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

摘要 尽管强化治疗通常结合联合收割机手术，化疗和放疗， 和颈部鳞状细胞癌（HNSCC），包括口腔和食管鳞状细胞癌 恶性肿瘤（OCSCC和ESCC）的长期存活率仅为15- 40%。的原因之一 不幸的是，这些癌症中有许多是在晚期才被诊断出来的。此外，“场 “癌变”导致原发部位复发率高。即使在初次手术/放疗后， 治疗后，患者复发的风险非常高。转移到区域淋巴结也发生 高频率。因此，非常需要改进癌症预防和治疗 头颈部鳞状细胞癌（HNSCC）的治疗方案。视黄酸受体γ（RARγ） 作为皮肤复层鳞状上皮细胞中的肿瘤抑制因子， 口腔鳞状上皮。此外，我们已经证明，维甲酸受体γ（RARγ） 选择性激动剂CD 1530可以显著减少小鼠中发生的癌的数量。 口腔癌变模型。因此，CD 1530在该模型中充当癌症化学预防药物。 我们的假设，这是基于我们发表的工作和新的，初步的数据，是这种选择性， 维甲酸受体γ（RARγ）激动剂在口腔癌预防中是有效的，因为通过改变 口腔干/祖细胞的转录谱，CD 1530增强干细胞的能力 以产生注定要分化而不是增殖的子细胞。为了验证这一假设， 具体目的（1）：确定这种RARγ选择性激动剂， CD 1530，影响干/祖细胞的增殖和分化特性，在预处理中， a）我们将对致癌物处理的小鼠进行高级谱系追踪， 转基因小鼠，以描述CD 1530对干/祖细胞的药理作用。 口腔上皮;和B）我们将定义CD 1530如何作用于人口腔上皮干/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 在口腔上皮干/祖细胞中特异性敲除RARγ，以评估 RARγ作为肿瘤抑制因子的功能和CD 1530配体对RARγ的选择性。我们 目标是改善人类OCSCC的癌症预防方法，并降低高频率的 复发，降低死亡率和发病率。在这里，我们将确定药理学机制（S） 我们的新型癌症预防疗法我们还将能够严格测试RARγ在 体内确实是用CD 1530治疗的药理学靶点。

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.