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

摘要 尽管密集的治疗通常结合了手术、化疗和放射治疗，但患有头部疾病的患者 和颈部鳞状细胞癌(HNSCCs)，包括口腔和食道鳞状细胞 癌症(OCSCCs和ESCCs)的长期存活率只有15%-40%。造成这种情况的原因包括 预后不佳的是，这些癌症中的许多是在晚期被诊断出来的。此外，“领域” 癌变“会导致原发部位复发率高。即使在最初的手术/放射治疗之后 在治疗过程中，患者复发的风险很高。区域淋巴转移也会发生。 频率很高。因此，在癌症预防和治疗方面都非常需要改进 头颈部鳞状细胞癌(HNSCCs)的治疗方案。维甲酸受体γ(RARγ)的作用 作为一种肿瘤抑制因子，在皮肤的层状鳞状上皮细胞中，层状结构的类型非常相似 口腔的鳞状上皮。此外，我们还发现维甲酸受体γ(RARγ) 选择性激动剂CD1530可以实质性地减少小鼠体内发生的癌症数量 口腔癌变模型的建立。因此，CD1530在该模型中作为癌症化学预防药物。 我们的假设是，基于我们已发表的工作和新的初步数据，这种选择性， 维甲酸受体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代细胞。为了检验这一假设，我们 将实现以下目标：具体目标(1)：确定这种RARγ选择性激动剂是如何， CD1530影响骨髓间充质干细胞的增殖和分化 致癌物处理小鼠的恶性状态：A)我们将对 转基因小鼠研究CD1530对小鼠干/祖细胞的药理作用 以及b)我们将定义CD1530如何作用于人类口腔上皮干/祖细胞 使用3D空气：液体培养系统。具体目标(2)：我们将在小鼠身上进行类似的实验 用RARγ在口腔上皮干/祖细胞中特异性敲除以评估 RARγ作为肿瘤抑制因子的功能及其配体对RARγ的选择性我们的 目标是改进人类口腔鳞状细胞癌的癌症预防方法，并减少 复发，降低死亡率和发病率。在这里，我们将确定其药理机制(S) 我们的新型癌症预防疗法。我们还将能够批判性地测试RARγ在 体内确实是CD1530治疗的药理靶点。

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.