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

• 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
• 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

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.

项目摘要/摘要 雄激素消融治疗后进展的转移性前列腺癌（PCA） PCA [CRPC]）仍然无法治愈。获得对PCA进展的机械理解已经是 由于缺乏临床相关的PCA模型而受到阻碍。最近，患者来源的癌症模型（PDMCS； 例如，患者衍生的Xenographictic [PDXS]和Oranoids已用于发展治疗相关 方法。我们假设肿瘤标本（和相应PDMC）的纵向研究 随着时间的流逝，从同一患者获得的将会更好地了解潜水员的主要途径 驱动转移性进展。我们还假设类型器会补充PDX作为 人体组织和衍生PDMC的综合分析（在单个时间点获得），以了解 CRPC中通常激活的反应和对目标途径的抗性机制。我们将测试这些 通过以下特定目的假设：目标1。分析人类供体肿瘤和相应 PDMC确定驱动PCA进展并选择研究模型的显性分子改变。我们 将从临床注释的肿瘤标本中开发PDMC，这些肿瘤标本来自具有潜在致命PCA的男性， 包括源自在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标本和PDMCS 与PCA进展相关的基因的形态和表达，并使它们遭受全面外观 测序和RNA测序。从纵向研究得出的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，我们将公开开发 可用的交互式数据库将PDMC表征与临床表征的分子和临床前结果联系起来 和供体人PCA的分子细节。这些研究的发现将作为识别的基础 和异常分子途径的优先级以进行进一步研究。这些知识对于 了解每个PDMC如何提供有关人类供体肿瘤改变的信息。目标2。 在纵向研究中，在转移标本中获得的研究基因组改变的潜力 会议转移性能力。我们将基因修改器官，以创建在中发现的基因组改变 转移。随后，我们将研究这些基因的遗传修饰如何影响特定 涉及转移的步骤，即入侵，迁移和在远处生长的能力。目标3。利用 PDMC研究PCA对靶向疗法的PCA反应/抗性机制在PCA实施的途径上 进展。我们将寻求对PCA反应和/或对疗法的抗药性的机械理解 针对AR，DNA损伤反应，Wnt-Canonical和PI3K途径的临床试验。这些研究会 告知抵抗机制的发现和阐明，有效疗法的发展，将 提供有关PDMC作为研究信号传导和治疗反应的模型系统作用的见解。