Defining and Targeting Lineage Transition Programs Operative in AR Pathway Independent Prostate Cancer

定义和靶向在 AR 通路独立的前列腺癌中起作用的谱系转变计划

基本信息

批准号：
10239227
负责人：
PETER S NELSON
金额：
$ 40.83万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10239227
关键词：
Address Adrenal Glands Androgen Antagonists Androgen Receptor Androgens Biological Models CYP17A1 gene Carcinoma Cell Line Cell Survival Cells Characteristics Clinical Clinical Management Clinical Trials Development Disease Disease model Drug Combinations Drug Targeting Endocrine Epigenetic Process Epithelial Event Feedback Fibroblast Growth Factor Generations Genetic Genome Genomics Genotype Growth HIV Heterogeneity Human In complete remission Incidence Intercept Ligands Malignant Neoplasms Malignant neoplasm of prostate Metastatic Prostate Cancer Modeling Molecular Neuroendocrine Carcinoma Neurosecretory Systems Oncogenes Oncogenic Outcome Pathway interactions Pharmacology Phenotype Prostate Prostate carcinoma Receptor Activation Receptor Signaling Regulatory Pathway Resistance Resistance development Signal Transduction Signal Transduction Pathway Source Testing Testis Testosterone Therapeutic abiraterone androgen deprivation therapy androgen sensitive androgenic autocrine castration resistant prostate cancer cell growth combinatorial dehydroepiandrosterone design effectiveness evaluation epigenome epigenomics in vivo Model infectious disease treatment inhibitor/antagonist men neoplastic cell patient derived xenograft model pressure programs prostate cancer cell resistance mechanism success targeted treatment therapeutic effectiveness therapeutically effective tumor tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT The Androgen Receptor (AR) may be the earliest known example of a lineage oncogene: a master regulator of cell survival and growth to which neoplastic cells derived from prostate epithelium are addicted. Recognizing this unique feature, concerted efforts have focused on developing therapeutics capable of suppressing AR signaling. Emerging strategies, mirroring successes in treatment for infectious diseases, will eventually deploy combinations of drugs that will likely extinguish AR signaling, an event that may cure a subset of prostate cancers. However, the plasticity of carcinomas, in part generated by highly unstable genomes, suggests that prostate cancers are likely to emerge from this therapeutic pressure with a phenotype/genotype that is entirely independent of AR signaling. This proposal is designed to anticipate that combinatorial AR pathway inhibition will contribute to cell plasticity and select for subpopulations of resistant tumor cells that are completely independent of AR signaling and do not exhibit neuroendocrine characteristics. We will test the hypothesis that AR Pathway-Independent Prostate Cancers (APIPC) activate, and are dependent upon, a limited set of specific survival and growth regulatory pathways that are regulated via de-repressed feedback loops and/or genetic/epigenetic alterations in specific oncogenic networks. Our Aims and strategies are as follows: Specific Aim 1: Determine the mechanisms by which fibroblast growth factor (FGF) signaling promotes the progression of AR-dependent PC to AR-null APIPC and assess outcomes of FGF-targeted therapeutics. Cell lines and PDX models of disease representing a spectrum of AR-dependent and AR-independent lines will be evaluated. Specific Aim 2: Determine the mechanisms contributing to FGF pathway activation in APIPC. We will utilize relevant in vivo model systems and biospecimens to determine genomic and epigenomic mechanism(s) that activate FGF signaling and determine how the FGF pathway promotes adverse prostate cancer phenotypes. Specific Aim 3: Identify and target mechanisms of resistance to FGF pathway inhibition and to other drivers of prostate cancer lineage plasticity. We will evaluate relevant model systems and human biospecimens for the heterogeneity and diversity of mechanisms contributing to tumor cell plasticity, and assess the effectiveness of therapeutics that intercept, reverse or inhibit emerging drivers. In order for effective therapeutics to be developed that can adequately address this new class of malignancy, the pathways utilized by APIPC must first be clearly defined; this project aims to elucidate those underlying mechanisms.

项目概要/摘要雄激素受体 (AR) 可能是已知最早的谱系癌基因示例：雄激素受体 (AR) 的主要调节因子来自前列腺上皮的肿瘤细胞对细胞的存活和生长成瘾。认识到这一点独特的功能，共同努力集中于开发能够抑制 AR 信号传导的疗法。反映传染病治疗成功的新兴战略最终将得到部署可能会消除 AR 信号传导的药物组合，这一事件可能会治愈前列腺的一部分癌症。然而，癌症的可塑性部分是由高度不稳定的基因组产生的，这表明前列腺癌很可能从这种治疗压力中出现，其表型/基因型完全不同。独立于 AR 信令。该提案旨在预测组合 AR 通路抑制将有助于细胞可塑性并选择完全耐药的肿瘤细胞亚群独立于 AR 信号传导并且不表现出神经内分泌特征。我们将检验以下假设： AR 通路非依赖性前列腺癌 (APIPC) 激活并依赖于一组有限的特定通过去抑制的反馈环路和/或调节的生存和生长调节途径特定致癌网络中的遗传/表观遗传改变。我们的目标和策略如下：具体目标 1：确定成纤维细胞生长因子 (FGF) 信号传导促进 AR 依赖性 PC 向 AR 无 APIPC 的进展并评估 FGF 靶向的结果疗法。细胞系和 PDX 疾病模型代表一系列 AR 依赖性疾病和 AR 无关的线路将被评估。具体目标 2：确定 APIPC 中 FGF 通路激活的机制。我们将利用相关的体内模型系统和生物样本，以确定基因组和表观基因组激活 FGF 信号传导并确定 FGF 通路如何促进的机制不利的前列腺癌表型。具体目标 3：识别并针对 FGF 通路抑制和其他驱动因素的耐药机制前列腺癌谱系可塑性。我们将评估相关模型系统和人类用于研究肿瘤细胞机制异质性和多样性的生物样本可塑性，并评估拦截、逆转或抑制疗法的有效性新兴驱动力。为了开发出能够充分解决这种新型恶性肿瘤的有效疗法，首先必须明确定义 APIPC 使用的途径；该项目旨在阐明那些潜在的机制。