The Cellular Geography of Therapeutic Resistance in Cancer

癌症治疗耐药的细胞地理学

• 批准号: 9791162
• 负责人: BRUCE E. JOHNSON
• 金额: $ 252.48万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9791162
• 关键词: Address; Affect; Algorithms; Atlases; Automobile Driving; Biological Assay; Biological Markers; Biopsy; Boston; Breast Melanoma; CDK4 gene; Cancer Center; Cell Line; Cells; Clinic; Clinical; Clinical Data; Coculture Techniques; Cohort Analysis; Collection; Colon Carcinoma; Complex; Computational Biology; Data; Data Science; Ecosystem; Excision; Experimental Designs; Genomics; Geography; Histologic; Human; Immune; Immunology; Immunotherapy; Institution; Large Intestine Carcinoma; Lead; Leadership; Malignant - descriptor; Malignant Neoplasms; Maps; Measures; Metastatic Melanoma; Microsatellite Repeats; Modality; Non-Malignant; Organoids; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Proteins; RNA; Research; Research Design; Resistance; Resolution; Risk; Sampling; Testing; Tissues; Treatment Efficacy; Treatment outcome; Validation; anticancer research; base; cancer therapy; cell community; cell type; experience; experimental study; genomic data; immune checkpoint blockade; improved outcome; innovation; malignant breast neoplasm; member; neoplastic cell; next generation; novel; patient stratification; precision oncology; predictive marker; predictive modeling; prospective; response; single-cell RNA sequencing; spatial integration; therapeutic target; therapy resistant; treatment response; treatment strategy; tumor; tumor progression

Most patients who die from cancer do so because their cancer is resistant to available therapies, either intrinsically, or as it evolves in response to treatment. However, the fundamental mechanisms driving resistance remain largely unknown. Tumors are comprised of a complex multicellular ecosystem of malignant and non- malignant cells, and changes in their composition, states, spatial organization and interactions are central to therapeutic resistance. Thus, there is an enormous need to chart an atlas of a tumor's cells, their spatial organization and interactions as those change dynamically in resistance to therapy. Technological breakthroughs in spatial and single-cell genomics, including many innovations by our team, now put an atlas within reach, but harnessing this remarkable opportunity, requires collection of multiple spatial and single cell genomics data in clinical samples; novel study design strategies; new experimental and computational strategies to integrate across cellular and spatial data; algorithms to construct tumor atlases that capture the resistant state; and showing how to use an atlas to formulate and test new predictive models of resistance. The Boston Human Tumor Atlas Network Research Center (HTA-RC) will address each of these challenges by creating three comprehensive atlases of the cellular geography of human cancer to understand how changes in the tumor ecosystem lead to therapeutic resistance in: (1) Primary and acquired resistance to CDK4/6 inhibition in breast cancer; (2) Primary and acquired resistance to immune checkpoint blockade in metastatic melanoma; and (3) Primary resistance to immunotherapy in microsatellite stable (MSS) colorectal carcinoma (CRC) compared with microsatellite instable (MSI) CRC. All three tumors types tackle an unmet clinical need; have an approximately equal rate of resistance and response to allow comparisons between states; and harness significant clinical experience and build on substantial preliminary results at our center. To construct the atlases, we will collect at least 100 biospecimens per year from resections and biopsies of the three tumor types and analyze them with histopathological data, high-resolution spatial multiplex RNA and protein data, single- cell genomics data, and temporal clinical data. Our algorithms will recover key features of each data modality, and integrate them into a single atlas to determine what predicts and underlies resistance. We build on a well-established interdisciplinary team in two major cancer centers (DFCI, MGH) and four research institutions (Broad, Harvard, Stanford, Princeton). Our leadership (Haining, Regev) and Units comprise of foremost experts and pioneers in clinical genomics (Biospecimens; Johnson, Wagle), spatial and single cell genomics (Shalek, Rozenblatt-Rosen, Nolan, Zhuang), and computational biology and data science (Regev, Van Allen, Engelhardt). Our atlases will allow identification of predictive biomarkers of resistance in the tumor ecosystem, and therapeutic target discovery, targeting diverse facets of the complex tumor ecosystem.

大多数死于癌症的病人是因为他们的癌症对现有的治疗方法有抗药性