Research Project 2 Proteogenomic-guided therapeutic targeting of breast cancer patient-derived xenograft metastases

研究项目 2 蛋白质基因组引导的乳腺癌患者异种移植转移的治疗靶向

基本信息

批准号：
10733315
负责人：
Joshua (Chuck) Harrell
金额：
$ 28.58万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-19 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733315
关键词：
Affect Bioinformatics Brain Breast Cancer Patient Cell Line Cells Chemoresistance Clinical Trials Collection Coupling Cytotoxic agent DNA Data Data Set Development Diagnosis Disease Disparity Drug Combinations Drug Compounding Drug Targeting ERBB2 gene Endocrine Environment Estrogen Receptors European ancestry Excision Exhibits Fostering Future Genetic Genomics Goals Growth Hi-C Human In Vitro Injections Investigational Drugs Lentivirus Liver Luciferases Lung Malignant Neoplasms Mammary Neoplasms Mass Spectrum Analysis Metastatic breast cancer Modeling Neoplasm Metastasis Nuclear Export Oncogenes Organ Organoids Patient-Focused Outcomes Patient-derived xenograft models of breast cancer Patients Persons Pharmaceutical Preparations Physiology Pilot Projects Property Proteomics Research Personnel Research Project Grants Resistance Resistance development Sampling Suspensions Testing Therapeutic Woman anticancer research antitumor agent black patient bone cancer cell cancer diagnosis cancer type chemotherapy chromosome conformation capture clinically actionable cytotoxic cytotoxicity data integration drug candidate efficacy evaluation exhaust exome sequencing experience experimental study genome sequencing health equity hormone therapy in vivo inhibitor insight interest malignant breast neoplasm novel therapeutics patient derived xenograft model phosphoproteomics preclinical study programs prospective proteogenomics receptor response single-cell RNA sequencing standard of care therapeutic evaluation therapeutic target therapy outcome transcriptome sequencing transcriptomics triple-negative invasive breast carcinoma tumor tumor growth whole genome

项目摘要

Project Summary/Abstract Breast cancer is diagnosed in 1-of-8 women and is the most common type of cancer diagnosed at VCU. There are several genetically distinct subtypes of human breast cancers defined largely based on proliferative status and expression of targetable receptors such as estrogen receptors and the HER2 oncogene. The majority of the cell lines and PDX models used for breast cancer research arise from White patients of European Ancestry, however, all ancestral groups are affected by breast cancers. Over the past twenty years, there has been a clear disparity identified in the subtype of breast tumors found based on genetic ancestry, with Black patients being diagnosed more frequently with Basal-like Triple-Negative Breast Cancers, which are highly metastatic. Therefore, in these studies, we are (1) focused on developing PDX models from breast cancer patients. With these models we will (2) quantitatively determine their genetic ancestry and then (3) select models that are genetically Basal-like and obtained from Black patients so that we can (4) use these models to determine the organs that the colonize, (5) determine the genomic and proteomic profile of the tumors and metastases, (6) define efficacy of NCI-INDs of interest, with a focus on selinexor based drug combinations on cells obtained from the PDXs, and (7) identifying new therapeutic drug combinations that are effective in the metastatic setting. At the conclusion of these studies, we may have identified a new effective two-drug approach that could be useful for Basal-like patients that have exhausted the current standard-of-care approaches for treatment of metastatic breast cancer.

项目概要/摘要八分之一的女性被诊断出乳腺癌，是弗吉尼亚联邦大学 (VCU) 诊断出的最常见的癌症类型。那里人类乳腺癌的几种遗传上不同的亚型主要根据增殖状态来定义以及雌激素受体和 HER2 癌基因等靶向受体的表达。大多数用于乳腺癌研究的细胞系和 PDX 模型来自欧洲白人患者然而，从血统来看，所有的祖先群体都受到乳腺癌的影响。过去二十年来，有根据遗传血统发现的乳腺肿瘤亚型存在明显差异，其中黑人患者更频繁地被诊断出患有基底样三阴性乳腺癌，这种乳腺癌的发病率很高转移性的。因此，在这些研究中，我们 (1) 专注于开发乳腺癌 PDX 模型患者。通过这些模型，我们将 (2) 定量确定它们的遗传祖先，然后 (3) 选择遗传上类似于 Basal 并从黑人患者获得的模型，以便我们可以 (4) 使用这些模型确定定植的器官，(5) 确定肿瘤的基因组和蛋白质组谱，以及转移，(6) 定义感兴趣的 NCI-IND 的功效，重点是基于 selinexor 的药物组合从 PDX 中获得的细胞，以及 (7) 鉴定有效的新治疗药物组合转移设置。在这些研究的结论中，我们可能已经确定了一种新的有效的两种药物这种方法可能对已经用尽当前标准护理的 Basal 样患者有用治疗转移性乳腺癌的方法。