Longitudinal models of breast cancer for studying mechanisms of therapy response and resistance

项目摘要 该提案的目标是测试三种类型的患者来源的乳腺癌模型的保真度， 基因组和表观遗传畸变、克隆异质性和进化以及治疗反应/抗性。 我们将比较PDX，患者来源的类器官（PDO）和患者来源的条件重编程细胞 （PDCRC）来自总共22名乳腺癌患者。模型将来自患者样本 在患者的癌症治疗期间的2-3个纵向时间点获得。据我们所知，这将是 首次尝试建立乳腺癌患者来源的纵向系列癌症模型（PDMC） 接受标准临床护理的癌症患者。重要的是，这些模型将与注释的 患者治疗和结局的临床数据。将对PDMC进行功能评价，以了解其对以下问题的反应： 患者匹配疗法。目标1的重点是测试接受治疗的患者的PDMC是否 复制患者临床病理学、分子、基因组和细胞表型 样品PDMC将由患者术前和术后获得的活乳腺癌标本生成。 治疗-无论是在新辅助或转移性设置。我们将生成一组患者匹配的PDMC (PDX，PDO，PDCRC）并比较肿瘤病理学，基因表达，WGS/WES，DNA甲基化，CNV， 突变谱和患者组织与PDMC之间的细胞克隆性/异质性。目标2将 调查PDMC是否适当地模拟了患者对治疗的反应-需要进行评估， 确定它们在基础研究、药物发现以及作为最佳治疗的预测因子中的潜在应用， 正在接受治疗的患者。将在联合临床研究中评价PDMC，以检测缓解的一致性 PDMC与患者中观察到的临床应答之间的关系。我们还将评估PDO的一致性 和PDMCs对一组FDA批准的癌症疗法，基因组指导疗法，并研究 PDO和PDCRC中克隆的化学敏感性是否与其观察到的克隆频率相关 在治疗后的患者肿瘤中。我们的研究不仅将确定PDMC是否可以模拟所有功能， 乳腺癌表型，但也将确定，通过共同临床研究，他们是否可以功能， 复制患者对治疗的反应。

PROJECT ABSTRACT The goal of this proposal is to test the fidelity of three types of patient-derived breast cancer models with regard to genomic and epigenetic aberrations, clonal heterogeneity and evolution, and treatment response/resistance. We will compare PDXs, patient-derived organoids (PDOs), and patient-derived conditionally-reprogrammed cells (PDCRCs) from a total of 22 patients with breast cancer. The models will be derived from patient samples acquired at 2-3 longitudinal time points during the patients’ cancer treatments. To our knowledge, this will be the first effort to establish a triad of patient-derived models of cancer (PDMCs) in longitudinal series from breast cancer patients undergoing standard clinical care. Importantly, the models will be associated with annotated clinical data on patient treatment and outcomes. PDMCs will be functionally evaluated for their response to patient-matched therapies. Aim 1 is focused on testing whether PDMCs from patients undergoing therapy replicate clinicopathological, molecular, genomic and cellular phenotypes observed in the patients’ clinical samples. PDMCs will be generated from viable breast cancer specimens obtained prior to and following patient therapy – either in the neoadjuvant or metastatic setting. We will generate a triad of patient-matched PDMCs (PDX, PDO, PDCRC) and compare tumor pathology, gene expression, WGS/WES, DNA methylation, CNV, mutation profiles, and cellular clonality/heterogeneity between the patient tissue and PDMCs. Aim 2 will investigate whether PDMCs appropriately model patient response to therapy – an assessment that is needed to determine their potential application in basic research, drug discovery, and as predictors of optimal therapies for patients undergoing treatment. PDMCs will be evaluated in a co-clinical study to test the concordance of response between PDMCs and the clinical response observed in patients. We will also evaluate the concordance of PDOs and PDMCs against a panel of FDA-approved cancer therapies, genomic-guided therapies, and investigate whether the chemo-sensitivity of clones in PDOs and PDCRCs is associated with their observed clonal frequency in patient tumors following treatment. Our study will not only determine whether PDMCs can model the repertoire of breast cancer phenotypes, but will also determine, through a co-clinical study, whether they can functionally replicate patient response to therapies.