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

项目摘要 小细胞肺癌(SCLC)每年困扰着30,000多名患者，95%的病例很快就会死亡， 中位生存期不到一年。与这种严峻的预后背道而驰的是，治疗不成熟的小细胞肺癌 对化疗敏感。然而，复发几乎是不可避免的，复发的小细胞肺癌存在两个障碍 至少30年来一直无法克服的问题：对化疗的交叉耐药性，以及缺乏 生物标记物驱动的靶向治疗。 复发后，耐药性通常从依托泊苷/铂(EP)延伸到其他DNA损伤剂。 尽管拓扑替康是唯一被批准的治疗小细胞肺癌的二线药物，但NCCN指南列出了10种药物 大致相当的疗效。没有一种药物对未经选择的患者特别有效，而这种疾病曾经是 对化学高度敏感的人会变得不可阻挡地进步。然而，交叉的分子决定因素- 小细胞肺癌的耐药性仍不清楚。尽管交叉耐药非常重要，但很难研究。 在实验上，因为它需要一个模型系统，真实地再现临床结果，并充分 有能力捕捉患者群体中肿瘤间分子的异质性。 我们已经建立了一个由44个小细胞肺癌患者衍生的异种移植模型(PDX)组成的小组，这些模型来自活检标本和 循环肿瘤细胞(CTCs)。我们的专家小组包括个别患者在不同时间点的连续模型 在特定的治疗路线前后，提供相应的临床反应的详细信息。 对于临床试验中的标准化疗药物和实验药物，这些模型都忠实地反映了患者 回应。然而，与患者体验不同的是，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来直接比较依赖于DNA诱导的三种临床策略 损害：标准一线EP，二线拓扑替康，以及一种有希望的实验方案，奥拉帕利布加 替莫唑胺(OT)，目前正处于MGH的I/II期试验。单独地，这些PDX人群试验是设计的 揭示敏感的生物标记物和耐药机制，为有前景的实验治疗提供依据。 总的来说，通过参照每种模式的临床历史进行比较分析，他们提出了一种 为交叉抗性建模的新机会，这是一个困扰SCLC管理层多年的问题 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.