DELINEATING THE EVOLUTION AND ECOLOGY OF CHEMORESISTANCE IN BREAST CANCER WITH SINGLE CELL GENOMICS

用单细胞基因组学描绘乳腺癌化疗耐药性的进化和生态学

• 批准号: 10310413
• 负责人: Nicholas Navin
• 金额: $ 36.32万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310413
• 关键词: Address; Aftercare; Biopsy; Breast Cancer Patient; Breast Cancer Treatment; CRISPR/Cas technology; Cell Line; Cells; Cessation of life; Chemoresistance; Clinic; Clinical; DNA; DNA sequencing; Data; Data Set; Diagnosis; Disease; Disease Resistance; Distant; Ecology; Evolution; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genomics; Genotype; Goals; Grant; Heterogeneity; Hormonal; Human; In Vitro; Inherited; Knowledge; Left; Metastatic to; Methods; Mission; Modeling; Morbidity - disease rate; Mutation; Neoadjuvant Therapy; Neoplasm Metastasis; Organ; Outcome; Patient Care; Patients; Phenotype; Primary Neoplasm; Quality of life; RNA; Refractory Disease; Resistance; Resistance development; Role; Sampling; Seeds; Signal Pathway; Site; Stromal Cells; Technology; The Cancer Genome Atlas; Therapeutic; Time; Tissue Sample; Translating; United States National Institutes of Health; base; cell type; chemotherapy; clinical application; cohort; diagnostic biomarker; diagnostic technologies; genetic signature; improved; knock-down; malignant breast neoplasm; neoplastic cell; new therapeutic target; novel diagnostics; overexpression; programs; receptor; response; single cell sequencing; single cell technology; single-cell RNA sequencing; targeted biomarker; targeted treatment; therapeutic target; transcriptional reprogramming; transcriptome sequencing; transcriptomics; treatment response; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

PROJECT SUMMARY Triple-negative breast cancer (TNBC) is an aggressive subtype in which patients display extensive intratumor genomic heterogeneity and frequently (50%) develop resistance to neoadjuvant chemotherapy (NAC) which leads to metastatic disease and death. Due to the absence of hormonal receptors and targeted therapies, TNBC patients with refractory disease are often left with limited treatment options. Currently, our understanding of the genomic evolution of tumor cells and the role of the tumor microenvironment in chemoresistant disease at primary and metastatic organ sites represents a major gap in knowledge that this proposal aims to address. Our group has developed cutting-edge single cell DNA and RNA sequencing technologies that can overcome previous technical barriers and limitations with `bulk' genomic methods for studying the genomic and phenotypic evolution of tumor cells in response to chemotherapy. Our preliminary data in a small number of TNBC patients suggests that genomic evolution of chemoresistance occurs through the adaptive selection of pre-existing mutations and copy number alterations, which is followed by transcriptional reprogramming, to achieve a chemoresistant phenotype (Kim et al. 2018, Cell). We further hypothesize that transcriptional reprogramming of cell types in the tumor microenvironment occurs in chemoresistant disease and that resistance programs are clonally inherited at distant metastatic organ sites. To comprehensively investigate these questions in matched longitudinal samples from TNBC patients in a large neoadjuvant chemotherapy trial (ARTEMIS), we propose three synergistic aims: Aim 1 will determine if copy number aberrations (CNAs) and subclonal mutations associated with chemoresistance are pre-existing and adaptively selected in response to therapy. Aim 2 will investigate if tumor cells and cell types in the microenvironment undergo transcriptional reprogramming in refractory disease. Aim 3 will determine if subpopulations of resistant cells in the primary tumor seed the metastatic lesions and confer resistance programs at distant organ sites. Completion of these aims will define the genomic and evolutionary basis of chemoresistance in TNBC patients and will provide new diagnostic biomarkers and therapeutic targets for overcoming chemoresistant disease, which is a critical unmet clinical need. Our long-term goal is to translate single cell sequencing technologies into the clinic, where they are poised to have a major impact on the diagnosis and treatment of breast cancer patients. The proposed aims are directly aligned with the mission of NIH to reduce morbidity and improve the quality of life for breast cancer patients.

项目总结