Molecular and immunological heterogeneity of Small Cell Lung Cancer (SCLC) and its impact on relapse and therapeutic response

项目摘要 小细胞肺癌（SCLC）是一种侵袭性恶性肿瘤，对于其而言，迫切需要改善的化疗方案。 治疗策略虽然靶向和免疫疗法已经显示出令人鼓舞的结果， 最近，它们仅在一部分患者中显示出益处，因此，对患者的治疗几乎没有影响。 耐药性的迅速出现限制了耐药群体的生存，甚至限制了这些益处。那里 目前没有标准的标记物用于选择治疗或评估治疗抗性， 由于缺乏可用于SCLC分子评估的组织而具有挑战性。我们小组最近的证据表明 等认为SCLC是一种分子多样性疾病，大致可分为四种亚型 通过三种转录因子[ASCL 1（SCLC-A）、NEUROD 1（SCLC-N）和 POU 2F 3（SCLC-P）]，以及炎症和间充质标志物高表达的第四种亚型 [发炎，（SCLC-I）]。每种亚型的特点是，在体外，由不同的治疗弱点。而且我们 表明基因组和免疫肿瘤内异质性（ITH）预示着较差的生存，而增加 转录ITH可能与SCLC中的治疗抗性相关。本提案的总体目标是 系统研究SCLC的异质性及其与治疗反应的关系， 在临床上评估这些特征的工具。更具体地说，我们假设（1）SCLC是异质性的 并且可以分为具有不同治疗脆弱性的主要亚组;以及（2）更大的ITH- 在基因组、免疫或转录水平上进行评估- SCLC，并且可以在治疗期间以非侵入性方式使用基于血液的 生物标志物。为了解决这些假设，在目标1中，我们将评估这四种分子亚型是否可以 在体内联合临床试验和回顾性患者组织分析中用作预测性生物标志物，同时还 开发基于血液的策略来识别亚型。在目标2中，我们将在多个分子水平评估ITH。 水平，包括基因组学、转录组学、甲基化组学和免疫学，以表征基线ITH 影响患者生存。最后，在目标3中，我们将评估以下转录ITH的动态变化 使用来自体内模型和患者样品的配对样品进行治疗，以确定 分子亚型驱动耐药性，以及表观遗传修饰是否可以预防或逆转耐药性。 这里检验的假设是，仔细的SCLC肿瘤的初始分子亚型，与针对SCLC肿瘤的策略相结合， 评估，然后限制/逆转ITH，可以更好地优化对治疗的反应速率和持续时间。的 患者来源的小鼠模型和广泛的临床数据的综合库将促进研究 由临床/实验室研究者、病理学家、计算机科学家、 生物学家和其他在SCLC创新方面有着良好记录的人，并将实验室发现转化为 诊所

PROJECT SUMMARY Small cell lung cancer (SCLC) is an aggressive malignancy for which there is a critical need for improved therapeutic strategies. While targeted and immune-based therapies have demonstrated encouraging results recently, they have shown benefit in only a subset of patients and, thus, have yielded little to no impact on the survival of unselected populations and even these benefits are limited by the rapid onset of resistance. There are currently no standard markers for selecting treatment or evaluating therapeutic resistance, issues made more challenging by the dearth of available tissue for molecular assessment in SCLC. Recent evidence from our group and others suggests that SCLC is a molecularly diverse disease and can be divided into four subtypes largely defined by the differential expression of three transcription factors [ASCL1 (SCLC-A), NEUROD1 (SCLC-N), and POU2F3 (SCLC-P)], and a fourth subtype with high expression of inflammatory and mesenchymal markers [Inflamed, (SCLC-I)]. Each subtype is characterized, in vitro, by distinct therapeutic vulnerabilities. Moreover, we showed that genomic and immune intra-tumoral heterogeneity (ITH) portends poorer survival, while increasing transcriptional ITH may be associated with therapeutic resistance in SCLC. The overarching goal of this proposal is to systematically investigate heterogeneity in SCLC and its association with therapeutic response, and develop tools to evaluate these features in the clinic. More specifically, we hypothesize (1) That SCLC is heterogeneous and can be divided into major subgroups with distinct therapeutic vulnerabilities; and (2) That greater ITH- assessed either at the genomic, immune, or transcriptional level- is associated with therapeutic resistance in SCLC and can be assessed dynamically during treatment in a non-invasive manner using blood-based biomarkers. To address these hypotheses, in Aim 1, we will assess whether these four molecular subtypes can serve as predictive biomarkers in co-clinical trials in vivo and in retrospective patient tissue analyses, while also developing blood-based strategies to identify the subtypes. In Aim 2, we will assess ITH at multiple molecular levels, including genomic, transcriptomic, methylomic, and immunologic, to characterize how baseline ITH influences patient survival. Lastly, in Aim 3, we will assess dynamic changes in transcriptional ITH following treatment, using paired samples from in vivo models and patient samples, to determine if increasing ITH of molecular subtype drives resistance and whether epigenetic modification may prevent or reverse it. The overall hypothesis tested here is that careful initial molecular subtyping of SCLC tumors, paired with strategies aimed at assessing, then limiting/reversing ITH, may better optimize the rate and duration of response to therapy. The studies will be facilitated by a comprehensive library of patient-derived murine models and extensive clinical data sets and executed by a multidisciplinary team of clinical/laboratory investigators, pathologists, computational biologists, and others with a strong track record of innovation in SCLC and translating laboratory findings into the clinic.