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

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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.