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

项目摘要 这项提案的目标是测试三种类型的患者来源的乳腺癌模型在以下方面的保真度 对基因组和表观遗传异常、克隆异质性和进化以及治疗反应/耐药性的影响。 我们将比较PDX、患者来源的有机体(PDO)和患者来源的条件性重编程细胞 (PDCRCs)来自22名乳腺癌患者。这些模型将从患者样本中提取 在患者的癌症治疗过程中，在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纵向序列的三种患者来源的癌症模型(PDMC) 接受标准临床护理的癌症患者。重要的是，模型将与带注释的 关于患者治疗和结果的临床数据。将对PDMC进行功能评估，以确定其对 患者匹配的疗法。目标1的重点是测试接受治疗的患者的PDMCs 患者临床观察到的临床病理、分子、基因组和细胞表型重复 样本。PDMC将从患者之前和之后获得的有活力的乳腺癌样本中生成 治疗--无论是在新辅助治疗还是在转移环境中。我们将产生与患者匹配的三种PDMC (PDX、PDO、PDCRC)，比较肿瘤病理、基因表达、WGS/WES、DNA甲基化、CNV、 突变谱，以及患者组织和PDMCs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--这是一项需要进行的评估 确定它们在基础研究、药物发现和预测最佳治疗方法方面的潜在应用。 正在接受治疗的病人。PDMCs将在一项联合临床研究中进行评估，以测试反应的一致性 PDMCs与患者的临床反应之间的关系。我们还将评估PDO的一致性 和PDMC对抗一组FDA批准的癌症疗法，基因组指导的疗法，并调查 PDO和PDCRC中克隆的化疗敏感性是否与其观察到的克隆频率有关 在患者肿瘤治疗后。我们的研究不仅将确定PDMC是否能够模拟剧目 乳腺癌表型，但也将通过一项联合临床研究确定它们是否可以在功能上 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.