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

• 批准号: 10457293
• 负责人: Gabor T Marth
• 金额: $ 80.63万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-06 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457293
• 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

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 该提案的目的是测试三种类型的患者来源的乳腺癌模型的保真度 对于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，患者衍生的器官（PDOS）和患者衍生的有条件编程的细胞 （PDCRC）来自总共22例乳腺癌患者。这些模型将源自患者样品 在患者的癌症治疗期间以2-3个纵向时间点获得。据我们所知，这将是 在纵向系列中建立患者衍生的癌症模型（PDMC）的第一个努力 接受标准临床护理的癌症患者。重要的是，模型将与注释 有关患者治疗和结果的临床数据。 PDMC将在功能上评估其对 患者匹配的疗法。 AIM 1专注于测试是否正在接受治疗的患者的PDMC 在患者的临床中观察到复制临床病理，分子，基因组和细胞表型 样品。 PDMC将是由在患者之前和之后获得的可行乳腺癌标本产生的 治疗 - 在新辅助或转移性环境中。我们将生成一定的患者匹配的PDMC （PDX，PDO，PDCRC）并比较肿瘤病理​​学，基因表达，WGS/WES，DNA甲基化，CNV， 患者组织和PDMC之间的突变谱以及细胞克隆性/异质性。 AIM 2意志 调查PDMC是否适当地对患者对治疗的反应进行适当模拟 - 需要评估 确定它们在基础研究，药物发现中的潜在应用，并作为最佳疗法的预测因素 接受治疗的患者。 PDMC将在一项共同研究中评估以测试响应的一致性 在PDMC和患者中观察到的临床反应之间。我们还将评估PDO的一致性 针对FDA批准的癌症疗法，基因组引导疗法和研究的PDMC和PDMC PDOS和PDCRC中克隆的化学敏感性是否与观察到的Cloneal频率有关 在治疗后的患者肿瘤中。我们的研究不仅将确定PDMC是否可以建模曲目 乳腺癌表型的，但也将通过共同链接研究来确定它们是否可以在功能上 复制患者对疗法的反应。

项目成果

Multiparametric quantitative phase imaging for real-time, single cell, drug screening in breast cancer.

• DOI: 10.1038/s42003-022-03759-1
• 发表时间: 2022-08-08
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Polanco, Edward R.;Moustafa, Tarek E.;Butterfield, Andrew;Scherer, Sandra D.;Cortes-Sanchez, Emilio;Bodily, Tyler;Spike, Benjamin T.;Welm, Bryan E.;Bernard, Philip S.;Zangle, Thomas A.
• 通讯作者: Zangle, Thomas A.