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

小细胞肺癌患者来源的异种移植 (PDX) 模型对 DNA 损伤药物的敏感性和耐药性机制。

• 批准号: 397797873
• 负责人: Dr. Marcello Stanzione, Ph.D.
• 金额: --
• 依托单位: Mass General Cancer Center
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/397797873?language=en
• 关键词: Mechanisms; sensitivity; resistance; DNA; damaging

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.

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270，000人受到影响。SCLC约占所有肺癌病例的10-20%，诊断后仅7%存活5年，转移性疾病患者的中位生存期不到1年。SCLC的所有疗法都涉及DNA损伤剂，今天使用的标准一线治疗与30年前的治疗非常相似。尽管SCLC对这种初始治疗具有高度反应性，但几乎所有患者都会复发，并且更多患者对治疗产生相对抵抗。大多数化疗方案对复发性SCLC显示出较差的疗效，并且SCLC的进展的特征在于初始化学反应状态和随后的化学抗性状态之间的转变。SCLC研究的主要挑战是了解获得化疗耐药性的分子机制，找到抑制这种耐药性的方法，并确定更好的二线治疗方案。尽管有迫切的需求，但SCLC新疗法的开发一直受到缺乏尖端实验室研究模型和缺乏有希望的靶点的影响。在建立SCLC患者来源的异种移植（PDX）小鼠模型方面取得了令人兴奋的新进展，可以支持对耐药性获得期间肿瘤细胞内发生的遗传和分子改变进行详细分析。通过将肿瘤材料直接植入小鼠体内（无中间体外培养）生成的PDX模型密切保持了原发性肿瘤的基因表达特征和关键特征。戴森实验室已经从患者中生成了一组广泛的SCLC PDX模型。这种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对治疗的敏感性和抗性谱。该资源为详细研究SCLC中肿瘤敏感性/耐药性的机制提供了新的机会。该项目旨在研究对DNA损伤剂敏感性和抗性的分子决定因素，并寻求改进的治疗方法。我们建议通过分析和比较SCLC患者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的临床试验的进展和未来SCLC患者有效治疗方案的发展。