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

用于研究治疗反应和耐药机制的乳腺癌纵向模型

基本信息

批准号：
10228719
负责人：
Gabor T Marth
金额：
$ 81.29万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-06 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10228719
关键词：
Aftercare Basic Science Breast Cancer Model Breast Cancer Patient Cancer Model Cancer Patient Cancer cell line Cell model Cells Clinical Clinical Data Clinical Research Clonal Evolution Clonality DNA Methylation DNA copy number Disease Drug Modelings Drug resistance Epigenetic Process Evolution Exhibits Exposure to FDA approved Frequencies Gene Expression Genomics Goals Heterogeneity Histopathology Investigation Lead Mammary Neoplasms Measures Metastatic breast cancer Methods Modeling Molecular Mutation Neoadjuvant Therapy Organoids Outcome Study Patient Care Patients Pharmaceutical Preparations Phenotype Physiological Population Process Research Resistance Sampling Series Specimen Testing Therapeutic Time Tissues Treatment outcome Triad Acrylic Resin Tumor Biology Tumor Pathology cancer therapy clinical care clinical practice clinical translation drug discovery drug sensitivity effective therapy experience high risk individual patient innovation malignant breast neoplasm optimal treatments patient derived xenograft model patient response personalized medicine primary outcome programs response treatment response tumor

项目摘要

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.

项目摘要该提案的目标是测试三种患者来源的乳腺癌模型在以下方面的保真度：基因组和表观遗传畸变、克隆异质性和进化以及治疗反应/耐药性。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。这些模型将源自患者样本。据我们所知，这将是在患者癌症治疗期间的 2-3 个纵向时间点获得的。首次尝试从乳腺癌中纵向系列建立三组患者来源的癌症模型 (PDMC) 重要的是，这些模型将与带注释的癌症患者相关联。有关患者治疗和结果的临床数据将对其反应进行功能评估。目标 1 的重点是测试是否来自接受治疗的患者的 PDMC。复制在患者临床中观察到的临床病理学、分子、基因组和细胞表型样本将从患者治疗前和治疗后获得的活乳腺癌样本中产生。治疗 – 无论是在新辅助治疗还是转移性治疗中，我们将生成与患者匹配的 PDMC 的三联体。（PDX、PDO、PDCRC）并比较肿瘤病理学、基因表达、WGS/WES、DNA 甲基化、CNV、目标 2 将检测患者组织和 PDMC 之间的突变谱以及细胞克隆性/异质性。调查 PDMC 是否适当地模拟患者对治疗的反应 – 需要进行一项评估确定它们在基础研究、药物发现中的潜在应用，并作为最佳治疗的预测因子接受治疗的患者将在联合临床研究中进行评估，以测试反应的一致性。我们还将评估 PDO 的一致性。和 PDMC 针对 FDA 批准的一组癌症疗法、基因组引导疗法，并进行调查 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，但也将通过联合临床研究确定它们是否可以发挥功能复制患者对治疗的反应。