TARGETING HISTONE DEMETHYLASE KDM5B IN BREAST CANCER

靶向组蛋白去甲基酶 KDM5B 治疗乳腺癌

• 批准号: 10398903
• 负责人: Qin Yan
• 金额: $ 37.55万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398903
• 关键词: Adaptive Immune System; Antibodies; Binding; Breast Cancer Model; Breast Cancer Patient; Breast Cancer cell line; CD4 Positive T Lymphocytes; CD8B1 gene; CTLA4 blockade; CTLA4 gene; CXCL9 gene; Cancer Etiology; Cells; Cessation of life; Chemotactic Factors; Clinic; Clinical Trials; Data; Development; Diagnosis; Disease; Dissection; Down-Regulation; Drug Targeting; Enzymes; Epigenetic Process; Flow Cytometry; Goals; Human; Immune; Immune checkpoint inhibitor; Immune system; Immunocompetent; Immunodeficient Mouse; Immunofluorescence Immunologic; Immunologics; Immunotherapy; KDM5B gene; Knock-out; Knowledge; Malignant Neoplasms; Mammary Neoplasms; Mission; Modeling; Mouse Mammary Tumor Virus; Mus; Outcome; PD-1/PD-L1; Patients; Phenotype; Play; Population; Public Health; Research; Role; STAT1 gene; STAT2 gene; T cell regulation; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Translating; Treatment Factor; Tumor Immunity; Tumor Suppression; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; United States; United States National Institutes of Health; Validation; Woman; anti-tumor immune response; base; cancer clinical trial; cancer initiation; cancer therapy; checkpoint inhibition; chemokine; chromatin immunoprecipitation; cohort; deep sequencing; experimental study; fighting; histone demethylase; immune checkpoint blockade; inhibitor; innovation; knock-down; malignant breast neoplasm; migration; neoplastic cell; neutralizing antibody; novel; overexpression; pre-clinical; recruit; small molecule inhibitor; therapeutic target; tumor; tumor growth; tumor progression

PROJECT SUMMARY In the United States, breast cancer is the most common cancer and the second leading cause of cancer death in women. Immune checkpoint inhibitors have shown remarkable efficacy on multiple cancers. However, only a small subset of breast cancer patients have benefited from these treatments. Lack of T-cell infiltration into the tumors is a key limiting factor for these treatments. KDM5B histone demethylase, commonly overexpressed and amplified in breast cancer, represents an attractive target to boost T-cell infiltration and enable more breast cancer patients to benefit from treatments with immune checkpoint inhibitors. The long-term goal is to translate our findings of novel mechanisms of cancer initiation and progression to the clinic. The objectives of this project are to dissect the mechanisms by which KDM5B represses antitumor immunity and to evaluate the therapeutic potential of targeting KDM5B in breast cancer. Our central hypotheses are that KDM5B promotes tumor growth by repressing CXCL9, a critical T-cell chemokine, and that KDM5B inhibition converts immunologically “cold” tumors into “hot” tumors, which are more likely to be eliminated by the immune system and to respond to immune checkpoint blockade. These hypotheses are based mainly on our own preliminary data from breast cancer cell lines and preclinical breast cancer models. The rationale of this project is that further dissection of KDM5B regulation of T-cell infiltration and validation of KDM5B histone demethylase as a therapeutic target are needed to translate these findings to the clinic. To test these hypotheses and attain the overall objectives, the following two specific aims will be pursued: 1) To determine and validate the mechanisms by which KDM5B suppresses antitumor immunity, and 2) To evaluate the therapeutic effects of KDM5B inhibition. The proposed research is conceptually and translationally innovative, because it aims to determine how KDM5B represses antitumor immunity and whether KDM5B inhibition converts breast tumors from an immunologically “cold” into “hot” state. The results from these studies could revolutionize the treatment for patients with breast cancer and could be broadly applicable to other cancers. The proposed research is significant, because it is expected to vertically advance and expand our understanding of immunotherapy. Such knowledge is critical for the development of new cancer therapies that can boost the human immune system to fight cancer.

项目摘要 在美国，乳腺癌是最常见的癌症，也是癌症死亡的第二大原因 在女人身上。免疫检查点抑制剂对多种癌症显示出显著的疗效。但只有 一小部分乳腺癌患者从这些治疗中获益。缺乏T细胞浸润 肿瘤是这些治疗的关键限制因素。KDM 5B组蛋白脱甲基酶，通常过表达 并在乳腺癌中扩增，代表了一个有吸引力的目标，以促进T细胞浸润，并使更多的 乳腺癌患者受益于免疫检查点抑制剂的治疗。长期目标是 将我们对癌症发生和发展的新机制的发现转化为临床。的目标 本项目旨在分析KDM5B抑制抗肿瘤免疫的机制，并评估KDM5B抑制抗肿瘤免疫的机制。 靶向KDM5B治疗乳腺癌的潜力。我们的中心假设是，KDM5B促进 通过抑制CXCL9（一种关键的T细胞趋化因子）和KDM5B抑制转化肿瘤生长 免疫学上的“冷”肿瘤变成“热”肿瘤，更容易被免疫系统消除。 并对免疫检查点封锁做出反应。这些假设主要基于我们自己的初步研究。 来自乳腺癌细胞系和临床前乳腺癌模型的数据。该项目的基本原理是， 进一步研究KDM5B对T细胞浸润的调节作用，并验证KDM5B组蛋白去甲基化酶作为一种免疫调节剂。 治疗靶点需要将这些发现转化为临床。为了验证这些假设， 总体目标，将追求以下两个具体目标：1）确定和验证 KDM5B抑制抗肿瘤免疫的机制，以及2）评估KDM5B的治疗作用。 KDM5B抑制作用。这项研究在概念和实践上都是创新的，因为 其目的是确定KDM5B如何抑制抗肿瘤免疫，以及KDM5B抑制是否会将乳腺癌转化为乳腺癌。 肿瘤从免疫学上的“冷”状态转变为“热”状态。这些研究的结果可能会彻底改变 这是一种治疗乳腺癌患者的新方法，并可广泛适用于其他癌症。拟议 研究是重要的，因为它有望纵向推进和扩大我们对 免疫疗法这些知识对于开发新的癌症疗法至关重要，这些疗法可以促进癌症的治疗。 人体免疫系统对抗癌症。