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.

项目总结/文摘