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

项目总结 小细胞肺癌(Sclc)是一种侵袭性的恶性肿瘤，迫切需要改进。 治疗策略。虽然靶向和基于免疫的治疗显示出令人鼓舞的结果 最近，它们只在一小部分患者中显示出好处，因此，对 未经选择的人群的生存，甚至这些好处，都受到迅速出现的耐药性的限制。那里 目前还没有选择治疗或评估治疗耐药性的标准标志，这使得问题变得更多 小细胞肺癌分子评估可用组织的缺乏带来的挑战。我们小组最近提供的证据 另一些人则认为小细胞肺癌是一种分子多样性疾病，大致可分为四种亚型。 由三个转录因子[ASCL1(SCLC-A)，NEUROD1(SCLC-N)，和 POU2F3(SCLC-P)]，以及高表达炎症和间质标志的第四种亚型 [炎症，(SCLC-I)]。在体外，每个亚型都有不同的治疗脆弱性。此外，我们 研究表明，基因组和免疫肿瘤内异质性(ITH)预示着较差的存活率，而 转录水平的ITH可能与小细胞肺癌耐药有关。这项提案的首要目标是 是系统地研究小细胞肺癌的异质性及其与治疗反应的关系，并发展 在临床上评估这些特征的工具。更具体地说，我们假设(1)SCLC是异质的 并可分为具有明显治疗脆弱性的主要亚组；以及(2)更大的ITH- 在基因组、免疫或转录水平进行评估-与治疗耐药有关 可以在治疗期间使用基于血液的非侵入性方式动态评估小细胞肺癌 生物标志物。为了解决这些假设，在目标1中，我们将评估这四个分子亚型是否可以 作为体内联合临床试验和回溯性患者组织分析的预测生物标记物，同时也 开发基于血液的策略来识别亚型。在目标2中，我们将从多个分子水平评估ITH 水平，包括基因组、转录组、甲基组和免疫学，以表征基线ITH 会影响患者的生存。最后，在目标3中，我们将评估以下转录ITH的动态变化 使用来自活体模型和患者样本的配对样本进行治疗，以确定是否增加ITH 分子亚型驱动耐药性，以及表观遗传修饰是否可以防止或逆转它。整体而言 这里检验的假设是，仔细的小细胞肺癌肿瘤的初始分子亚型，结合旨在 在评估，然后限制/逆转ITH，可能会更好地优化治疗的应答率和持续时间。这个 研究将通过患者衍生的小鼠模型和广泛的临床数据的综合资料库来促进 由临床/实验室调查人员、病理学家、计算专家组成的多学科团队设置和执行 生物学家和其他在SCLC创新方面有良好记录的人，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.