TARGETING HISTONE DEMETHYLASE KDM5B IN BREAST CANCER

项目总结 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。免疫检查点抑制剂已显示出对多种癌症的显著疗效。然而，只有一个 一小部分乳腺癌患者从这些治疗中受益。缺乏T细胞对周围组织的渗透 肿瘤是这些治疗的关键限制因素。KDM5B组蛋白去甲基酶，通常过度表达 并在乳腺癌中扩增，代表了一个有吸引力的靶点，以促进T细胞的渗透并使更多 乳腺癌患者将受益于免疫检查点抑制剂的治疗。长期目标是 将我们关于癌症发生和发展的新机制的发现转化为临床。的目标 本项目旨在剖析KDM5B抑制抗肿瘤免疫的机制，并评价KDM5B的抗肿瘤免疫作用。 靶向KDM5B对乳腺癌的治疗潜力。我们的中心假设是KDM5B促进 抑制关键T细胞趋化因子CXCL9的肿瘤生长及KDM5B的抑制作用 免疫“冷”瘤转变为“热”瘤，更有可能被免疫系统清除 并对免疫检查站封锁做出反应。这些假设主要是基于我们自己的初步假设 来自乳腺癌细胞系和临床前乳腺癌模型的数据。这个项目的基本原理是 进一步剖析KDM5B对T细胞浸润的调控及KDM5B组蛋白去甲基酶作为一种 需要治疗靶点才能将这些发现转化为临床。为了检验这些假设并实现 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；2)疗效评价 KDM5B的抑制作用。拟议的研究在概念和翻译上都是创新的，因为 它的目的是确定KDM5B是如何抑制抗肿瘤免疫的，以及KDM5B的抑制是否会改变乳房 肿瘤从免疫“冷”状态进入“热”状态。这些研究的结果可能会彻底改变 该方案适用于乳腺癌患者的治疗，并可广泛适用于其他癌症。建议数 研究意义重大，因为它有望垂直推进和扩大我们对 免疫疗法。这些知识对于开发新的癌症疗法至关重要，这种疗法可以促进 人体免疫系统与癌症抗争。

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.