Using patient-derived models to understand drug responses in SCLC

使用源自患者的模型来了解 SCLC 的药物反应

• 批准号: 10247067
• 负责人: NICHOLAS J DYSON
• 金额: $ 61.34万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-17 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247067
• 关键词: Aftercare; Apoptotic; BCL2 gene; Biological Assay; Biological Markers; Biological Models; Biopsy; Biopsy Specimen; Blood specimen; Cancer cell line; Chemoresistance; Cisplatin; Clinic; Clinical; Clinical Trials; Collection; Communities; DNA Damage; Dependence; Development; Diagnosis; Disease; Dissection; Etoposide; Frequencies; Guidelines; Heterogeneity; Human; In Vitro; Investigational Therapies; MCL1 gene; Malignant Neoplasms; Methods; Modeling; Molecular; Molecular Profiling; Mus; Mutation Spectra; National Comprehensive Cancer Network; Neoplasm Circulating Cells; Outcome; Patient Selection; Patients; Pattern; Pharmaceutical Preparations; Pharmacology Study; Phase I/II Trial; Platinum; Population; Prognosis; Proteomics; Recording of previous events; Regimen; Relapse; Resistance; Resources; Specimen; Subgroup; System; Therapeutic; Time; Topotecan; United States; Work; anticancer research; base; biomarker discovery; biomarker-driven; cancer therapy; candidate marker; chemotherapy; comparative; compare effectiveness; drug sensitivity; early phase clinical trial; effusion; exome sequencing; experience; experimental study; genome sequencing; in vivo; individual patient; inhibitor/antagonist; lung small cell carcinoma; neoplastic cell; novel; novel marker; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; patient population; patient response; pre-clinical; relapse patients; repaired; resistance mechanism; response; targeted treatment; temozolomide; transcriptome sequencing; trial design; tumor

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.

项目总结 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，对依托泊苷/铂的有效率超过70%。然而，复发是 几乎不可避免地，小细胞肺癌复发带来了两个至少30年来无法克服的障碍 几年：对化疗交叉耐药，缺乏生物标记物驱动的靶向治疗。 复发后，耐药性往往超出依托泊苷/铂类药物，这是一种曾经高度敏感的疾病 对化学药物敏感的人会变得势不可挡。然而，交叉耐药的分子决定因素在 SCLC仍不清楚。尽管交叉抗性非常重要，但很难通过实验进行研究，因为它 需要一个忠实地再现临床结果的模型系统。 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种几乎相同的药物 功效。没有一种方法对未经选择的患者特别有效，尽管有显著的分子水平 小细胞肺癌的异质性，这并不指导患者的选择。作为新的靶点和治疗方案 随着生物标记物的发现，将需要一个概括患者分子特征的模型系统 肿瘤，因此分子的异质性可以被解析成具有临床意义的亚群。 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标准的一线和二线化疗与两种 在临床或临床前试验中取得有希望结果的实验方案：奥拉帕利加 替莫唑胺，在MGH的I/II期试验中，以及Mcl-1/Bcl-2联合抑制剂。单独而言，这些PDX 群体试验旨在揭示生物标记物的敏感性和抗药性机制。 实验性疗法。总而言之，它们提供了一种新的机会，通过 参照每种模式的临床病史进行对比分析。 这项工作的成功完成将建立一个庞大的PDX型号集合，具有全面的 分子和功能图谱。此外，这些实验还将研究分子决定因素 化疗后的交叉耐药，一个困扰小细胞肺癌管理多年的问题 三十年了。