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: 10229495
• 负责人: CHRISTINE L. HANN
• 金额: $ 59.82万
• 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/10229495
• 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 局限期小细胞肺癌（LS SCLC）是SCLC的唯一可治愈形式，对化疗非常敏感。 依托泊苷+顺铂联合胸部放疗的缓解率> 70%;然而， 难治性复发是常见的。LS SCLC的5年总生存率（OS）低于25%， 改善长期SCLC结果的策略需要成功靶向肿瘤细胞群， 在标准治疗中存活并引起疾病复发。然而，在以下方面存在着相当大的差距： 了解SCLC放化疗抵抗的具体机制。我们的项目是 在SCLC资助的项目目前的投资组合中，我们专注于 提高LS SCLC的治愈率。最近，我们的工作建议使用病人- 衍生的SCLC异种移植（PDX）模型可能是阐明治疗机制的重要工具 阻力这种方法是非常成功的，确定了一个可容忍的和强烈的协同抗- SCLC相互作用导致基于我们的临床前数据的CTEP批准的试验-（NCI #10070;研究主席： 汉恩）。在这项研究计划中，我们将通过三个具体目标来测试关键假设， 在LS SCLC中观察到的快速出现的放化疗抗性的机制见解。 这一提议的一个中心假设是，适应性基因表达变化介导了细胞的快速出现。 LS SCLC的放化疗抗性表型。我们开发了一种新的放化疗疗法 方案与SCLC PDX模型，以促进这些研究。这部小说的发展和特点 该模型涉及医学肿瘤学家，放射肿瘤学家，生物信息学家， 医学物理学家，兽医和分子/细胞生物学家，非常适合开发一种 致力于解决SCLC放化疗抗性问题的综合计划。最后，我们已经 确定了与SCLC放化疗抗性相关的新基因靶点。 我们的研究计划组织如下：目标#1：表征响应的自然历史 SCLC实验模型的体内放化疗。我们将确定响应率和复发率 一组SCLC PDX和转基因小鼠模型的模式。目标#2：分子表征 SCLC放化疗抗性的基础。我们将重建基因调控网络， 与放化疗抗性相关的表达谱，并开发小规模预测分类器， 在后续研究中验证治疗反应。目的#3：药理学和遗传学验证 体外和体内SCLC放化疗抗性的候选基因。我们将验证我们的新基因 使用药理学和遗传学方法对SCLC赋予放化疗抗性的候选物 PDX衍生的类器官和SCLC转基因小鼠模型。