Identifying Molecular Signatures of Cancer

识别癌症的分子特征

• 批准号: 6738346
• 负责人: SUBHA SRINIVASAN
• 金额: $ 15.51万
• 依托单位: JIVAN BIOLOGICS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-03 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6738346
• 关键词: RNA splicing; biomarker; biotechnology; clinical research; early diagnosis; gene expression profiling; high throughput technology; human genetic material tag; human tissue; messenger RNA; neoplasm /cancer classification /staging; serine threonine protein kinase; technology /technique development

DESCRIPTION (provided by applicant): The purpose of this project is to identify sensitive molecular signatures for classification and early detection of complex diseases such as cancer by high-throughput expression profiling of splice variants of the human kinome. Current high-throughput expression technologies such as gene chips, only profile gene expression and do not provide the resolution required to measure splice variant expression, thus compromising functional relevance and sensitivity required for the identification of reproducible molecular signatures of cancer. Molecular profiling enabled by high-throughput expression technologies holds the promise for cost effective ways for detection and classification of cancer, saving millions in cure and improving quality of life for those living with the disease. Solicitations by Cancer Diagnostics Program (CDP) at National Cancer Institute including a special solicitation PA-03-O13 titled "Small Business Grants for Identifying Molecular Signatures of Cancer" further corroborates the heightened need for sensitive high-throughput technologies to identify molecular signatures of cancer. The large scale mapping of ESTs onto the completed human genome sequence has now revealed that much more than 50% of the human genes code for multiple and functionally distinct splice products. Our internal EST data mining efforts with 323 kinases suggests that most kinases are alternately spliced. The functional importance of kinase splice variants in human physiology and pathology is not yet understood. However the relatively small number of human kinases (518) compared to that in C. elegans (430) suggests functional diversity in the human kinome from alternate splicing. Preliminary studies by Jivan, in collaboration with a pharmaceutical company, shows that splice variants of some members of STE kinases are unique to tumor tissues and may be involved in cell transformation, invasion and Adhesion. ]ivan Biologics has developed and patented an innovative technology, TransExpressTM for simultaneous discovery and profiling of splice variants of hundreds of genes expressed in biological samples. TransExpress (tm) fills a technology gap not addressed by the current gene chip technologies. TransExpress (tm) has now been validated through two corporate research collaborations. Dr. Subha Srinivasan, the Principal Investigator, served as Global Chair of Genomics for Schering AG, holds 6 US patents, has 31 publications, and managed a $2 million annual budget while at Berlex Biosciences. The goal is to apply TransExpress TM technology to perform systematic genome-scale profiling of splice variants of all 518 human kinases across large number of tumor and normal samples. During Phase I of this project, the company will test the feasibility of identifying molecular signatures of cancer by profiling splice variants of the STE sub-family of human kinases containing 48 sedne/threonine kinases. For Phase II, the company will profile splice products of all 518 kinases in the human kinome across a large number of normal and neoplastic tissue samples for several cancer types. Profiling splice products provides additional insight in our efforts to understand molecular mechanisms of cancer. Also, expression profiles of splice variants of kinases add value at multiple stages during the drug development pipeline, including target selection, immunotherapy, diagnostics, patient subtyping and clinical biomarkers.

描述(由申请人提供)：该项目的目的是通过高通量表达谱分析人类亲属基因组的剪接变体，识别敏感的分子特征，用于癌症等复杂疾病的分类和早期检测。目前的高通量表达技术，如基因芯片，只提供基因表达谱，没有提供测量剪接变体表达所需的分辨率，从而影响了识别癌症可重复分子特征所需的功能相关性和敏感性。由高通量表达技术实现的分子图谱为癌症的检测和分类提供了具有成本效益的方法，节省了数百万的治疗费用，并提高了癌症患者的生活质量。国家癌症研究所癌症诊断计划(CDP)的征集活动包括题为“用于识别癌症分子签名的小企业赠款”的特别征集活动，进一步证实了对用于识别癌症分子签名的敏感高通量技术的高度需求。 将EST大规模地映射到完整的人类基因组序列上，现在已经发现超过50%的人类基因编码多个功能不同的剪接产物。我们内部对323个激酶的EST数据挖掘工作表明，大多数激酶是交替剪接的。目前尚不清楚激酶剪接变异体在人体生理学和病理学中的功能重要性。然而，与线虫相比，人类蛋白激酶的数量(518个)相对较少(430个)，这表明人类基因组中存在着交替剪接的功能多样性。Jivan与一家制药公司合作的初步研究表明，STE激酶某些成员的剪接变体是肿瘤组织所特有的，可能参与细胞转化、侵袭和粘连。]Ivan Biologics开发了一项创新技术TransExpressTM并获得了专利，该技术可同时发现和分析生物样本中表达的数百个基因的剪接变体。TransExpress(Tm)填补了当前基因芯片技术没有解决的技术空白。TransExpress(Tm)现在已经通过两个企业研究合作得到了验证。首席研究员苏比亚·斯里尼瓦桑博士在伯莱克斯生物科学公司期间曾担任先灵公司基因组学全球主席，拥有6项美国专利，发表了31篇出版物，管理着200万美元的年度预算。 其目标是应用TransExpress TM技术对大量肿瘤和正常样本中所有518个人类激酶的剪接变体进行系统的基因组规模分析。在该项目的第一阶段，该公司将通过分析包含48种sedne/苏氨酸激酶的人类激酶STE亚家族的剪接变体来测试识别癌症分子特征的可行性。在第二阶段，该公司将在几种癌症类型的大量正常和肿瘤组织样本中描述人类基因组中所有518个激酶的剪接产品。 分析剪接产物为我们理解癌症的分子机制提供了更多的洞察力。此外，在药物开发过程中的多个阶段，包括靶点选择、免疫治疗、诊断、患者亚型和临床生物标志物，激酶剪接变体的表达谱增加了价值。