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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要 Gavin Ha 博士是丹娜—法伯癌症研究所 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大学布罗德研究所。他的长期职业目标与公司的使命相一致 NCI 旨在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、开发癌症诊断以及确定候选治疗靶点。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通过肿瘤和液体活检研究晚期癌症。晚期晚期癌症导致大多数癌症相关死亡。转移性去势抵抗前列腺癌 (mCRPC) 是一种无法治愈的致命疾病的一个例子。有几个 mCRPC 的全基因组研究，因为肿瘤通常较难接近。最近，哈博士等人发现了驱动癌基因表达的 DNA 增强子元件的改变。因此，有一个紧急的需要对编码区域之外的癌症基因组进行更深入的分析，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从肿瘤和液体活检中表征转移性癌症的整个基因组的工具。在目标 1 中，Dr. Ha 将开发新的计算方法来分析链接读测序，这是一种新技术提供远程基因组数据，以更准确地表征肿瘤基因组的变化。在目标 2 中，他将使用患者血液中的游离 DNA 作为非侵入性接触大量患者的手段来检测肿瘤特异性改变。然后，在目标 3 中，他将分析肿瘤和游离 DNA 以识别非编码影响 mCRPC 患者调节元件的基因组改变。他将进行纵向分析治疗期间收集的血液样本，以确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建急需的分析方法来分析肿瘤和游离 DNA 并将提供对 mCRPC 治疗耐药机制的见解。 K22奖将使哈博士进一步增强他进行尖端癌症研究的能力通过科学合作获取分子生物学技术知识。拟议的发展计划将使他成为一名全面的独立调查员，并为他领导一个多学科小组，在癌症研究的计算和实验方面拥有专业知识。哈博士拥有出色的研究环境、最先进的设施和高性能计算在达纳法伯癌症研究所和布罗德研究所。哈博士期望获得独立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。