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: 10436173
• 负责人: David MacPherson
• 金额: $ 33.82万
• 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/10436173
• 关键词: Fred Hutchinson Cancer Research Center; KDM1A gene; Lung

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.

项目总结/摘要 – 项目 3 小细胞肺癌 (SCLC) 在美国每年导致超过 30,000 人死亡，而治疗方法则导致 非常需要持久的反应。该提案的重点是一种有效且选择性的 LSD1 抑制剂， ORY1001。在初步数据中，我们发现 ORY1001 作为单一疗法对一部分患者的疗效 SCLC 的异种移植 (PDX) 模型。 PDX模型对ORY1001的敏感性差异很大，只有一种模型 ORY1001 治疗后表现出完全且持久的消退。我们发现肿瘤明显消退 与强大的 NOTCH 通路激活有关，从而导致转录因子 ASCL1 的抑制 对于 SCLC 至关重要。我们假设 NOTCH 的强烈激活和 ASCL1 的抑制驱动强 SCLC 模型子集对 LSD1 抑制的反应。我们还假设染色质突变 调节基因可能有助于 NOTCH 通路的强烈激活并增加对 LSD1 的敏感性 SCLC 中的抑制作用。具体目标1：利用基因工程小鼠和PDX模型来测试疗效 SCLC 中的 ORY1001。我们将扩大 PDX 研究以确定其他强反应模型和 将包括我们的染色质调节基因（例如 CREBBP 和 KMT2D）发生突变的模型 假设可能有助于产生强烈的反应。该目标还将测试一种新的 Crebbp 缺陷基因 我们生成的 SCLC 工程小鼠模型可以清楚地确定 Crebbp 是否失活 增加 SCLC 中对 LSD1 抑制的反应。具体目标 2：了解 LSD1-NOTCH-ASCL1 的作用 控制 SCLC 细胞活力的轴。我们将使用来自体内治疗的 PDX 和 GEM 模型的肿瘤以及 PDX 用 ORY1001 离体处理肿瘤，以探究 NOTCH-ASCL1 轴在赋予强 SCLC 中对 ORY1001 的反应。我们还将在离体研究的 SCLC 的 PDX 模型中进行研究，以 识别并更好地理解强响应模型和无响应模型之间的差异。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. 进行一项研究者发起的临床试验，在 SCLC 患者中测试 ORY1001。在这里，我们将学习 循环肿瘤细胞（CTC）作为临床试验中 LSD1 抑制反应的生物标志物。这个的设计 当我们确定潜在的生物标志物时，试验可能会根据 SCLC 模型系统中进行的工作进行修改 这可以预测响应能力。这项工作旨在将 LSD1 抑制直接作用于最有可能发生的 SCLC 患者 益处。