Identifying driver non-coding alterations in metastatic prostate cancer from tumor and cell-free DNA

从肿瘤和游离 DNA 中识别转移性前列腺癌的驱动非编码改变

• 批准号: 10380659
• 负责人: Gavin Ha
• 金额: $ 18.94万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380659
• 关键词: 3-Dimensional; Address; Advanced Malignant Neoplasm; Affect; Algorithms; Androgens; Automobile Driving; Benchmarking; Biological Markers; Biopsy; Blood; Blood specimen; Cancer Diagnostics; Cancer Patient; Cessation of life; Chromatin Structure; Clinical; Code; Collaborations; Complex; Computational Biology; DNA; DNA Sequence Alteration; Dana-Farber Cancer Institute; Data; Development; Development Plans; Disease; Disease Progression; Disseminated Malignant Neoplasm; Elements; Emerging Technologies; Enhancers; Environment; Event; Gene Mutation; Generations; Genes; Genetic; Genetic Enhancer Element; Genetic study; Genome; Genomics; Goals; High Performance Computing; Impairment; Institutes; Institution; Joints; K22 Award; Knowledge; Laboratories; Lead; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Metastatic to; Mission; Modeling; Molecular; Molecular Biology; Molecular Biology Techniques; Mutation Detection; Neoplasm Circulating Cells; Oncogenes; Pathway interactions; Patient Monitoring; Patients; Plasma; Positioning Attribute; Recurrence; Regulatory Element; Reporting; Research; Research Personnel; Resistance; Resolution; Role; Route; Sampling; Structure; Technology; Tissue Sample; Tumor-Derived; Untranslated RNA; Variant; Work; advanced disease; advanced prostate cancer; analytical method; analytical tool; androgen deprivation therapy; anticancer research; blood-based biomarker; cancer cell; cancer gene expression; cancer genome; cancer therapy; career; castration resistant prostate cancer; cell free DNA; cohort; curative treatments; design; exome; genome analysis; genome sequencing; genome-wide; genomic data; improved; infancy; inhibitor; insight; liquid biopsy; longitudinal analysis; minimally invasive; mortality; multidisciplinary; neoplastic cell; new technology; novel; patient response; prostate cancer cell line; prostate cancer progression; reconstruction; risk variant; screening; therapeutic candidate; therapeutic target; therapy resistant; treatment response; tumor; tumor progression; whole genome

Project Summary/Abstract Dr. Gavin Ha is a postdoctoral research fellow in the laboratory of Dr. Matthew Meyerson at Dana-Farber Cancer Institute and the Broad Institute of MIT & Harvard. His long-term career goal, in alignment with the mission of the NCI, is to reduce cancer-associated mortality by determining the mechanisms driving cancer progression and treatment resistance, developing cancer diagnostics, and identifying candidate therapeutic targets. To accomplish this goal, Dr. Ha will integrate computational biology, genomics, and molecular biology approaches to study advanced cancers from both tumor and liquid biopsies. Late-stage advanced cancers lead to the majority of cancer-related deaths. Metastatic castration-resistant prostate cancer (mCRPC) is an example of a disease that is lethal with no curative treatment. There are few whole genome studies of mCRPC because tumors are often less accessible. Recently, Dr. Ha and others have discovered alterations of DNA enhancer elements driving the expression of oncogenes. Thus, there is an urgent need for deeper analysis of cancer genomes, beyond coding regions, to uncover new non-coding alterations driving cancer progression. This proposal will address these challenges by building the necessary analytical tools to characterize the whole genomes of metastatic cancers from both tumor and liquid biopsies. In Aim 1, Dr. Ha will develop novel computational approaches to analyze linked-read sequencing, a new technology that provides long-range genomic data, to more accurately characterize alterations in tumor genomes. In Aim 2, he will use cell-free DNA from patient blood as a means to non-invasively access large cohorts of patients to detect tumor-specific alterations. Then, in Aim 3, he will analyze both tumor and cell-free DNA to identify non-coding genomic alterations affecting regulatory elements in mCRPC patients. He will perform longitudinal analysis from blood samples collected during treatment to identify alterations that may be implicated in resistance. These proposed projects will create much-needed analytical methods for emerging technologies to analyze tumor and cell-free DNA and will provide insights into the mechanisms underpinning treatment resistance in mCRPC. The K22 award will allow Dr. Ha to further enhance his ability to perform cutting-edge cancer research by acquiring knowledge in techniques of molecular biology through scientific collaborations. The proposed development plan will enable him to become a well-rounded independent investigator and to prepare him to lead a multi-disciplinary group with expertise in computational and experimental aspects of cancer research. Dr. Ha has access to an outstanding research environment, state-of-the-art facilities, and high-performance computing at the Dana-Farber Cancer Institute and the Broad Institute. Dr. Ha is expecting to obtain an independent position at a research institution with the same world-class facilities and intellectual environment.

项目总结/摘要 博士Gavin Ha是Dana-Farber Cancer的Matthew Meyerson博士实验室的博士后研究员 研究所和麻省理工学院和哈佛的布罗德研究所。他的长期职业目标，符合使命的 NCI是通过确定驱动癌症进展的机制来降低癌症相关死亡率， 治疗耐药性，开发癌症诊断和确定候选治疗靶点。到 为了实现这一目标，哈博士将整合计算生物学、基因组学和分子生物学方法 从肿瘤和液体活检中研究晚期癌症。 晚期晚期癌症导致大多数癌症相关死亡。转移性去势抵抗性 前列腺癌（mCRPC）是没有治愈性治疗的致命疾病的一个例子。很少 mCRPC的全基因组研究，因为肿瘤通常不太容易获得。最近，哈博士和其他人 发现了驱动癌基因表达的DNA增强子元件的改变。因此，迫切需要 需要对癌症基因组进行更深入的分析，超越编码区域，以发现新的非编码改变 推动癌症进展该提案将通过建立必要的分析机制来应对这些挑战。 用于表征来自肿瘤和液体活检的转移性癌症的全基因组的工具。在目标1中，博士 HA将开发新的计算方法来分析连接阅读测序，这是一项新技术， 提供了长范围的基因组数据，以更准确地表征肿瘤基因组的变化。在Aim 2中， 将使用患者血液中的无细胞DNA作为非侵入性访问大量患者的手段， 肿瘤特异性改变。然后，在目标3中，他将分析肿瘤和无细胞DNA，以识别非编码基因。 影响mCRPC患者调控元件的基因组改变。他将进行纵向分析， 在治疗期间采集血液样本，以鉴定可能与耐药性有关的变化。这些 拟议的项目将为新兴技术创造急需的分析方法，以分析肿瘤， 细胞游离DNA，并将提供对mCRPC治疗耐药性的基础机制的见解。 K22奖将使哈博士进一步提高他进行尖端癌症研究的能力， 通过科学合作获得分子生物学技术知识。拟议 发展计划将使他成为一个全面的独立调查员，并准备他领导 一个在癌症研究的计算和实验方面具有专业知识的多学科小组。哈医生 拥有出色的研究环境、最先进的设施和高性能计算 在丹娜-法伯癌症研究所和布罗德研究所。哈博士希望获得独立的职位 在一个拥有同样世界一流设施和智力环境的研究机构。