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

项目摘要 局限性小细胞肺癌(LS SCLC)是唯一可治愈的小细胞肺癌，对 依托泊苷加顺铂联合胸部放疗有效率70%；然而，治疗- 难治性复发是常见的。LS SCLC的5年总生存率(OS)不到25%，最终 改善小细胞肺癌长期疗效的策略需要成功地靶向肿瘤细胞群 在标准治疗中幸存下来，并引发复发的疾病。然而，有一个相当大的差距， 了解小细胞肺癌放化疗耐药的具体机制。我们的项目是 在当前SCLC资助的项目组合中独一无二的是，我们专注于 化疗-放射抵抗可提高LS小细胞肺癌的治愈率。最近，我们的工作建议使用患者- 衍生异种移植(PDX)模型可能是阐明治疗机制的重要工具 抵抗。这种方法非常成功，确定了一种可以容忍和强烈协同的反 小细胞肺癌的相互作用导致了基于我们临床前数据的CTEP批准的试验-(NCI#10070；研究主席： Hann)。在这个研究计划中，我们将通过三个具体的目标来检验关键假设，这三个目标将提供更多 对LS小细胞肺癌中观察到的快速显现的化疗耐药的机制洞察。 这一建议的一个中心假设是，适应性基因表达的变化介导了快速的 LS小细胞肺癌的放化疗耐药表型。我们已经开发出一种新的放化疗疗法。 使用SCLC PDX模型的治疗方案以促进这些研究。这部小说的发展和人物塑造 该模式涉及医学肿瘤学家、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 致力于解决小细胞肺癌化疗耐药问题的综合计划。最后，我们已经 发现了与小细胞肺癌化疗-放射耐药相关的新基因靶点。 我们的研究计划安排如下：目标1：描述自然反应的历史 小细胞肺癌对体内放化疗的实验模型。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：分子的特性 小细胞肺癌化疗耐受的基础。我们将重建基因调控网络和基因 与化疗耐药相关的表达谱并开发小规模预测分类器 治疗反应有待后续研究验证。目标3：药理学和遗传学验证 体内外小细胞肺癌化疗耐受候选基因的研究。我们将验证我们的新基因 用药理学和遗传学方法对小细胞肺癌进行化疗耐药候选研究 PDX衍生的有机化合物和SCLC转基因小鼠模型。

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.