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

• 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
• 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

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.

项目总结/摘要 乳腺癌是诊断在1-8妇女，是最常见的癌症类型诊断在VCU。那里 是主要基于增殖状态定义的几种遗传上不同的人类乳腺癌亚型 以及靶向受体如雌激素受体和HER 2癌基因的表达。大多数 用于乳腺癌研究的细胞系和PDX模型来自欧洲的白色患者 然而，所有祖先群体都受到乳腺癌的影响。在过去的二十年里， 根据遗传血统发现的乳腺肿瘤亚型存在明显差异，黑人 患者更频繁地被诊断为基底样三阴性乳腺癌，这是高度 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 患者有了这些模型，我们将（2）定量地确定它们的遗传祖先，然后（3）选择 从黑人患者中获得的基因基础相似的模型，以便我们可以（4）使用这些模型来 确定定殖的器官，（5）确定肿瘤的基因组和蛋白质组谱， 转移，（6）定义感兴趣的NCI-IND的疗效，重点是基于赛林克斯的药物组合， 从PDX获得的细胞，和（7）鉴定在PDX中有效的新的治疗药物组合。 转移性疾病在这些研究的结论，我们可能已经确定了一个新的有效的两种药物， 对于已经用尽当前标准治疗的基础治疗样患者可能有用的方法 转移性乳腺癌的治疗方法。