In vitro models as a window to learn how to change outcomes in women at high risk of developing breast cancer

体外模型作为了解如何改变乳腺癌高危女性结局的窗口

• 批准号: 10691569
• 负责人: Jennifer M. Rosenbluth
• 金额: $ 44.28万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10691569
• 关键词: Age; Age Distribution; Antiestrogen Therapy; Atypia; BRCA1 gene; BRCA2 Mutation; BRCA2 gene; Back; Benefits and Risks; Biological; Biopsy; Breast; Breast Cancer Prevention; Breast Cancer Prevention Trial; Breast Cancer Risk Factor; Breast Epithelial Cells; Cancer Biology; Cancer Model; Cell Lineage; Cells; Cellular biology; Characteristics; Clinic; Clinical; Coculture Techniques; Complex; Core Biopsy; Cytometry; Data; Development; Disease; Environment; Estrogen receptor positive; Excision; Family; Future; High Risk Woman; Histologic; Human; Image; Immunofluorescence Immunologic; Immunologic Surveillance; Immunological Models; Individual; Inherited; Intercept; International; Intervention; Lead; Learning; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Mammary Gland Parenchyma; Mammographic Density; Measures; Medical Oncologist; Methods; Modeling; Molecular; Mutation; New Agents; Noninfiltrating Intraductal Carcinoma; Normal Cell; Operative Surgical Procedures; Organoids; Outcome; Pathway interactions; Patients; Phenotype; Precancerous Conditions; Premalignant Cell; Prevention strategy; Recording of previous events; Research; Research Personnel; Risk; Sampling; Suggestion; Susceptibility Gene; System; T-Cell Development; Techniques; Testing; Texture; Tissues; Translations; Woman; aggressive breast cancer; anticancer research; base; biobank; cancer genetics; cancer invasiveness; cancer prevention; cell type; experience; high risk; high risk population; hormone therapy; imaging biomarker; improved; in vitro Model; insight; malignant breast neoplasm; mammary; mammary epithelium; novel; patient screening; precision medicine; precursor cell; premalignant; prevent; preventive intervention; racial diversity; radiological imaging; response; single cell analysis; single-cell RNA sequencing; stem cells; stressor; surveillance study; three dimensional cell culture; triple-negative invasive breast carcinoma; tumor; young woman

PROJECT 3 SUMMARY/ABSTRACT Breast cancer is a heterogeneous disease, with different subtypes likely arising from distinct precursor cells in the normal breast. What remains unknown is how we can target distinct precancerous cell types to prevent or intercept breast cancers in high-risk populations in a personalized manner. We previously combined detailed single-cell analyses of histologically normal breast tissues from patients with inherited mutations in BRCA1 and BRCA2 to identify aberrant cell types enriched in these cancer-prone tissues. This proposal seeks to develop models to identify new targets for breast cancer prevention in diverse high-risk states, and to help determine who would benefit from these interventions. This will be performed by combining advances in organoid culturing with single-cell RNA sequencing, mass cytometry, and multiplexed immunofluorescence studies. First, organoids will be generated from the breast tissue of patients at increased risk of developing breast cancer based on the presence of imaging-based markers, focusing on background parenchymal enhancement (BPE) on MRI as an indicator of global risk of developing invasive cancer. Tissue-based and organoid-based techniques will be used to determine the cell types enriched and pathways deregulated in this disease state. Second, the tissue environment of women with DCIS in the setting of BPE who demonstrate response and nonresponse to endocrine therapies (in Project 4) will be evaluated. Third, high-risk states including young women who developed triple-negative breast cancer before the age of 40 will be evaluated for potential cancer prevention targets and deregulated pathways at the tissue level, including by the development of T cell-organoid co-culture systems to model immune surveillance. Finally, candidate prevention/ intervention strategies will be assessed in patient-derived organoid models of high-risk tissues to identify potential compounds for a future adaptive platform trial for breast cancer prevention (Project 4 aim 4). The project lead, Dr. Rosenbluth, is a breast medical oncologist with a research background in cell and cancer biology and with expertise in 3D culture models of cancer prevention. An expert team has been assembled for this project including Dr. Laura Esserman, an internationally recognized expert in breast cancer research, Dr. Laura van 't Veer, world renowned molecular biologist and inventor of MammaPrint, and Dr. Funmi Olopade, a leader in clinical cancer genetics and breast cancer prevention, as well as additional collaborators and experts in aspects of breast cancer research and in adaptive platform trials.

项目 3 摘要/摘要 乳腺癌是一种异质性疾病，不同的亚型可能源自正常乳房中不同的前体细胞。目前尚不清楚的是，我们如何针对不同的癌前细胞类型，以个性化的方式预防或拦截高危人群的乳腺癌。我们之前对 BRCA1 和 BRCA2 遗传突变患者的组织学正常乳腺组织进行了详细的单细胞分析，以确定这些易患癌症的组织中富含的异常细胞类型。该提案旨在开发模型来确定不同高风险州乳腺癌预防的新目标，并帮助确定谁将从这些干预措施中受益。这将通过将类器官培养方面的进展与单细胞 RNA 测序、质谱流式分析和多重免疫荧光研究相结合来实现。首先，基于成像标记物的存在，将从罹患乳腺癌风险增加的患者的乳腺组织中生成类器官，重点关注 MRI 上的背景实质增强 (BPE)，作为罹患侵袭性癌症的整体风险指标。基于组织和类器官的技术将用于确定在这种疾病状态下富集的细胞类型和失调的途径。其次，将评估患有 BPE 的 DCIS 女性对内分泌治疗有反应和无反应的组织环境（在项目 4 中）。第三，将评估高风险国家，包括 40 岁之前患上三阴性乳腺癌的年轻女性，以寻找潜在的癌症预防目标，并在组织水平上放松管制途径，包括开发 T 细胞-类器官共培养系统建立免疫监视模型。最后，将在源自患者的高风险组织类器官模型中评估候选预防/干预策略，以确定未来乳腺癌预防适应性平台试验的潜在化合物（项目 4 目标 4）。该项目负责人 Rosenbluth 博士是一位乳腺肿瘤医学专家，拥有细胞和癌症生物学研究背景，并拥有癌症预防 3D 培养模型方面的专业知识。该项目组建了一个专家团队，包括国际公认的乳腺癌研究专家Laura Esserman博士、世界著名分子生物学家、MammaPrint发明者Laura van 't Veer博士，以及乳腺癌领域领军人物Funmi Olopade博士。临床癌症遗传学和乳腺癌预防，以及乳腺癌研究和适应性平台试验方面的其他合作者和专家。