DNA damaging therapy and immune response in small cell lung cancer subtypes

项目总结 小细胞肺癌(Sclc)是一种高度侵袭性的疾病，目前仍迫切需要治疗。 提供持久的益处和生物标记物来指导治疗选择。虽然免疫疗法提供了临床 对一些患者有利，当前化疗-免疫治疗组合的总存活率未经选择 患者人数只有12个月左右。小细胞肺癌的一个特别未被研究的特点是治疗性。 针对这种基本上免疫的“感冒”癌症，加强免疫介导性反应的方法。我们的团队已经 以前确定的有前景的药物靶点、增强免疫治疗反应的策略和候选药物 小细胞肺癌的预测生物标志物(包括PARP和其他DNA损伤反应抑制剂单独和 结合免疫疗法)。这些已迅速转化为临床试验。解决当前的问题 研究差距(在NCI的SCLC进展工作组报告中概述)，包括(1)调查 小细胞肺癌微环境(包括免疫治疗的潜力和局限性)，(2)肿瘤异质性，(3) 纵向患者样本的特征，(4)新确定的亚型的模型，以及(5)发展 基于血液的生物标记物方法，我们组建了一个多学科团队，拥有科学、临床、 在小细胞肺癌和癌症免疫学领域的翻译和计算方面的专业知识。与我们的 胸部生物信息学工作组最近发现，有四种不同的、基于表情的 小细胞肺癌的分子亚型，包括一种新的“炎症”亚型(Gay等人，癌细胞，2021)。重要的是 这些SCLC亚型(SCLC-ASCLC、NeUROD1、POU2F3和SCLC-炎症)具有明显的治疗作用 可用于增强对ICB组合的响应的漏洞。我们已经生成并分析了 新的患者来源的异种移植模型来自活检和循环肿瘤细胞(“CDX”)代表的主要 SCLC亚型。这些，再加上已建立的人性化的老鼠模型系统，将使我们能够深入 描述ICB和DNA损伤治疗组合的免疫反应机制。基于 我们的数据，我们假设SCLC亚型和SLFN11状态将决定不同的，免疫调节的 对DNA损伤疗法和ICB的反应以及针对复制应激的新组合可能 增强免疫寒冷型小细胞肺癌的ICB反应。为了解决这些假设，在目标1中，我们将确定 DNA损伤治疗对小细胞肺癌分子亚型特异性免疫调节作用的联合临床试验 治疗前后的活体标本和患者标本。在目标2中，我们将研究癌细胞SLFN11作为 预测生物标志物及其在刺痛通路激活和抗肿瘤免疫中的作用。最后，在目标3中，我们将 评估克服耐药性的方法，包括与ICB结合的替代DNA损伤剂。这个 总体假设是小细胞肺癌肿瘤的分子亚型与加强免疫治疗的策略相结合 响应，将通过提供个性化的、生物标志物信息的方法来提高小细胞肺癌患者的生存率 去接受治疗。

PROJECT SUMMARY Small cell lung cancer (SCLC) is a highly aggressive disease for which there remains a critical need for therapies that provide durable benefit and biomarkers to guide treatment selection. While immunotherapy provides clinical benefit for some patients, overall survival with current chemotherapy-immunotherapy combinations in unselected patient populations remains only ~12 months. A particularly understudied feature of SCLC is therapeutic approaches to enhance immune-mediated responses for this largely immune “cold” cancer. Our group has previously identified promising drug targets, strategies to enhance immunotherapy response, and candidate predictive biomarkers for SCLC (including PARP and other DNA damage response inhibitors alone an in combination with immunotherapy). These have been rapidly translated into clinical trials. To address current research gaps (outlined in the NCI’s SCLC Progress Working Group report), including (1) investigation of the SCLC microenvironment (including the potential and limitations of immunotherapy), (2) tumor heterogeneity, (3) characterization of longitudinal patient samples, (4) models of newly identified subtypes, and (5) development of blood-based biomarker approaches, we have assembled a multidisciplinary team with scientific, clinical, translational, and computational expertise in the field of SCLC and cancer immunology. Together with our Thoracic Bioinformatics Working Group, we recently found that there are four distinct, expression-based molecular subsets of SCLC, including a novel “Inflamed” subtype (Gay et al, Cancer Cell, 2021). Importantly, these SCLC subtypes (SCLC-ASCLC, NEUROD1, POU2F3, and SCLC-Inflamed) have distinct therapeutic vulnerabilities that can be leveraged to enhance response to ICB combinations. We have generated and profiled new patient-derived xenograft models from biopsies and circulating tumor cells (“CDXs”) representing the major SCLC subtypes. These, together with an established humanized mouse model system, will enable us to deeply characterize mechanisms of immune response to combinations of ICB and DNA damaging therapies. Based on our data, we hypothesize that SCLC subtypes and SLFN11 status will determine distinct, immune mediated responses to DNA damaging therapies and ICB and that novel combinations targeting replication stress may enhance ICB response in immune “cold” SCLC. To address these hypotheses, in Aim 1, we will determine the SCLC molecular subtype-specific immune modulatory effects of DNA damaging therapy in co-clinical trials in vivo and in patient specimens before and after treatment. In Aim 2, we will investigate cancer cell SLFN11 as a predictive biomarker and its role in STING pathway activation and anti-tumor immunity. Lastly, in Aim 3, we will assess methods to overcome resistance, including alternative DNA damaging agents combined with ICB. The overall hypothesis is that molecular subtyping of SCLC tumors, paired with strategies to enhance immunotherapy response, will improve survival for patients with SCLC by providing a personalized, biomarker-informed approach to therapy.