Using patient-derived models to understand drug responses 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，依托泊苷/铂的反应率超过70%。然而，复发是 几乎不可避免的，复发的SCLC提出了两个障碍，已经不可逾越的至少30 年：对化疗的交叉耐药性，以及缺乏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，而这种疾病曾经是高度耐药的。 化学敏感性变得不可阻挡地进步。然而，交叉耐药的分子决定因素， SCLC仍不清楚。尽管交叉耐药性非常重要，但很难通过实验进行研究，因为它 需要一个模型系统来忠实地再现临床结果。 拓扑替康是唯一被批准的二线治疗药物，但NCCN指南列出了10种几乎等效的药物 功效没有一种药物对乳腺癌患者特别有效，尽管有显著的分子生物学效应， 在SCLC的异质性中，这并不能指导患者的选择。作为新的靶点和治疗方案 生物标志物的发现将需要一个模型系统，概括患者的分子特征， 肿瘤，因此分子异质性可以被解析为临床上有意义的亚组。 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标准的一线和二线化疗与两种化疗方案。 在临床或临床前试验中获得有希望结果的实验方案：奥拉帕尼+ 替莫唑胺，在MGH的I/II期试验中，和组合的Mcl-1/Bcl-2抑制剂。这些PDX单独 群体试验旨在揭示敏感性的生物标志物和有希望的耐药机制， 实验疗法总的来说，他们提供了一个新的机会，通过 参考每个模型的临床历史进行比较分析。 这项工作的成功完成将建立一个全面的PDX模型的大集合 分子和功能概况。此外，这些实验还将研究 化疗后的交叉耐药，一个困扰SCLC治疗超过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, with response rates in excess of 70% for etoposide/platinum. 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, 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. Topotecan is the only approved second-line therapy, but NCCN guidelines list 10 agents of nearly equivalent efficacy. None are particularly effective in unselected patients, and although there is significant molecular heterogeneity in SCLC, this does not guide patient selection. As novel targets and therapeutic regimens emerge, biomarker discovery will require a model system that recapitulates the molecular features of patient tumors, so that molecular heterogeneity can be parsed into clinically meaningful subgroups. 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 standard first and second-line chemotherapy with two experimental regimens that have given promising results in the clinic or in preclinical assays: olaparib plus temozolomide, in a phase I/II trial at MGH, and a combined Mcl-1/Bcl-2 inhibitors. Individually, these PDX population trials are designed to reveal biomarkers of sensitivity and mechanisms of resistance for promising experimental therapies. Collectively, they present a novel opportunity to model cross-resistance through comparative analysis with reference to the clinical histories of each model. The successful completion of this work will establish a large collection of PDX models with comprehensive molecular an functional profiles. In addition, these experiments will investigate the molecular determinants of cross-resistance following chemotherapy, a problem that has beleaguered management of SCLC for over three decades.