Project 4: Therapeutic Targeting of Replication Stress Vulnerabilities in Small Cell Lung Cancer

项目4项目摘要/摘要 该项目的目标是为小细胞肺癌开发新的、合成致死的、复制应激相关的方法。 患者基于他们的肿瘤的分子特征。小细胞肺癌治疗有两个主要未得到满足的需求：第一， 大多数患者将对临床上可用的化疗和 免疫疗法；第二，尽管有新的数据支持小细胞肺癌的分子和生物学亚群， 目前还没有用于生物标记物驱动的个性化治疗的既定方法(例如 非小细胞肺癌中的目标致癌驱动因素)。许多目前无法用药的致癌变化是 在小细胞肺癌中常见的通过复制应激(RS)和基因组不稳定性促进肿瘤发生。这些 “癌症的特征”会导致高肿瘤突变负担和染色体异常。SCLC有一个 由于P53和RB1功能的普遍丧失以及P53和RB1的频繁激活导致的持续高度RS 癌基因，如myc。在RS存在的情况下，癌细胞依赖于RS反应(RSR)，这是一种 DNA损伤修复反应(DDR)的一个分支，用于解决DNA损伤和复制分叉停滞问题。几个 RSR抑制剂正在临床开发中，我们在临床前模型中的初步发现表明 小细胞肺癌细胞系、异种移植和基因工程小鼠模型(GEMM)对靶向药物敏感 RSR或增加RS或基因组不稳定超过可容忍水平。后一组包括极光激酶 抑制剂(在高RS水平的情况下诱导有丝分裂灾难，以及直接抑制DNA 修复和降低复制叉稳定性)和6-硫代-DG(不同于著名药物6-硫代鸟嘌呤) 它被端粒酶阳性细胞掺入，导致端粒破裂，增加RS。 此外，我们最近发现RS的治疗靶向(例如，通过Chk1或PARP的抑制剂) 增加细胞质DNA，从而激活先天免疫反应(通过干扰素刺激物 基因[刺痛途径]、免疫介导的细胞毒性和对免疫检查点的增强反应 封锁。我们假设：1.RS靶向(通过Aurora激酶抑制或端粒破坏)将 导致小细胞肺癌分子定义亚群的合成致死性(目标1)；和2.RS靶向将增强 免疫治疗中对免疫检查点阻断的反应--小细胞肺癌难治性亚群通过激活 先天免疫系统(目标2和3)。具体地说，我们预计针对RS的治疗将导致复制 癌基因驱动的肺癌中的突变和细胞死亡与增强免疫检查点的反应 阻断(例如，抗PD-L1)。我们将在一个广泛的分子表征的小组中测试我们的假设 孢子肺癌细胞系，患者来源的异种移植(PDX，肿瘤和循环肿瘤细胞(CTC来源))， 创业板衍生的动物模型(目标1和2)，以及来自研究人员发起的第二阶段的临床标本 极光激酶抑制联合检查点抑制免疫治疗广泛应用的临床试验(AIM 3) 小细胞肺癌分期。

Project 4 Project Summary/Abstract The goal of this project is to develop novel, synthetic lethal, replication stress related, approaches for SCLC patients based on their tumor’s molecular profiles. There are two major unmet needs for SCLC therapy: first, the majority of patients will experience primary or acquired resistance to clinically available chemotherapy and immunotherapy; and second, despite new data supporting molecularly and biologically distinct subsets of SCLC, there are no established approaches for biomarker-driven personalized treatments (such as is standard for targetable oncogenic drivers in NSCLC). Many of the currently “undruggable” oncogenic changes that are common in SCLC promote tumorigenesis through replication stress (RS) and genomic instability. These “hallmarks of cancer” lead to high tumor mutational burden and chromosomal aberrations. SCLCs have a continuous high degree of RS due to the universal loss of p53 and RB1 function, and frequent activation of oncogenes such as MYC. In the presence of RS, cancer cells depend on RS responses (RSR), which are a branch of DNA damage repair responses (DDR), to resolve DNA damage and stalled replication forks. Several RSR inhibitors are in clinical development, and we have preliminary findings in preclinical models indicating that SCLC lines, xenografts, and genetically engineered mouse models (GEMMs) are sensitive to agents that target RSR or that increase RS or genomic instability beyond tolerable levels. The latter group includes aurora kinase inhibitors (which induce mitotic catastrophe in the setting of high RS levels, as well as directly inhibiting DNA repair and decreasing replication fork stability) and 6-thio-dG (distinct from the well-known drug 6 thioguanine) which is incorporated by telomerase positive cells, leading to telomere disruption, and increased RS. Furthermore, we have recently found that therapeutic targeting of RS (e.g., by inhibitors of Chk1 or PARP) increases cytoplasmic DNA, resulting in activation of the innate immune response (via the Stimulator of Interferon Genes [STING] pathway), immune-mediated cytotoxicity, and enhanced response to immune checkpoint blockade. We hypothesize that: 1. RS targeting (through Aurora Kinase inhibition or telomere disruption) will lead to synthetic lethality in molecularly-defined subsets of SCLC (Aim 1); and 2. that RS targeting will enhance response to immune checkpoint blockade in immunotherapy-refractory subsets of SCLC via activation of the innate immune system (Aims 2 and 3). Specifically, we expect that RS-targeted therapies will lead to replication catastrophe and cell death in oncogene-driven lung cancers and enhance responses to immune checkpoint blockade (e.g., anti-PD-L1). We will test our hypotheses in an extensive panel of molecularly characterized SPORE lung cancer cell lines, patient derived xenografts (PDXs, tumor and circulating tumor cell (CTC)-derived), GEM-derived animal models (Aims 1 and 2), and in clinical specimens from an investigator-initiated Phase 2 clinical trial (Aim 3) of Aurora Kinase inhibition combined with checkpoint inhibitor immunotherapy in extensive- stage SCLC.