Mechanisms of sensitivity and resistance to DNA damaging drugs in patient-derived xenograft (PDX) models of small cell lung cancer.

小细胞肺癌（SCLC）是一种侵袭性和高度转移性的癌症，全球每年约有27万人受其影响。SCLC约占所有肺癌病例的10-20%，诊断后只有7%的患者存活5年，转移性疾病患者的中位生存期不足1年。SCLC的所有治疗都涉及DNA损伤剂，目前使用的标准一线治疗与30年前的治疗非常相似。尽管SCLC对这种初始治疗有很高的反应，但几乎所有患者都会复发，并且对治疗产生相对耐药性。大多数化疗方案对复发性SCLC疗效不佳，SCLC的进展特点是在初始化疗反应状态和随后的化疗耐药状态之间转变。SCLC研究面临的主要挑战是了解获得化疗耐药的分子机制，找到抑制这种耐药性的方法，并确定二线治疗的更好治疗方案。尽管有迫切的需求，但SCLC新疗法的发展一直受到缺乏尖端实验室模型和缺乏有希望的靶点的影响。建立患者源性异种移植（PDX）小鼠SCLC模型的令人兴奋的新进展可以支持对肿瘤细胞在获得耐药性过程中发生的遗传和分子改变的详细分析。通过将肿瘤材料直接植入小鼠体内（无中间体外培养）产生的PDX模型密切保持了原发肿瘤的基因表达特征和关键特征。Dyson实验室已经从患者身上建立了广泛的SCLC PDX模型。这一独特的资源包括未经治疗的肿瘤和对化疗产生耐药性的肿瘤的PDX模型。重要的是，PDX模型具有与临床反应直接平行的治疗敏感性和耐药谱。这一资源为SCLC中肿瘤敏感性/耐药的详细机制研究提供了新的机会。该项目旨在研究对DNA损伤剂的敏感性和耐药性的分子决定因素，并寻找改进的治疗方法。我们建议通过分析和比较SCLC患者在治疗前后产生的连续PDX模型，来剖析PDX模型对DNA损伤药物的反应。从该研究项目中获得的见解可以促进新型临床试验的进展和SCLC患者有效治疗方案的未来发展。

Small cell lung cancer (SCLC) is an aggressive and highly metastatic type of cancer, which affects an estimated 270,000 individuals per year worldwide. SCLC accounts for about 10-20% of all lung cancer cases, only 7% survive for five years after diagnosis, and the median survival for patients with metastatic disease is less than one year. All therapies for SCLC involve DNA damaging agents and the standard first-line treatment used today is very similar to the treatment given thirty years ago. Despite SCLC is highly responsive to this initial treatment, almost all patients will experience relapse and more become relatively resistant to therapy. Most chemotherapy regimens show poor efficacy for relapsed SCLC and the progression of SCLC is characterized by a shift between an initial chemoresponsive state and a subsequent chemoresistant state. The major challenges for SCLC research are to understand the molecular mechanisms that underlie the acquisition of chemotherapeutic resistance, to find ways to suppress this, and to identify better treatment options for second line therapy. Despite the critical need, the development of new therapies for SCLC has suffered from a scarcity of cutting-edge laboratory models for research and absence of promising targets. Exciting new progress in the establishment of patient-derived xenograft (PDX) mouse models of SCLC can support a detailed analysis of genetic and molecular alterations that take place within the tumor cells during resistance acquisition. PDX models generated via direct implantation of tumor material into mice (with no intermediate in vitro culture) closely maintain the gene expression signatures and key characteristics of the primary tumor. The Dyson laboratory has generated an extensive panel of PDX models of SCLC from patients. This unique resource includes PDX models of treatment-naive tumors and tumors that have developed resistance to chemotherapy. Importantly, PDX models have a spectrum of sensitivity and resistance to treatment that directly parallel the clinical response. This resource provides new opportunities for detailed mechanistic investigation of tumor sensitivity/resistance in SCLC. The proposed project aims to investigate the molecular determinants of sensitivity and resistance to DNA damaging agents, and to search for improved therapeutic approaches. We propose to dissect the response of PDX models to DNA damaging drugs, by analyzing and comparing successive PDX models generated from SCLC patients, before and after their treatments. The insights gained from this research project can foster the progress of novel clinical trials and the future development of effective therapeutic programs for SCLC patients.