Investigating mechanisms of bladder cancer metastasis

研究膀胱癌转移的机制

基本信息

批准号：
10718278
负责人：
Cory Abate-Shen
金额：
$ 51.68万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10718278
关键词：
ARID1A gene Algorithms Biological Assay Biological Process Biology Bladder Cancer Etiology Cancer Patient Carcinogens Cells Cessation of life Computational algorithm Data Disease Disease Outcome Dose Drug Targeting Epigenetic Process Evolution Foundations Genetically Engineered Mouse Goals Health Human Incidence Investigation Malignant Neoplasms Malignant neoplasm of urinary bladder Metastatic to Modeling Molecular Molecular Analysis Mus Neoplasm Metastasis Nitrosamines Organ Organoids Outcome Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Reporter Research Site System Systems Biology TP53 gene United States actionable mutation biobank candidate identification driver mutation drug candidate improved in vitro Model in vivo in vivo Model longitudinal analysis loss of function muscle invasive bladder cancer new therapeutic target non-muscle invasive bladder cancer novel novel strategies novel therapeutics pre-clinical single-cell RNA sequencing translational goal tumor tumor microenvironment tumorigenesis

项目摘要

The major cause of bladder cancer deaths is due to metastasis, yet to date metastatic bladder cancer (mMIBC) has not been extensively studied and many salient issues remain unresolved. One of the major challenges that has hampered progress in studying mMIBC is the lack of suitable models to investigate metastatic progression in vivo. We have now generated novel genetically-engineered mouse models (GEMMs) that develop highly penetrant mMIBC. These new are based on our established GEMM, in which bladder-specific co-inactivation of the Pten and p53 tumor suppressors leads to invasive disease with a low incidence of metastasis. Crossing these Pten; p53 mice with mice harboring loss-of-function of Arid1a, an epigenetic regulator that is dysregulated in a high percentage of human bladder cancers, results in lethal bladder cancer with >80% incidence of metastasis. In addition, treatment of the Pten; p53 mice with a low dose of the carcinogen N-butyl- N-(4-hydroxybutyl)-nitrosamine (BBN) leads to mMIBC with >60% incidence. In parallel, we have implemented state-of-the-art systems biology approaches to identify mechanistic determinants—master regulators (MRs)—of metastatic progression in the GEMMs. MRs enriched in metastatic tumors in the GEMMs are conserved with human bladder cancer, and are enriched for those associated with lineage plasticity. To identify drugs that target these conserved MRs, we implemented OncoTreat, a computational algorithm that prioritizes drugs based on their ability to invert the activities of biologically-relevant MR. To validate these drugs, we have generated an extensive biobank of human patient derived organoid models. Leveraging these GEMMs, human patient derived organoids and systems approaches, we are ideally poised to investigate the hypothesis that the transition from pre-invasive to metastatic disease is driven by the sequential activities of master regulators, including for lineage plasticity, which can be elucidated and targeted by studying metastatic progression in these GEMMs. We will pursue three Specific Aims: In Aim 1, we will leverage our GEMMs of mMIBC to systematically investigate the biological processes and molecular mechanisms underlying metastatic progression in vivo. In Aim 2, we will elucidate master regulators of metastatic progression, focusing on those associated with the transition from pre- metastatic to metastatic MIBC, and/or that distinguish tumors from their corresponding metastases, metastases to different organ sites, and, as feasible, pre-metastatic clusters from overt metastases. We will prioritize MRs that are conserved with human bladder cancer, as well as those associated with lineage plasticity. In Aim 3, we will seek to identify new drugs for mMIBC using the OncoTreat algorithm to identify compounds that invert the activity of MRs of metastasis. We will prioritize candidate drugs that (1) target lineage plasticity mechanisms, and/or (2) are inferred for patients that do not have evident actionable driver mutations. Altogether, our studies will provide a comprehensive analysis of the biology, mechanisms, and treatments for mMIBC, with the translational goal of identifying new therapeutic targets that may improve patient outcomes.

膀胱癌死亡的主要原因是转移，迄今为止转移性膀胱癌（mMIBC）尚未得到广泛研究，许多突出问题仍未解决是主要问题之一。阻碍 mMIBC 研究进展的挑战是缺乏合适的模型来研究我们现在已经生成了新型基因工程小鼠模型（GEMM）。开发高渗透性 mMIBC 这些新产品基于我们建立的 GEMM，其中膀胱特异性。 Pten 和 p53 肿瘤抑制因子的共同失活会导致侵袭性疾病，且发生率较低将这些 Pten 小鼠与具有表观遗传调节因子 Arid1a 功能丧失的小鼠进行杂交。在高比例的人类膀胱癌中失调，导致 80% 以上的人患上致命的膀胱癌此外，用低剂量的致癌物N-丁基治疗Pten；p53小鼠。 N-(4-羟丁基)-亚硝胺 (BBN) 导致 mMIBC 的发生率 >60% 同时，我们已经实施了这一措施。最先进的系统生物学方法来识别机械决定因素 - 主调节器（MR） - GEMM 中富含转移性肿瘤的 MR 的转移进展是保守的。人类膀胱癌，并丰富了与谱系可塑性相关的药物，以确定靶向药物。对于这些保守的 MR，我们实施了 OncoTreat，这是一种计算算法，可根据以下因素对药物进行优先级排序：它们逆转生物学相关 MR 活性的能力为了验证这些药物，我们生成了一个利用这些 GEMM，人类患者衍生的类器官模型的广泛生物库。类器官和系统方法，我们完全准备好研究以下假设：从侵袭前到转移性疾病是由主调节因子的连续活动驱动的，包括谱系我们将通过研究这些 GEMM 的转移进展来阐明和靶向可塑性。追求三个具体目标：在目标 1 中，我们将利用 mMIBC 的 GEMM 系统地研究在目标 2 中，我们将探讨体内转移进展的生物学过程和分子机制。阐明转移进展的主要调节因子，重点关注那些与转移前转变相关的调节因子转移性至转移性 MIBC，和/或将肿瘤与其相应的转移瘤、转移瘤区分开来到不同的器官部位，并且在可行的情况下，我们将优先考虑来自明显转移的转移前簇。在目标 3 中，我们研究了人类膀胱癌中保守的基因以及与谱系可塑性相关的基因。将寻求使用 OncoTreat 算法来识别 mMIBC 新药，以识别逆转 mMIBC 的化合物我们将优先考虑以下候选药物：（1）针对谱系可塑性机制，和/或 (2) 是针对没有明显可操作驱动突变的患者推断的。将提供 mMIBC 的生物学、机制和治疗的全面分析，确定可能改善患者预后的新治疗靶点的转化目标。