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PROTAC Targeting of Tip60 in Syngeneic Cancer Models Using Cereblon Knock-in Mice

使用 Cereblon 敲入小鼠的同基因癌症模型中的 PROTAC 靶向 Tip60

基本信息

批准号：
10163146
负责人：
Wayne William Hancock
金额：
$ 39.91万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
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：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10163146
关键词：
Acetyltransferase Affect Amino Acids Androgen Receptor Apoptosis Autoimmunity Binding Birth C57BL/6 Mouse Cancer Model Cause of Death Cell Survival Cells Cessation of life Chemotherapy and/or radiation Cisplatin Clinical Trials Complex DNA Binding DNA Damage DNA Repair Data Development Dimerization Enzymes Event FOXP3 gene Genes Genomic Instability Growth HTATIP gene Histones Human Immune Immunity Immunocompetent Immunodeficient Mouse Immunotherapy Impairment In Vitro Individual Investigation Ionizing radiation Knock-in Knock-in Mouse Lead Lung Neoplasms Lysine Malignant Neoplasms Malignant neoplasm of lung Modeling Molecular Mus Organ Patients Population Protac Proteins Proteolysis Radiation Radiation therapy Regulatory T-Lymphocyte Resistance Role T cell response T-Lymphocyte TP53 gene Testing Therapeutic Treatment Efficacy Tumor Escape Vaccination Work Xenograft procedure anti-tumor immune response antitumor effect base cancer cell cancer initiation cancer type castration resistant prostate cancer checkpoint therapy chemotherapy clinical development conventional therapy effector T cell immune checkpoint blockade immunoregulation in vivo inhibitor/antagonist irradiation lung cancer cell mouse model neoplastic cell novel therapeutics phase 1 study preservation prevent protein degradation recruit response screening therapeutic target tool tumor tumor growth tumor microenvironment ubiquitin ligase ubiquitin-protein ligase

项目摘要

Project Summary We will investigate whether therapeutic targeting of Tip60, a histone/protein acetyltransferase essential for the functions and survival of Foxp3+ T-regulatory (Treg) can significantly decrease Treg functions in vivo while preserving conventional T cell responses, leading to inhibition of lung tumor growth in murine models. We will also assess the effects of Tip60 targeting on the DNA damage response within tumors induced by conventional therapies for lung cancer, including irradiation and cisplatin therapy. We have developed Tip60 PROTAC (proteolysis targeting chimeric) molecules that recruit the Cereblon E3 ligase so as to promote Tip60 degradation, and we employ Cereblon knock-in (CrbnI391V) immunocompetent C57BL/6 mice in compound screening and tumor models to facilitate identification of compounds for subsequent clinical development. Aim 1 - Can Tip60i limit growth of tumors in immunocompetent hosts by decreasing Foxp3+ Treg suppressive function? We have developed several Tip60i, including Crbn- and VHL-based PROTAC compounds. We will test if Tip60i PROTAC compounds can modulate Treg function and control growth of experimental lung cancers by (1.1) optimizing Tip60i PROTAC compounds, and testing them (1.2) alone, or in conjunction with (1.3) vaccination or (1.4) checkpoint inhibitor therapy in CrbnI391V mice. We will also assess effects of Tip60i on 1.5) normal human Treg and/or Teff cells, and 1.6) human lung cancer associated Treg cells. Aim 2 – Determine if Tip60i disrupts DDR actions essential for tumor cell survival. Our molecular investigations will explore Tip60-dependent mechanisms that promote cellular resistance to genome instability and normal programmed mechanisms of death, and which underpin cancer initiation and chemotherapeutic resistance crucial for lung cancer cell survival. We will test if Tip60i compounds have direct anti-tumor effects by disrupting 2.1) Tip60-dependent p53 activation and/or 2.2) DNA repair mechanisms. Our studies will facilitate the development of new strategies for immunotherapy in patients with malignancies, given that the new Tip60-directed therapies have dual mechanisms of action, involving targeting Foxp3+ Treg cells and intrinsic tumor cell responses to therapy. The data to be generated will likely lead to clinical trials in patients with lung cancers, and should also have relevance to additional individuals, given the increasingly recognized potential for immunotherapy in the management of many other types of cancers.

项目概要我们将研究 Tip60（一种组蛋白/蛋白质乙酰转移酶）的治疗靶向是否对于 Foxp3+ T 调节性 (Treg) 的功能和存活可显着降低体内 Treg 功能，同时保留传统的 T 细胞反应，从而抑制小鼠模型中的肺肿瘤生长。我们将还评估了 Tip60 靶向对传统疗法诱导的肿瘤内 DNA 损伤反应的影响肺癌的治疗，包括放射治疗和顺铂治疗。我们开发了Tip60 PROTAC （针对嵌合体的蛋白水解）分子招募 Cereblon E3 连接酶以促进 Tip60 降解，并且我们在化合物中使用 Cereblon 敲入 (CrbnI391V) 免疫活性 C57BL/6 小鼠筛选和肿瘤模型，以促进后续临床开发的化合物鉴定。目标 1 - Tip60i 能否通过减少 Foxp3+ 来限制免疫功能正常宿主中肿瘤的生长 Treg的抑制功能？我们开发了多种 Tip60i，包括基于 Crbn 和 VHL 的 PROTAC 化合物。我们将测试 Tip60i PROTAC 化合物是否可以调节 Treg 功能并控制 Treg 的生长实验性肺癌通过 (1.1) 优化 Tip60i PROTAC 化合物，并单独测试它们 (1.2)，或在与 CrbnI391V 小鼠的 (1.3) 疫苗接种或 (1.4) 检查点抑制剂治疗联合使用。我们还将评估 Tip60i 对 1.5) 正常人 Treg 和/或 Teff 细胞以及 1.6) 人肺癌相关 Treg 的影响细胞。目标 2 – 确定 Tip60i 是否会破坏肿瘤细胞存活所必需的 DDR 作用。我们的分子研究将探索Tip60依赖性机制，促进细胞对基因组的抵抗不稳定性和正常的死亡程序机制，是癌症发生和发展的基础化疗耐药对于肺癌细胞的存活至关重要。我们将测试 Tip60i 化合物是否具有直接通过破坏 2.1) Tip60 依赖性 p53 激活和/或 2.2) DNA 修复机制来发挥抗肿瘤作用。我们的研究将促进恶性肿瘤患者免疫治疗新策略的开发，鉴于新的 Tip60 导向疗法具有双重作用机制，涉及靶向 Foxp3+ Treg 细胞和肿瘤细胞对治疗的内在反应。生成的数据可能会导致临床试验肺癌患者，并且也应该与其他个体相关，因为越来越多的人认识到免疫疗法在治疗许多其他类型癌症方面的潜力。