Dissecting and overcoming cross-resistance to DNA damaging agents in SCLC

项目摘要 小细胞肺癌（SCLC）每年折磨超过30，000名患者，并且在95%的病例中迅速致命， 中位生存期不到一年。与这种严峻的预后相反，未经治疗的SCLC高度 对化疗敏感然而，复发几乎是不可避免的，复发的SCLC存在两个障碍 至少30年来无法克服的问题：对化疗的交叉耐药性， 生物标志物驱动的靶向治疗。 复发后，耐药性往往超出依托泊苷/铂（EP），扩展到其他DNA损伤剂。 虽然拓扑替康是唯一批准的SCLC二线治疗，但NCCN指南列出了10种药物， 大致相同的功效。没有一种对糖尿病患者特别有效，这种疾病曾经是 高度化学敏感性会变得越来越严重然而，交叉的分子决定因素- SCLC的耐药性仍不清楚。尽管交叉耐药性非常重要，但研究起来却很困难 实验上，因为它需要一个模型系统，忠实地再现临床结果， 能够捕获患者群体中的肿瘤间分子异质性。 我们已经从活检标本中产生了一组44个SCLC患者来源的异种移植物模型（PDX）， 循环肿瘤细胞（CTC）。我们的小组包括来自各个患者的连续模型， 在特定治疗线之前和之后，以及有关相应临床反应的详细信息。 对于标准化疗和临床试验中的实验性药物，这些模型忠实地反映了患者 应答然而，与患者经验不同的是，对于相同的肿瘤，可以比较多种策略。 我们建议使用这些模型直接比较三种依赖于DNA诱导的临床策略 损害：标准一线EP，二线拓扑替康，以及一个有希望的实验方案，奥拉帕尼加 替莫唑胺（OT），目前在MGH进行I/II期试验。这些PDX人群试验分别设计为 揭示敏感性的生物标志物和有希望的实验疗法的耐药机制。 总的来说，通过参考每种模型的临床历史进行比较分析， 一个新的机会来模拟交叉耐药性，一个困扰SCLC管理超过10年的问题， 三十年了

Project Summary Small cell lung cancer (SCLC) afflicts more than 30,000 patients per year and is rapidly fatal in 95% of cases, with median survival is less than one year. Belying this grim prognosis, treatment-naive SCLC is highly sensitive to chemotherapy. However, relapse is nearly inevitable, and relapsed SCLC presents two obstacles that have been insurmountable for at least 30 years: cross-resistance to chemotherapy, and absence of biomarker-driven targeted therapy. Following relapse, resistance often extends beyond etoposide/platinum (EP) to other DNA damaging agents. Although topotecan is the only approved second-line therapy for SCLC, the NCCN guidelines list 10 agents of roughly equivalent efficacy. None are particularly effective in unselected patients, and a disease that was once highly chemosensitive becomes inexorably progressive. However, the molecular determinants of cross- resistance in SCLC remain unclear. Although critically important, cross-resistance is difficult to study experimentally, as it requires a model system that faithfully reproduces clinical outcomes, and is adequately powered to capture inter-tumoral molecular heterogeneity across a population of patients. We have generated a panel of 44 SCLC patient-derived xenograft models (PDXs) from biopsy specimens and circulating tumor cells (CTCs). Our panel includes successive models from individual patients at time points before and after specific lines of therapy, with detailed information about the corresponding clinical response. For both standard chemotherapy and experimental agents in clinical trial, these models faithfully mirror patient responses. However, unlike the patient experience, multiple strategies can be compared for identical tumors. We propose to use these models to directly compare three clinical strategies that depend on induction of DNA damage: standard first line EP, second line topotecan, anad a promising experimental regimen, olaparib plus temozolomide (OT), currently in a phase I/II trial at MGH. Individually, these PDX population trials are designed to reveal biomarkers of sensitivity and mechanisms of resistance for promising experimental therapies. Collectively, through comparative analysis with reference to the clinical histories of each model, they present a novel opportunity to model cross-resistance, a problem that has beleaguered management of SCLC for over three decades.