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

• 批准号: 10601278
• 负责人: PETER S NELSON
• 金额: $ 0.8万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601278
• 关键词: Defining; Targeting; Lineage; Transition; Programs

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.

项目总结/摘要 雄激素受体（AR）可能是已知的最早的谱系癌基因的例子： 来源于前列腺上皮的肿瘤细胞依赖的细胞存活和生长。认识到这一点 由于AR具有独特的特征，因此一致的努力集中在开发能够抑制AR信号传导的治疗剂上。 反映传染病治疗成功经验的新兴战略最终将部署到 药物组合可能会熄灭AR信号，这可能会治愈前列腺的一个子集， 癌的然而，癌的可塑性，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 独立于AR信令。该提案旨在预测组合AR途径抑制 将有助于细胞的可塑性，并选择完全耐药的肿瘤细胞亚群， 不依赖于AR信号传导并且不表现出神经内分泌特征。我们将检验这个假设， AR途径非依赖性前列腺癌（APIPC）激活并依赖于一组有限的特异性 通过去阻遏反馈环调节的存活和生长调节途径，和/或 特定致癌网络中的遗传/表观遗传改变。 我们的目标和战略如下： 具体目标1：确定成纤维细胞生长因子（FGF）信号转导促进细胞增殖的机制。 AR依赖性PC向AR无效APIPC的进展，并评估FGF靶向治疗的结局 治疗学代表AR依赖性疾病谱的细胞系和PDX疾病模型 和AR非依赖性系进行评价。 具体目标2：确定在APIPC中促进FGF通路活化的机制。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信号传导并决定FGF途径如何促进 不良前列腺癌表型。 具体目标3：确定和靶向FGF途径抑制和其他驱动因素的抗性机制 前列腺癌谱系的可塑性。我们将评估相关的模型系统和人类 生物标本的异质性和多样性的机制，有助于肿瘤细胞 可塑性，并评估治疗的有效性，拦截，逆转或抑制 新兴驱动力。 为了开发能够充分解决这类新的恶性肿瘤的有效治疗方法， APIPC使用的途径必须首先明确定义;该项目旨在阐明这些潜在途径 机制等