Investigating mechanisms of bladder cancer metastasis

研究膀胱癌转移的机制

• 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
• 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

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由于转移而引起的，但迄今为止转移性膀胱癌 （MMIBC）尚未进行广泛研究，许多显着问题仍未解决。专业之一 阻碍了研究MMIBC进展的挑战是缺乏适当的模型来调查 体内转移进展。我们现在已经生成了新型的遗传工程小鼠模型（GEMM） 发展出高度渗透的MMIBC。这些新的是基于我们既定的宝石，其中膀胱特异性 PTEN和p53肿瘤补充剂的共同吸收会导致侵入性疾病，低发生率 转移。越过这些pten； p53小鼠，带有ARID1A功能丧失的小鼠，一种表观遗传调节剂 在人类膀胱癌中，这在高百分比中失调，导致致命的膀胱癌> 80％ 转移的发生率。此外，对PTEN的处理； p53小鼠，低剂量的致癌物N-丁基 - N-（4-羟基丁基） - 硝酸（BBN）导致MMIBC，入射率> 60％。同时，我们已经实施了 最先进的系统生物学方法来识别机械决定者（MRS）（MRS） 宝石中的转移进展。在宝石中富含转移性肿瘤的MRS是保守的 人类膀胱癌，并富含与谱系可塑性相关的人。识别靶向的药物 这些保守的MRS，我们实施了Oncotreat，这是一种计算算法，优先于基于 他们颠倒与生物学相关的MR活动的能力。为了验证这些药物，我们已经产生了 人类患者衍生的类器官模型的广泛生物库。利用这些宝石，人类患者得出 器官和系统的方法是，我们理想地毒化了以下假设。 对转移性疾病的侵入性是由主调节剂的顺序活动驱动的，包括谱系 可塑性，可以通过研究这些宝石中的转移进展来阐明和靶向。我们将 追求三个具体目标：在AIM 1中，我们将利用MMIBC的宝石系统研究 体内转移进展的生物过程和分子机制。在AIM 2中，我们将 阐明转移性进展的主要调节剂，重点是与前相关的转移 转移到转移性MIBC和/或将肿瘤与相应转移酶区分开的转移 到不同的器官位点，并且作为可行的，可从明显转移的群体簇。我们将优先考虑太太 与人类膀胱癌以及与谱系可塑性相关的癌症保存的。在AIM 3中，我们 将寻求使用Oncotreat算法来识别MMIBC的新药，以识别逆转的化合物 转移MRS的活性。我们将优先考虑（1）目标谱系可塑性机制的候选药物， 对于没有证据可行的驾驶员突变的患者，可以推断出/或（2）。总共，我们的研究 将对MMIBC的生物学，机制和治疗方法进行全面分析 识别可能改善患者预后的新治疗靶标的转化目标。