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BLR&D Merit Review Research Career Scientist (RCS) Award (IK6)

BLR

基本信息

批准号：
10618231
负责人：
Ann Richmond
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618231
关键词：
3-Dimensional Ablation Accounting Affect Age Age Years Aging Agonist Area Attenuated Award BRAF gene Basic Science Biological Models Biological Response Modifiers Biopsy Bortezomib Breast Cancer Patient Breast Cancer Risk Factor Breast Melanoma CD8-Positive T-Lymphocytes CDK4 gene CXCL1 gene CXCR4 gene Cancer Etiology Cancer Model Cell Death Cell Separation Cells Cessation of life Chemical Exposure Chemotaxis Clinical Clinical Trials Coculture Techniques Collaborations Combined Modality Therapy Coupled Dana-Farber Cancer Institute Data Development Disease Epidemic Estrogen receptor positive Future Gender Genetic Genetic Transcription Growth Gulf War Human IL8RB gene Immune Immune checkpoint inhibitor Immunocompetent Immunologics Immunotherapy Incidence Infiltration Inflammation Inflammation Mediators Investments Laboratories Laboratory Finding Ligands MDM2 gene Malignant Neoplasms Mediating Metastatic breast cancer Modeling Mus Mutate Myeloid Cells Myeloid-derived suppressor cells Natural Killer Cells Neoplasm Metastasis Oncogenes Oncogenic Operative Surgical Procedures Organoids PTEN gene Paclitaxel Pathway interactions Patient-derived xenograft models of breast cancer Patients Phenotype Population Productivity Progression-Free Survivals Proteins Proto-Oncogene Proteins c-akt Raf Kinase Inhibitor Recycling Regulation Research Resistance Resistance development Role Scientist Signal Pathway Stromal Cells Sun Exposure Sunbathing Survival Rate T-Cell Activation Testing Therapeutic Therapeutic Intervention Time Tissues Translational Research Tumor Cell Invasion Tumor Immunity Tumor Tissue Tumor-associated macrophages Ultraviolet Rays Veterans Wild Type Mouse Woman angiogenesis antagonist anti-CTLA4 anti-tumor immune response aurora kinase A breast cancer diagnosis cancer cell cancer diagnosis cancer type career checkpoint therapy chemokine combinatorial cytokine release syndrome design driver mutation experience humanized mouse immunogenic improved inhibitor malignant breast neoplasm melanoma men military veteran mouse model multicatalytic endopeptidase complex negative affect neoplastic cell new therapeutic target novel novel therapeutic intervention novel therapeutics older men patient derived xenograft model pembrolizumab pre-clinical precision medicine programmed cell death protein 1 programs receptor recruit resistance mechanism response senescence tanning booths targeted treatment trafficking translational study trend tumor tumor growth tumor microenvironment tumorigenesis wound healing young woman

项目摘要

Abstract: Currently, therapeutic treatment with immune checkpoint inhibitors(ICI’s), such as α-CTLA4 and/or α-PD1, are increasing survival rates (>50% four-year survival), particularly in highly mutated tumors. Moreover, combining ICIs with therapies that target tumor oncogenes has been highly effective in some tumors. Our hypothesis is that response to ICI therapy in immunologically “cold” tumors can be enhanced by combining ICIs with therapies targeted to oncogenic drivers that also induce expression of key chemokines that recruit CD8+T cells and DCs to the TME and shift tumor associated macrophages to an anti-tumor phenotype, and reduce the infiltration by myeloid-derived suppressor cells. To test this hypothesis, we will utilize immune competent mouse models, humanized mouse models bearing patient-derived xenograft (PDX), and organotypic cultures of human tumor co- cultured with patient immune cells to determine if these specific precision medicine approaches to targeted therapies enhance response to ICIs, and improve survival in mice. We propose to advance therapeutic strategies for melanoma and breast cancer in four areas. There are two approaches we will develop for melanoma studies: 1) Using immune competent BRAFV600E/PTEN-/-, NRASQ61K,R/CDKN2a-/- or triple wild type mouse models, humanized PDX models and 3D organoids of human melanoma tumors co-cultured with immune cells isolated from the patient, we will determine whether treatment with either rigosertib (NRAS pathway inhibitor), CDK4/6 inhibitor +MDM2 antagonist combined with ICI therapy induces tumor regression. Mechanisms for alterations in anti-tumor immune response will be determined. 2). Using CyTOF and sc-NGS analysis we will characterize biopsy tissue and PBLs from melanoma patients who develop resistance to immune checkpoint inhibitors, evaluate the expression of other checkpoint proteins as well as activation of new driver mutations, and use these data to develop new strategies for treatment with other checkpoint inhibitors and targeted therapies using our organoid culture model. For our breast cancer studies: 1) We will treat tumors with AKT inhibitors plus paclitaxel in combination with ICI therapies or prior to ICI treatment using immune competent mouse models, humanized PDX models, and organotypic cultures of patient tumors co-cultured with patient immune cells; 2) We will examine the tumor growth in mice with targeted deletion of CXCR2 or CXCR4 in tumor tissue or in specific immune cell populations with or without targeted therapies and immune therapy. Where appropriate, CXCR2 and/or CXCR4 antagonists may be combined with the targeted therapies to enhance response to ICI therapy. Altogether these studies will provide key information for the design of new clinical trials I melanoma and breast cancer with our clinical collaborators and inform mechanisms of resistance to ongoing therapies. Melanoma and breast cancer can be major issues for our Veterans and development of improved therapeutic contributions that enhance overall survival is of key importance.

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