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

项目概要/摘要-项目3 小细胞肺癌（SCLC）每年在美国导致> 30，000人死亡，并且治疗导致 非常需要持久的对策。该提议集中于有效的和选择性的LSD 1抑制剂， ORY1001在初步数据中，我们发现ORY 1001作为单药治疗在一个患者亚组中的疗效， SCLC的异种移植（PDX）模型。PDX模型对ORY 1001的敏感性差异很大，其中一个模型 在ORY 1001治疗后显示完全和持久的消退。我们发现肿瘤的强烈消退 与NOTCH途径的强烈激活有关，这导致转录因子ASCL 1的抑制 对SCLC至关重要。我们假设NOTCH的强烈激活和ASCL 1的抑制强烈驱动了 在SCLC模型的子集中对LSD 1抑制的反应。我们还假设染色质突变 调节基因可能有助于稳健的NOTCH途径激活和对LSD 1的敏感性增加 抑制SCLC。具体目标1：使用基因工程小鼠和PDX模型来测试功效 ORY 1001在SCLC中的作用我们将扩大我们的PDX研究，以确定其他强烈反应的模型， 将包括染色质调节基因突变的模型，如CREBBP和KMT 2D，我们 假设可能会导致强烈反应。这一目标也将测试一种新的Crebbp缺陷基因， 我们产生的SCLC的工程小鼠模型，以清楚地确定Crebbp的失活是否 增加对SCLC中LSD 1抑制的反应。具体目标2：了解LSD 1-NOTCH-ASCL 1的作用 轴控制SCLC细胞活力。我们将使用来自体内治疗的PDX和GEM模型的肿瘤， 用ORY 1001离体处理的肿瘤，以询问NOTCH-ASCL 1轴在赋予肿瘤细胞强免疫应答中的作用。 在SCLC中对ORY 1001的反应。我们还将在离体研究的SCLC的PDX模型中进行研究， 识别并更好地理解强响应和非响应模型之间的差异。这一目标 将包括RNAseq和ChIPseq研究，以确定这些群体之间的关键差异。具体目标 3.进行研究者发起的临床试验，以测试ORY 1001在SCLC患者中的作用。在这里，我们将研究 循环肿瘤细胞（CTC）作为临床试验中对LSD 1抑制的响应的生物标志物。设计这 当我们确定潜在的生物标志物时，可以基于在SCLC模型系统中进行的工作来修改试验 可以预测反应性。这项工作的目的是直接LSD 1抑制SCLC患者最有可能 效益

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.