CD 1530, an RAR Gamma Agonist for Oral Cavity Squamous Cell Carcinoma Prevention

CD 1530，一种 RAR γ 激动剂，用于预防口腔鳞状细胞癌

基本信息

批准号：
10583911
负责人：
LORRAINE J GUDAS
金额：
$ 45.72万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-11 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583911
关键词：
3-Dimensional 4 hydroxynonenal 4-Nitroquinoline-1-oxide Affect Agonist Air All-Trans-Retinol Antibodies Area Bexarotene Bioinformatics Body Weight Carcinogens Carcinoma Cells Cellular Retinol Binding Protein Chemopreventive Agent Clinical Treatment Clinical Trials Collaborations Data Diagnosis Disease model Doxycycline Epithelial Cells Esophageal Squamous Cell Carcinoma Faculty Frequencies Funding Gene Expression Profile Genomics Goals Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Head and Neck Surgery Histone Deacetylase Human Immunohistochemistry Knock-out Ligands Liquid substance Malignant Neoplasms Medical Medicine Modeling Morbidity - disease rate Mus NGFRAP1 gene Neoplasm Metastasis Oncologist Operative Surgical Procedures Oral Leukoplakia Oral cavity Otolaryngology Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Actions Precancerous Conditions Prevention Prevention approach Prevention therapy Prognosis Proliferating Property Publications Publishing RXR Radiation Radiation therapy Reactive Oxygen Species Recurrence Relapse Research Research Personnel Retinoic Acid Receptor Retinoic Acid Response Element Retinoids Running Site Skin Squamous cell carcinoma Stratified Squamous Epithelium Survival Rate System Tamoxifen Testing Training Transgenes Transgenic Mice Transgenic Organisms Treatment Protocols Tretinoin Tumor Suppressor Proteins United States National Institutes of Health Universities Vitamin A Work cancer diagnosis cancer initiation cancer prevention cancer stem cell cancer therapy cancer type carcinogenesis cellular retinoic acid binding protein chemotherapy chromatin immunoprecipitation daughter cell draining lymph node drug action epithelial stem cell experience experimental study high risk high risk population improved in vivo indexing lecithin-retinol acyltransferase meetings member mortality mouse model mouth squamous cell carcinoma novel oral cancer prevention oral cavity epithelium pharmacologic prevent professor recruit retinoic acid receptor gamma stem cells success targeted treatment transcription factor tumor

项目摘要

Abstract Despite intensive treatments that often combine surgery, chemotherapy, and radiation, patients with head and neck squamous cell carcinomas (HNSCCs), including oral cavity and esophageal squamous cell carcinomas (OCSCCs & ESCCs), have a long-term survival rate of only 15-40%. Among the reasons for the poor prognoses are that many of these cancers are diagnosed at late stages. Furthermore, “field cancerization” leads to high rates of primary site recurrences. Even after initial surgery/radiotherapy for treatment, patients are at a very high risk for recurrence. Metastases to regional lymph nodes also occur with high frequency. Thus, there is a great need for improvements in both cancer prevention and treatment regimens for head and neck squamous cell carcinomas (HNSCCs). The retinoic acid receptor γ (RARγ) acts as a tumor suppressor in stratified squamous epithelial cells of the skin, a very similar type of stratified squamous epithelium to the oral cavity. Moreover, we have shown that a retinoic acid receptor γ (RARγ) selective agonist, CD1530, can substantively reduce the numbers of carcinomas that develop in a murine model of oral cavity carcinogenesis. Thus, CD1530 acts as a cancer chemopreventive drug in this model. Our hypothesis, which is based on both our published work and new, preliminary data, is that this selective, retinoic acid receptor γ (RARγ) agonist is effective in oral cancer prevention because by changing the transcriptional profile of the oral cavity stem/progenitor cells, CD1530 enhances the ability of stem cells to generate daughter cells destined to differentiate rather than to proliferate. To test this hypothesis we will carry out the following aims: Specific Aim (1): To determine how this RARγ selective agonist, CD1530, affects the proliferation and differentiation properties of the stem/progenitor cells in the pre- malignant state in the carcinogen treated mice: a) we will perform advanced lineage tracing on transgenic mice to delineate the pharmacological actions of CD1530 on the stem/progenitor cells of the oral epithelium; and b) we will define how CD1530 acts on human oral epithelial stem/progenitor cells using a 3D air:liquid culture system. Specific Aim (2): We will perform similar experiments on mice with RARγ specifically knocked out in the stem/progenitor cells of the oral cavity epithelium to assess the function of RARγ as a tumor suppressor and the selectivity of the CD1530 ligand for RARγ. Our goal is to improve cancer prevention approaches for human OCSCCs and to reduce the high frequency of relapse, reducing both mortality and morbidity. Here we will identify the pharmacological mechanism(s) of our novel cancer prevention therapy. We will additionally be able to test critically the idea that RARγ in vivo is indeed the pharmacological target for therapy with CD1530.

抽象的尽管经常结合手术、化疗和放疗进行强化治疗，但头部患者和颈部鳞状细胞癌（HNSCC），包括口腔和食管鳞状细胞癌癌症（OCSCC 和 ESCC）的长期生存率仅为 15-40%。预后不佳的原因是许多癌症在晚期才被诊断出来。即使在初次手术/放疗后，“癌化”也会导致原发部位复发率很高。治疗后，患者复发区域淋巴结转移的风险也非常高。因此，非常需要改进癌症的预防和治疗。头颈鳞状细胞癌 (HNSCC) 的治疗方案视黄酸受体 γ (RARγ) 起作用。作为皮肤复层鳞状上皮细胞的肿瘤抑制因子，这是一种非常相似的复层鳞状上皮细胞类型此外，我们还发现，口腔鳞状上皮存在视黄酸受体γ（RARγ）。选择性激动剂 CD1530 可以显着减少小鼠体内发生的癌症数量因此，CD1530 在该模型中充当癌症化学预防药物。我们的假设基于我们已发表的工作和新的初步数据，即这种选择性的、视黄酸受体 γ (RARγ) 激动剂可有效预防口腔癌，因为通过改变口腔干/祖细胞的转录谱，CD1530增强干细胞的能力产生注定要分化而不是增殖的子细胞为了检验这个假设，我们将实现以下目标：具体目标 (1)：确定这种 RARγ 选择性激动剂如何， CD1530，影响干细胞/祖细胞的增殖和分化特性致癌物治疗小鼠的恶性状态：a）我们将进行高级谱系追踪转基因小鼠描绘 CD1530 对干细胞/祖细胞的药理作用口腔上皮；b) 我们将定义 CD1530 如何作用于人类口腔上皮干细胞/祖细胞使用 3D 空气：液体培养系统具体目标 (2)：我们将对小鼠进行类似的实验。在口腔上皮干细胞/祖细胞中专门敲除 RARγ 来评估 RARγ 作为肿瘤抑制因子的功能以及 CD1530 配体对 RARγ 的选择性。目标是改进人类 OCSCC 的癌症预防方法并减少高频率复发，降低死亡率和发病率。在这里，我们将确定其药理学机制。我们还将能够批判性地测试 RARγ 在我们的新型癌症预防疗法中的作用。体内确实是 CD1530 治疗的药理学靶点。