘤脑转移（MBM）造成了越来越严重的临床问题。在缺乏MBM的预测性生物标志物的情况下，MBM的早期识别和有效管理仍然不足以损害国家的医疗保健经济和患者的生活质量。我们将确定基因组和表观基因组畸变的MBM的签名。然后，我们将开发和验证这些分子畸变作为MBM发生高风险的III期和IV期黑色素瘤的预测性分子MBM生物标志物特征。我们的主要假设是，特定的基因组和表观基因组生物标志物可以被鉴定为MBM的特征，并用于MBM发生的III期和早期IV期黑色素瘤转移。具体目的是基于我们对MBM中鉴定的基因组和表观基因组畸变的强有力的初步研究。具体目标如下：目标一。鉴定并开发MBM基因组生物标志物的特征组，其可用作MBM发生的III期和IV期黑素瘤的预测生物标志物。单核苷酸多态性（SNP）将用于识别拷贝数变异（CNV）的损失和收益作为预测生物标志物，使用定制的定量PCR测定。然后将优先的MBM基因组生物标志物评估为MBM发生的预测因子。Aim II.鉴定和开发表观基因组MBM生物标志物的特征组，其可用作MBM发生的III期和早期IV期的预测生物标志物。甲基化阵列和定量甲基化特异性PCR测定已用于筛选和鉴定MBM的生物标志物特征。这些预测性MBM表观基因组生物标志物将通过优化的定量甲基化特异性PCR测定来开发和分析。然后将优先的MBM表观基因组生物标志物评估为MBM发生的预测因子。Aim III.验证III期和IV期转移的基因组和/或表观基因组MBM生物标志物的MBM预测特征。在目的I和II中鉴定的最佳MBM生物标志物特征组将分别在具有III期和IV期转移的患者中测试其预测MBM发生的能力，使用III期多中心临床试验患者， 已经接受了手术切除以使其无病。这些研究将验证高危III期和IV期患者的黑色素瘤亚型发展为MBM，确定新的治疗靶点，并确定MBM分子特征。