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

• 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
• 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; 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

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，化学疗法和放射线的强化治疗，但头部患者 和颈部鳞状细胞癌（HNSCCS），包括口腔和食管鳞状细胞 癌（OCSCCS＆ESCC）的长期存活率仅为15-40％。在原因 预后不佳的是，这些癌症中有许多是在晚期被诊断出来的。此外，“字段 癌化”导致主要现场回报率很高。即使在初次手术/放疗之后 治疗，患者的复发风险很高。向区域淋巴结的转移也发生 高频。这很需要改善癌症预防和治疗 头颈部鳞状细胞癌（HNSCCS）的方案。视黄酸受体γ（RARγ）作用 作为皮肤分层的鳞状上皮细胞中的肿瘤抑制剂，一种非常相似的分层类型 鳞状上皮到口腔。此外，我们已经证明了视黄酸受体γ（RARγ） 选择性激动剂CD1530可以实质性地减少在鼠中发展的癌的数量 口腔癌变模型。在此模型中，CD1530充当癌症化学预防药物。 我们的假设是基于我们已发表的工作和新的，初步数据的假设，是这种选择性的， 视黄酸受体γ（RARγ）激动剂在预防口腔癌中有效，因为通过改变 口腔茎/祖细胞的转录曲线，CD1530增强了干细胞的能力 产生注定要分化而不是增殖的子细胞。为了检验这一假设 将执行以下目的：特定目标（1）：确定这种RARγ选择性激动剂， CD1530会影响前茎/祖细胞的增殖和分化特性 致癌治疗的小鼠中的恶性状态：a）我们将在上高级谱系跟踪 转基因小鼠描绘CD1530对茎/祖细胞的药物作用 口腔上皮； b）我们将定义CD1530如何作用于人口腔上皮茎/祖细胞 使用3D空气：液体培养系统。特定目的（2）：我们将对小鼠进行类似的实验 RARγ在口腔上皮的茎/祖细胞中特异性撞倒以评估 RARγ作为肿瘤抑制剂的功能以及CD1530配体对RARγ的选择性。我们的 目标是改善人类OCSCC的癌症预防方法，并降低 复发，降低死亡率和发病率。在这里，我们将确定药物机制 我们的新型癌症预防疗法。我们还将能够批判性地测试RARγ 体内确实是CD1530治疗的药理靶标。