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Principal Investigator: LORRAINE J GUDAS
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2024
Award: $434,366
Funding agency: National Cancer Institute
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.
Terms: <3-D><3-Dimensional><3-methyl TTNEB><3D><4 hydroxynonenal><4-HNE cpd><4-Nitroquinoline-1-oxide><4-Nitroquinoline-N-oxide><4-hydroxy-2,3-nonenal><4-hydroxy-2-nonenal><4-hydroxynonen-2-al><9-cis-Retinoic Acid Receptor><ATRA><Active Oxygen><Affect><Agonist><Air><All-Trans-Retinol><Anti-Infective vitamin><Antibodies><Antixerophthalmic vitamin><Approaches to prevention><Area><Axerophthol><Axerophtholum><BEX3><Basal Transcription Factor><Basal transcription factor genes><Bex><Bexarotene><Bio-Informatics><Bioinformatics><Biosterol><Body Weight><Buccal Cavity><Buccal Cavity Head and Neck><CRABP><Cancer Causing Agents><Cancer Induction><Cancer Treatment><Cancers><Carcinogens><Carcinoma><Cavitas Oris><Cell Body><Cells><Cellular Retinol Binding Protein><ChIP assay><Chemopreventive><Chemopreventive Agent><Clinical Treatment><Clinical Trials><Collaborations><DXS6984E><Data><Diagnosis><Doxycycline><Drugs><Epidermoid Carcinoma><Epithelial Cells><Epithelial cancer><Esophageal Epidermoid Carcinoma><Esophageal SCC><Esophageal Squamous Cell Carcinoma><Expression Signature><Faculty><Frequencies><Funding><Gene Expression Profile><General Transcription Factor Gene><General Transcription Factors><Genomics><Goals><HDAC><HDAC Proteins><HGR74><HNSCC><Head and Neck Cancer><Head and Neck Carcinoma><Head and Neck Squamous Cell Carcinoma><Head and Neck Surgery><Histone Deacetylase><Human><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Investigators><Knock-out><Knockout><Lard-Factor><Ligands><Liquid substance><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><Malignant Head and Neck Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Medical><Medication><Medicine><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Mouth><Mouth Leukoplakia><Murine><Mus><NGFRAP1 gene><NIH><National Institutes of Health><Neoplasm Metastasis><Oleovitamin A><Oncogens><Oncologist><Operative Procedures><Operative Surgical Procedures><Ophthalamin><Oral Cavity Leukoplakia><Oral Cavity Squamous Cell Carcinoma><Oral Keratosis><Oral Leukoplakia><Oral cavity><Oral squamous cell carcinoma><Otolaryngology><Oxygen Radicals><Pathologic><Pathology><Pathway interactions><Patients><Pharmaceutical Preparations><Pharmacologic Actions><Planocellular Carcinoma><Precancerous Conditions><Premalignant Condition><Premalignant State><Prevention><Prevention approach><Prevention therapy><Pro-Oxidants><Progenitor Cells><Prognosis><Proliferating><Property><Publications><Publishing><Quinoline, 4-nitro-, 1-oxide><RAR gamma><RARγ><RXR><RXR Protein><Radiation><Radiation therapy><Radiotherapeutics><Radiotherapy><Reactive Oxygen Species><Recurrence><Recurrent><Relapse><Research><Research Personnel><Researchers><Retinoic Acid><Retinoic Acid Agent><Retinoic Acid Receptor><Retinoic Acid Receptor RXR><Retinoic Acid Response Element><Retinoic Acid and Derivatives><Retinoid X Receptors><Retinoids><Running><SCC of the Esophagus><SCCHN><Scientific Publication><Secondary Neoplasm><Secondary Tumor><Site><Skin><Squamous Carcinoma><Squamous Cell Carcinoma of the Esophagus><Squamous Cell Epithelioma><Squamous cell carcinoma><Stratified Squamous Epithelium><Surgical><Surgical Interventions><Surgical Procedure><Survival Rate><System><Tamoxifen><Targretin><Testing><Training><Trans Vitamin A Acid><Transcription Factor Proto-Oncogene><Transcription factor genes><Transgenes><Transgenic Mice><Transgenic Organisms><Treatment Protocols><Treatment Regimen><Treatment Schedule><Tretinoin><Tretinoinum><Tumor Suppressor Proteins><United States National Institutes of Health><Universities><Vibramycin><Vitamin A><Vitamin A Acid><Vitamin A Alcohol><Work><all-trans-Retinoic Acid><all-trans-Vitamin A acid><alpha-6-Deoxyoxytetracycline><anti-cancer therapy><anti-carcinogenic><anticarcinogenic><cancer diagnosis><cancer initiation><cancer metastasis><cancer prevention><cancer progenitor><cancer progenitor cells><cancer stem cell><cancer therapy><cancer type><cancer-directed therapy><carcinogenesis><cellular retinoic acid binding protein><chemoprevention agent><chemotherapy><chromatin immunoprecipitation><daughter cell><disease model><disorder model><draining lymph node><drug action><drug/agent><epithelial carcinoma><epithelial progenitor><epithelial progenitor cell><epithelial stem cell><experience><experiment><experimental research><experimental study><experiments><fluid><gene expression pattern><gene expression signature><head and neck squamous carcinoma><head and neck squamous cell cancer><head/neck cancer><high risk><high risk group><high risk individual><high risk people><high risk population><improved><in vivo><indexing><lecithin-retinol acyltransferase><liquid><malignancy><malignant head and neck tumor><malignant progenitor><malignant stem cell><meeting><meetings><member><mortality><mouse model><mouth SCC><mouth squamous cell carcinoma><murine model><neoplasm/cancer><novel><oncogenic agent><oral cancer prevention><oral cavity SCC><oral cavity epithelium><oral epithelia><oral epithelium><oral mucosa leukokeratosis><oral mucosa leukoplakia><oral squamous cancer><oral squamous carcinoma><otorhinolaryngology><pathway><pharmacologic><precancerous state><prevent><preventing><professor><radiation treatment><recruit><regional lymph node><retinoic acid receptor gamma><retinoic acid receptor γ><retinol><stem cells><success><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><three dimensional><trans-Retinoic Acid><transcription factor><transcriptional profile><transcriptional signature><transgene><transgenic><treatment with radiation><trial regimen><trial treatment><tumor><tumor cell metastasis><tumor suppressor>