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

BLR

基本信息

批准号：
10454101
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/10454101
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 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 Cells Cessation of life Chemicals Chemotaxis Clinical Clinical Trials Collaborations Coupled Dana-Farber Cancer Institute Data Development Disease Epidemic Estrogen receptor positive Future Gender Genetic Genetic Transcription Gulf War Human IL8RB gene Immune Immune checkpoint inhibitor Immunocompetent Immunologics Immunotherapy Incidence Infiltration Inflammation Inflammation Mediators 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 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-Lymphocyte 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 Yang angiogenesis antagonist anti-CTLA4 anti-tumor immune response aurora kinase A base 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 negative affect neoplastic cell new therapeutic target novel 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 treatment strategy trend tumor tumor growth tumor microenvironment tumorigenesis wound 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.

抽象的：目前，通过免疫粘液抑制剂（ICI）（例如α-CTLA4和/或α-PD1）进行治疗治疗增加存活率（> 50％的四年生存率），特别是在高度突变的肿瘤中。而且，结合ICIS 靶向肿瘤基因的疗法在某些肿瘤中一直非常有效。我们的假设是，可以通过将ICIS结合来增强免疫学上“冷”肿瘤中对ICI治疗的反应使用针对致癌驱动因素的疗法也影响募集CD8+T细胞的关键趋化因子的表达 DC到TME并将肿瘤相关的巨噬细胞转移到抗肿瘤表型，并减少浸润由髓样衍生的抑制细胞。为了检验这一假设，我们将利用免疫能力的小鼠模型，带有患者衍生的元素（PDX）的人源化小鼠模型以及人类肿瘤共同培养用患者免疫细胞培养，以确定这些特定的精度药物是否用于靶向疗法增强对ICI的反应，并改善小鼠的生存。我们建议在四个地区推进黑色素瘤和乳腺癌的理论策略。有两个我们将开发用于黑色素瘤研究的方法：1）使用免疫胜任的BRAFV600E/PTEN - / - ， NRASQ61K，R/CDKN2A - / - 或三重野生型小鼠模型，人源化PDX模型和人类的3D器官与从患者分离的免疫细胞共培养的黑色素瘤肿瘤，我们将确定是否治疗丝带（NRAS途径抑制剂），CDK4/6抑制剂 +MDM2拮抗剂与ICI治疗的影响肿瘤回归。将确定改变抗肿瘤免疫反应的机制。 2）。使用cytof 和SC-NGS分析，我们将表征来自黑色素瘤患者的活检组织和PBL的表征要进行免疫检查点抑制剂，评估其他检查点蛋白的表达以及新的激活驾驶员突变，并使用这些数据制定新的策略，以使用其他检查点抑制剂和使用我们的器官培养模型的靶向疗法。对于我们的乳腺癌研究：1）我们将使用AKT抑制剂加上紫杉醇与ICI的肿瘤治疗肿瘤使用免疫胜任的小鼠模型，人源化PDX模型和有机的疗法或ICI治疗之前与患者免疫细胞共培养的患者肿瘤的培养； 2）我们将检查小鼠的肿瘤生长在肿瘤组织或特定免疫细胞群体中的CXCR2或CXCR4的靶向缺失，有或没有靶向疗法和免疫治疗。在适当的情况下，CXCR2和/或CXCR4拮抗剂可以与有针对性的疗法增强对ICI疗法的反应。这些研究总共将为设计新临床试验I黑色素瘤和乳腺癌的设计提供关键信息借助我们的临床合作者，并为持续疗法的抗性机制提供了信息。黑色素瘤和乳房癌症可能是我们退伍军人的主要问题，并发展了改进的治疗贡献，以增强总体生存至关重要。