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

项目摘要/摘要-项目3 在美国，小细胞肺癌(SCLC)每年导致30,000人死亡，治疗方法导致 非常需要持久的应对措施。这项提议的重点是一种有效和选择性的LSD1抑制剂， ORY1001。在初步数据中，我们发现ORY1001作为单一疗法在一组患者中的有效性 小细胞肺癌异种移植模型。PDX型号对ORY1001的敏感度差异很大，只有一个型号 在ORY1001治疗后表现出完全和持久的消退。我们发现强烈的肿瘤消退 与强大的Noch途径激活有关，这导致了转录因子ASCL1的抑制 对SCLC至关重要。我们假设Notch的强烈激活和ASCL1的抑制驱动了强大的 部分SCLC模型对LSD1抑制的反应。我们还假设染色质中的突变 调节基因可能有助于Notch通路的激活和对LSD1的敏感性增加 小细胞肺癌中的抑制作用。具体目标1：使用基因工程小鼠和PDX模型来测试疗效 在SCLC中的ORY1001。我们将扩展我们的PDX研究，以确定更多反应强烈的型号和 将包括染色质调节基因突变的模型，如CREBBP和KMT2D，我们 假设可能会导致强烈的反应。这一目标还将测试一种新的CREBBP基因缺陷 我们建立了SCLC的工程化小鼠模型，以清楚地确定CREBBP的失活 增加小细胞肺癌对LSD1抑制的反应。具体目标2：了解LSD1-NOTCH-ASCL1的角色 AXIS在控制小细胞肺癌细胞活性中的作用。我们将使用PDX和GEM模型体内治疗的肿瘤和PDX 用ORY1001体外治疗肿瘤以询问缺口-ASCL1轴在授予强阳性信号中的作用 SCLC对ORY1001的回应。我们还将对体外研究的小细胞肺癌的PDX模型进行研究，以 识别并更好地理解强响应和无响应模式之间的差异。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。特定目标 3.进行调查者发起的临床试验，在小细胞肺癌患者中测试ORY1001。在这里，我们将学习 临床试验中循环肿瘤细胞(CTCs)对LSD1抑制反应的生物标志物。这款车的设计 当我们确定潜在的生物标志物时，试验可能会根据在SCLC模型系统中所做的工作进行修改 这可能预示着人们的反应能力。这项工作的目的是将LSD1抑制作用引导到最有可能发生 利益。

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.