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

项目摘要/摘要 加文·哈博士是达纳-法伯癌症研究所马修·迈耶森博士实验室的博士后研究员 麻省理工学院和哈佛大学博德学院。他的长期职业目标，与 NCI的目的是通过确定癌症进展的机制和降低癌症相关死亡率 治疗耐药性、发展癌症诊断学和确定候选治疗靶点。至 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 从肿瘤和液体活检两方面研究晚期癌症。 晚期癌症导致癌症相关死亡的大部分。抗转移性去势 前列腺癌(MCRPC)是一种致命的疾病，没有根治方法。几乎没有几个 对mCRPC进行全基因组研究，因为肿瘤往往不太容易获得。最近，哈博士和其他人已经 发现了驱动癌基因表达的DNA增强子元件的变化。因此，有一个紧急的 需要对癌症基因组进行更深入的分析，超越编码区，以发现新的非编码变化 推动癌症的发展。该提案将通过建立必要的分析工具来应对这些挑战 用于描述来自肿瘤和液体活检的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阅读测序，这是一项新技术 提供远程基因组数据，以更准确地描述肿瘤基因组的变化。在《目标2》中，他 将使用患者血液中的无细胞DNA作为一种手段，以非侵入性方式访问大量患者队列，以检测 肿瘤特有的改变。然后，在目标3中，他将分析肿瘤和无细胞DNA，以识别非编码 影响mCRPC患者调节元件的基因组改变。他将从以下方面进行纵向分析 在治疗过程中采集血液样本，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造急需的分析方法，以分析肿瘤和 无细胞DNA，并将为mCRPC耐药的机制提供见解。 K22奖将使哈博士通过以下方式进一步增强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方面的知识。建议数 发展计划将使他成为一名全面的独立调查员，并为他领导 一个在癌症研究的计算和实验方面拥有专业知识的多学科小组。哈博士 拥有卓越的研究环境、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。哈博士希望获得一个独立的职位 在拥有相同世界级设施和智力环境的研究机构。

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.