Bioinformatic-Chemical Approach to Credential Molecular Targets to Combat Rapid Chemo-Radiation Resistance in SCLC

对抗 SCLC 快速化疗放疗耐药性的可信分子靶点的生物信息化学方法

• 批准号: 10474701
• 负责人: CHRISTINE L. HANN
• 金额: $ 36.84万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-03 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474701
• 关键词: BCL2 gene; Bioinformatics; Cancer Model; Cancer Therapy Evaluation Program; Candidate Disease Gene; Cell Line; Cells; Chemicals; Chemoresistance; Chest; Cisplatin; Clinical; Collaborations; Complex; Data; Development; Drug Combinations; Epigenetic Process; Etiology; Etoposide; Experimental Models; Follow-Up Studies; Funding; Gene Expression; Gene Expression Profiling; Gene Targeting; Genetic; Genetic Transcription; Genetically Engineered Mouse; Human; In Vitro; Limited Stage; Malignant Neoplasms; Mediating; Medical; Medical Oncologist; Modeling; Molecular; Molecular Target; Natural History; Organoids; Outcome; Pathway interactions; Patients; Pattern; Pharmacology; Phenotype; Population; Positioning Attribute; Radiation Oncologist; Radiation therapy; Recurrence; Recurrent disease; Refractory; Regulator Genes; Research; Research Design; Resistance; Signaling Protein; Techniques; Testing; Transgenic Mice; Treatment Protocols; Variant; Veterinarians; Work; Xenograft procedure; animal imaging; base; candidate validation; chemoradiation; chemotherapy; combat; genetic approach; improved; in vivo; inhibitor/antagonist; innovation; insight; irradiation; lung small cell carcinoma; mouse model; neoplastic cell; novel; patient derived xenograft model; pre-clinical; programs; resistance gene; resistance mechanism; response; therapy resistant; tool; transcription factor; transcriptome sequencing; tumor

PROJECT ABSTRACT Limited stage small cell lung cancer (LS SCLC), the only curable form of SCLC, is remarkably sensitive to etoposide plus cisplatin combined with thoracic radiotherapy with response rates > 70%; however, therapy- refractory recurrence is common. LS SCLC has less than a 25% 5-year overall survival (OS) and ultimately a strategy for improving long-term SCLC outcomes needs to successfully target tumor cell populations that survive standard therapy and give rise to recurrent disease. There is, however, a considerable gap in understanding the specific mechanisms responsible for chemoradiotherapy resistance in SCLC. Our project is unique among the current portfolio of SCLC funded programs in that we have focused on chemoradioresistance to increase cure rates in LS SCLC. Recently, our work has suggested using patient- derived xenograft (PDX) models of SCLC may be an important tool to elucidate mechanisms of therapy resistance. This approach was remarkably successful, identifying a tolerable and strongly synergistic anti- SCLC interaction that led to a CTEP-approved trial based on our preclinical data - (NCI #10070; Study Chair: Hann). In this research program, we will test key hypotheses via three specific aims that will provide more mechanistic insights into the rapidly emergent chemoradiation resistance observed in LS SCLC. One central hypothesis of this proposal is that adaptive gene expression changes mediate rapid emergence of the chemoradiation resistance phenotype in LS SCLC. We have developed a novel chemoradiation treatment regimen with SCLC PDX models to facilitate these studies. Development and characterization of this novel model involves a unique collaboration between medical oncologists, radiation oncologists, bioinformaticians, medical physicists, veterinarians and molecular/cell biologists that is extremely well suited to develop an integrated program dedicated to resolving questions of SCLC chemoradioresistance. Finally, we have already identified novel gene targets that are correlated with SCLC chemoradioresistance. Our research program is organized as follows: Aim #1: Characterize natural history of response of experimental models of SCLC to chemoradiation in vivo. We will determine response rates and recurrence patterns of a panel of SCLC PDXs and transgenic mouse models. Aim #2: Characterization of molecular underpinnings of SCLC chemoradiation resistance. We will reconstruct gene regulatory networks and gene expression profiles associated with chemoradiation resistance and develop small-scale predictive classifiers for therapy response to be validated in follow-up studies. Aim #3: Pharmacologic and genetic validation of candidate genes for SCLC chemoradiation resistance in vitro and in vivo. We will validate our novel gene candidates for conferring chemoradiation resistance using pharmacologic and genetic approach with SCLC PDX-derived organoids and SCLC transgenic mouse models.

项目摘要 有限的阶段小细胞肺癌（LS SCLC）是SCLC的唯一可治愈形式，对 依托泊苷加顺铂结合胸腔放射疗法，反应率> 70％；但是，治疗 - 难治性复发很常见。 LS SCLC的总生存率不到25％，最终 改善长期SCLC结果的策略需要成功针对肿瘤细胞群体 生存标准疗法并引起复发性疾病。但是，存在很大的差距 了解SCLC中负责化学放疗抗性的特定机制。我们的项目是 在当前的SCLC资助计划的投资组合中，我们一直专注于 化学放电剂以提高LS SCLC的治疗速率。最近，我们的工作建议使用患者 SCLC的衍生异种移植（PDX）模型可能是阐明治疗机制的重要工具 反抗。这种方法非常成功，确定了一种可忍受的和强烈协同的反 - 基于我们的临床前数据（NCI＃10070；学习主席： 汉恩）。在该研究计划中，我们将通过三个特定目标来检验关键假设，以提供更多 对LS SCLC中观察到的快速出现的化学放疗性的机械洞察力。 该提议的一个中心假设是自适应基因表达改变了介导的介导的快速出现 LS SCLC中的化学放疗抗性表型。我们已经开发了一种新型的化学放疗处理 具有SCLC PDX模型的方案，以促进这些研究。这部小说的发展和特征 模型涉及医学肿瘤学家，辐射肿瘤学家，生物信息学家之间的独特合作， 医学物理学家，兽医和分子/细胞生物学家非常适合发展 综合计划致力于解决SCLC化学放电的问题。最后，我们已经 鉴定出与SCLC化学降低相关的新型基因靶标。 我们的研究计划的组织如下：AIM＃1：表征自然的回应的自然历史 SCLC对体内化学放疗的实验模型。我们将确定响应率和复发 SCLC PDX和转基因小鼠模型的图案。目标＃2：分子的特征 SCLC化学放疗的基础。我们将重建基因调节网络和基因 与化学放疗抗性相关的表达曲线并为小规模的预测分类器开发 治疗反应在后续研究中得到验证。目的＃3：药理和遗传验证 用于体外和体内SCLC化学放疗的候选基因。我们将验证我们的新基因 使用SCLC使用药理和遗传方法赋予化学放疗耐药性的候选者 PDX衍生的类器官和SCLC转基因小鼠模型。