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：
10054519
负责人：
Wayne William Hancock
金额：
$ 42.77万
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/10054519
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 Eragrostis 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 immune checkpoint blockade immunoregulation in vivo inhibitor/antagonist irradiation 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.

项目摘要我们将研究TIP60的治疗靶向是Hisstone/Hisstone/蛋白乙酰转移酶 FOXP3+ T调节（TREG）的功能和存活可以显着降低体内Treg功能保留常规T细胞反应，导致鼠模型中抑制肺肿瘤的生长。我们将还要评估TIP60靶向对常规诱导的肿瘤内DNA损伤反应的影响肺癌的疗法，包括辐照和顺铂治疗。我们已经开发了TIP60 PROTAC （靶向靶向嵌合）分子的分子，募集Cereblon E3连接酶，以促进TIP60 降解，我们在化合物中采用了Cereblon敲入（CRBNI391V）免疫能力C57BL/6小鼠筛查和肿瘤模型，以促进化合物鉴定以进行随后的临床发育。 AIM 1-可以通过减少FOXP3+来限制免疫能力宿主中肿瘤的限制生长 Treg抑制功能？我们已经开发了几个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功能并控制实验性肺癌（1.1）优化TIP60I Protac化合物，单独测试（1.2）或与（1.3）疫苗接种或（1.4）CRBNI391V小鼠中的检查点抑制剂治疗有关。我们还将评估 TIP60I对1.5）正常人treg和/或teff细胞的影响，以及1.6）与人类肺癌相关的treg 细胞。 AIM 2 - 确定TIP60I是否破坏了肿瘤细胞存活必不可少的DDR动作。我们的分子投资将探索依赖于TIP60的机制，以促进细胞对基因组的抗性不稳定性和正常的死亡机制，以及基础癌症的启动和化学治疗性耐药性对于肺癌细胞存活至关重要。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。我们的研究将促进恶性肿瘤患者的免疫疗法新策略的发展鉴于新的TIP60定向疗法具有双重作用机理，涉及针对Foxp3+ Treg 细胞和内在肿瘤细胞对治疗的反应。要生成的数据可能会导致鉴于越来越多的人在许多其他类型的癌症管理中，公认的免疫疗法潜力。