权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Patient-Derived Models of Prostate Cancer for Personalized Medicine

用于个体化医疗的前列腺癌患者衍生模型

基本信息

批准号：
10219178
负责人：
Yu Chen
金额：
$ 102.6万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219178
关键词：
1-Phosphatidylinositol 3-Kinase Address Androgen Receptor Area Biological Biological Models Cancer Model Cells Clinical Clinical Research Clinical Trials Complement Critical Pathways DNA Damage DNA Sequence Alteration Databases Development Distant Evolution Gene Expression Gene-Modified Genes Genetic Genetic study Genomics Germ Lines Goals Growth Human Investigation Knowledge Link Longitudinal Studies Malignant Bone Neoplasm Malignant Neoplasms Malignant neoplasm of prostate Metastatic Prostate Cancer Modeling Molecular Morphology Mutation Neoplasm Metastasis Organoids Pathologic Pathologist Pathway interactions Patients Pharmaceutical Preparations Physicians Poly(ADP-ribose) Polymerases Research Personnel Resistance Role Sampling Scientist Seminal Signal Transduction Site Specimen Structure Testing Therapeutic Time Tissues Tumor-Derived Ursidae Family Variant androgen deprivation therapy base cancer genomics castration resistant prostate cancer clinically relevant design drug testing effective therapy epigenomics exome sequencing genome sequencing human tissue improved inhibitor/antagonist insight men migration patient derived xenograft model personalized medicine pre-clinical prostate cancer model prostate cancer progression resistance mechanism response success targeted treatment therapy development therapy resistant transcriptome sequencing treatment response treatment strategy tumor whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Metastatic prostate cancer (PCa) that progresses after androgen ablation therapy (i.e., castration-resistant PCa [CRPC]) remains incurable. Gaining a mechanistic understanding of PCa progression has been hampered by a lack of clinically relevant PCa models. Recently, patient-derived models of cancer (PDMCs; e.g., patient-derived xenografts [PDXs] and organoids) have been used to develop therapeutically relevant approaches. We hypothesize that longitudinal studies of tumor specimens (and corresponding PDMCs) obtained over time from the same patient will lead to a better understanding of the diverse dominant pathways that drive metastatic progression. We also hypothesize that organoids will complement PDXs as part of an integrated analysis of human tissue and derived PDMCs (obtained at single time points) to understand the mechanisms of response and resistance to target pathways commonly activated in CRPC. We will test these hypotheses through the following specific aims: Aim 1. Analyze human donor tumors and corresponding PDMCs to identify dominant molecular alterations that drive PCa progression and select models to study. We will develop PDMCs from clinically annotated tumor specimens derived from men with potentially lethal PCa, including PDMCs derived from tumor specimens obtained at different times during progression (longitudinal studies) and from different areas of the same tumor. We will assess human PCa specimens and PDMCs’ morphology and expression of genes associated with PCa progression and subject them to whole-exome sequencing and RNA sequencing. PCa specimens and PDMCs derived from the longitudinal studies will also be subjected to whole-genome sequencing and epigenomic analysis. Finally, we will develop a publicly available interactive database linking molecular and preclinical results of PDMC characterization with clinical and molecular details of donor human PCa. These studies' findings will serve as the basis for the identification and prioritization of aberrant molecular pathways for further study. This knowledge is also essential to understanding how each PDMC provides information about the alterations in human donor tumor. Aim 2. Study genomic alterations acquired in metastasis specimens in the longitudinal studies for their potential to confer metastatic ability to cells. We will genetically modify organoids to create the genomic alterations found in the metastases. We will subsequently study how the genetic modification of these genes influences specific steps involved in metastasis, namely invasion, migration, and ability to grow at distant sites. Aim 3. Utilize PDMCs to study mechanisms of PCa response/resistance to targeted therapies on pathways implicated in PCa progression. We will seek a mechanistic understanding of PCa response and/or resistance to therapies in clinical trials targeting the AR, DNA damage response, Wnt-canonical, and PI3K pathways. These studies will inform the discovery and elucidation of resistance mechanisms, the development of effective therapies and will provide insights into the roles of PDMCs as model systems for studying signaling and therapeutic response.

项目概要/摘要雄激素消融治疗后进展的转移性前列腺癌 (PCa)（即去势抵抗性癌症） PCa [CRPC]）仍然无法治愈。对 PCa 进展的机制了解已经由于缺乏临床相关的 PCa 模型而受到阻碍。最近，源自患者的癌症模型（PDMC；例如，患者来源的异种移植物 [PDX] 和类器官）已被用于开发治疗相关的接近。我们假设肿瘤标本（和相应的 PDMC）的纵向研究随着时间的推移从同一患者获得的数据将有助于更好地理解不同的主要途径驱动转移进展。我们还假设类器官将作为 PDX 的补充对人体组织和衍生的 PDMC（在单个时间点获得）进行综合分析，以了解对 CRPC 中常见激活的靶途径的反应和抵抗机制。我们将测试这些通过以下具体目标提出假设：目标 1. 分析人类供体肿瘤和相应的 PDMC 可识别驱动 PCa 进展的主要分子改变并选择要研究的模型。我们将利用来自患有潜在致命 PCa 的男性的临床注释肿瘤标本开发 PDMC，包括源自进展过程中不同时间获得的肿瘤标本的 PDMC（纵向研究）和来自同一肿瘤的不同区域。我们将评估人类 PCa 样本和 PDMC 与 PCa 进展相关的基因的形态和表达，并将其置于全外显子组中测序和RNA测序。来自纵向研究的 PCa 标本和 PDMC 也将进行全基因组测序和表观基因组分析。最后，我们将开发一个公开的可用的交互式数据库将 PDMC 表征的分子和临床前结果与临床联系起来以及供体人类 PCa 的分子细节。这些研究结果将作为鉴定的基础以及异常分子途径的优先顺序以供进一步研究。这些知识对于了解每个 PDMC 如何提供有关人类供体肿瘤变化的信息。目标2。研究纵向研究中转移标本中获得的基因组改变，以了解其潜在的赋予细胞转移能力。我们将对类器官进行基因改造，以产生在转移。我们随后将研究这些基因的遗传修饰如何影响特定的涉及转移的步骤，即侵袭、迁移和在远处生长的能力。目标 3. 利用 PDMC 将研究 PCa 对 PCa 相关通路靶向治疗的反应/耐药机制进展。我们将寻求对 PCa 反应和/或治疗耐药的机制理解针对 AR、DNA 损伤反应、Wnt 经典和 PI3K 通路的临床试验。这些研究将为耐药机制的发现和阐明、有效疗法的开发和意志提供信息深入了解 PDMC 作为研究信号传导和治疗反应的模型系统的作用。