Exploiting convergent evolution to design biomarker extraction tools for the prediction of therapeutic response in cancer

项目摘要/摘要 抗药性肿瘤的有效治疗是肿瘤学中尚未得到满足的最大需求之一。 研究。癌症治疗耐药的演变是一个动态的过程，受许多外部因素的影响 力量，包括选择压力、微环境和临床治疗的时间尺度。作为肿瘤 在这些不同的环境下进化，出现了各种基因类型，并导致了药物的巨大差异 患者之间的反应表型。通过根据治疗反应对肿瘤进行分组，我们可以 利用趋同进化的原理，即相似的表型在个体之间独立进化。在……里面 为此，这项工作旨在通过识别具有类似药物的肿瘤之间的共性来辅助精确医学 反应表型。 基因表达谱是预测药物敏感状态的有力工具。 坚毅和抵抗。使用大量的开源数据集，本提案的目标1将演示一种新的方法 提取和验证基因表达特征以预测癌症的治疗反应。细胞系与 对一种药物的最佳反应和最差反应进行汇总，并使用差异基因表达分析进行比较。 在敏感或抗性状态下表达增加的基因成为共表达的种子基因 基于肿瘤样本的基因表达的网络。从那时起，只有强共表达的种子基因 在患者体内，提取样本以形成fiNAL基因表达特征。这种新的方法集成了 将临床样本数据转化为特征提取方法，以提高翻译价值。 仅使用细胞线数据集提取的圆形签名。接下来，本提案的目标2调查了这一现象 间接敏感性，对一种药物的耐药性与对另一种药物的敏感性一致。因为埃沃- 附属阻力和敏感性的解决可能是不可预测的，收敛状态的分子签名 一旦对fi一线耐药，侧支敏感性和耐药性可以极大地提高治疗计划 APY已经进化了。以EGFR+非小细胞肺癌细胞系为模型系统，本项目旨在 鉴定进化趋同的侧支敏感/耐药表型的分子特征 靶向治疗耐药的实验进展。

PROJECT SUMMARY/ABSTRACT The effective treatment of drug resistant tumors represents one of the greatest unmet needs in oncology research. The evolution of therapeutic resistance in cancer is a dynamic process, shaped by many external forces, including selection pressures, microenvironment, and the timescales of clinical treatments. As tumors evolve under these heterogeneous settings, a variety of genotypes emerge and lead to large differences in drug response phenotypes between patients. By grouping tumors based on their response to treatment, we can exploit principles of convergent evolution, where similar phenotypes evolve independently between individuals. In doing so, this work aims to aid precision medicine by identifying commonalities between tumors with similar drug response phenotypes. Gene expression signatures are a powerful tool that can be used to predict convergent states of drug sensitiv- ity and resistance. Using vast open-source datasets, Aim 1 of this proposal will demonstrate a novel method for extracting and validating gene expression signatures to predict therapeutic response in cancer. Cell lines with the best and worst response to a given drug are pooled and compared using differential gene expression analysis. Genes with increased expression in a state of sensitivity or resistance become seed genes in a co-expression network based on gene expression from tumor samples. From there, only seed genes with strong co-expression within patient samples are extracted to form the final gene expression signature. This novel approach integrates clinical sample data to the signature extraction method in order to increase translational value compared to molec- ular signatures extracted using only cell line datasets. Next, Aim 2 of this proposal investigates the phenomenon of collateral sensitivity, where resistance to one drug aligns with sensitivity to another drug. Because the evo- lution of collateral resistance and sensitivity can be unpredictable, molecular signatures of convergent states of collateral sensitivity and resistance could greatly enhance treatment planning once resistance to first-line ther- apy has evolved. Using EGFR+ non-small cell lung cancer cell lines as a model system, this project aims to identify molecular signatures of evolutionarily convergent collateral sensitivity/resistance phenotypes during the experimental evolution of therapeutic resistance to targeted therapies.