Project 3: Identifying Determinants of Sensitivity to LSD1 Inhibition in SCLC

项目 3：确定 SCLC 中 LSD1 抑制敏感性的决定因素

• 批准号: 10601292
• 负责人: David MacPherson
• 金额: $ 8.06万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10601292
• 关键词: Project; Identifying; Determinants; Sensitivity; LSD1

Project Summary/Abstract – Project 3 Small cell lung cancer (SCLC) leads to >30,000 deaths in the USA each year and therapies resulting in durable responses are greatly needed. This proposal is focused on a potent and selective LSD1 inhibitor, ORY1001. In preliminary data, we found efficacy of ORY1001 as monotherapy in a subset of patient derived xenograft (PDX) models of SCLC. PDX models differed greatly in sensitivity to ORY1001, with one model exhibiting complete and durable regression upon ORY1001 treatment. We found that strong tumor regression was linked to robust NOTCH pathway activation, which led to suppression of ASCL1, a transcription factor critical for SCLC. We hypothesize that robust activation of NOTCH and suppression of ASCL1 drives strong response to LSD1 inhibition in a subset of SCLC models. We also hypothesize that mutation in chromatin regulating genes may contribute to robust NOTCH pathway activation and increased sensitivity to LSD1 inhibition in SCLC. Specific Aim 1: To use genetically engineered mouse and PDX models to test the efficacy of ORY1001 in SCLC. We will expand our PDX studies to identify additional strongly responding models and will include models with mutations in chromatin regulating genes such as CREBBP and KMT2D that we hypothesize may contribute to strong responses. This aim will also test a novel Crebbp-deficient genetically engineered mouse model of SCLC that we generated to clearly determine whether inactivation of Crebbp increases response to LSD1 inhibition in SCLC. Specific Aim 2: To understand roles for LSD1-NOTCH-ASCL1 axis in control of SCLC cell viability. We will use tumors from PDX and GEM models treated in vivo and PDX tumors treated ex vivo with ORY1001 to interrogate roles for a NOTCH-ASCL1 axis in conferring strong responses to ORY1001 in SCLC. We will also perform studies in PDX models of SCLC studied ex vivo, to identify and better understand differences between strongly responding and non-responsive models. This Aim will include RNAseq and ChIPseq studies that will identify key differences between these groups. Specific Aim 3. Perform an Investigator Initiated clinical trial to test ORY1001 in SCLC patients. Here, we will study circulating tumor cells (CTCs) for biomarkers of response to LSD1 inhibition in a clinical trial. The design of this trial may be modified based on work performed in SCLC model systems as we identify potential biomarkers that may predict responsiveness. This work aims to direct LSD1 inhibition to SCLC patients most likely to benefit.

项目摘要/摘要 - 项目3 小细胞肺癌（SCLC）每年在美国导致30,000人死亡，疗法导致 非常需要耐用的响应。该建议集中于潜在的和选择性的LSD1抑制剂， Ory1001。在初步数据中，我们发现ORY1001的效率是一部分患者的单一疗法 SCLC的异种移植（PDX）模型。 PDX模型在对Ory1001的敏感性方面有很大不同，一个模型 在ORY1001治疗时表现出完整耐用的回归。我们发现强烈的肿瘤回归 与稳健的Notch途径激活相关，这导致了ASCL1的抑制，ASCL1是转录因子 SCLC至关重要。我们假设Notch的强大激活和ASCL1的抑制驱动力很强 SCLC模型子集中对LSD1抑制的响应。我们还假设染色质中的突变 调节基因可能有助于稳健的Notch途径激活和对LSD1的敏感性提高 SCLC的抑制作用。特定目标1：使用一般设计的鼠标和PDX模型来测试效率 SCLC中的Ory1001。我们将扩展我们的PDX研究，以确定其他强烈响应的模型和 将包括在调节染色质基因（例如Crebbp和kmt2d）中具有突变的模型 假设可能会导致强烈的反应。这个目标还将在缺乏新颖的CREBBP上测试 我们生成的工程鼠标模型清楚地确定Crebbp失活是否失活 增加对SCLC中LSD1抑制的反应。特定目标2：了解LSD1-Notch-ASCl1的角色 控制SCLC细胞活力的轴。我们将使用来自体内和PDX处理的PDX和宝石模型的肿瘤 用ORY1001处理过的肿瘤，以询问Notch-Ascl1轴的角色 SCLC中对Ory1001的响应。我们还将在sclc studioded ex Vivo的PDX模型中进行研究 识别并更好地理解强烈响应和无反应模型之间的差异。这个目标 将包括RNASEQ和CHIPSEQ研究，这些研究将确定这些组之间的关键差异。具体目标 3.执行研究人员启动临床试验，以测试SCLC患者的ORY1001。在这里，我们将学习 在临床试验中，循环肿瘤细胞（CTC）可用于对LSD1抑制的反应。这个设计 可以根据SCLC模型系统中执行的工作来修改试验，因为我们识别潜在的生物标志物 这可能会预测响应能力。这项工作旨在将LSD1抑制向最有可能的SCLC患者 益处。