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Principal Investigator: Frank G. Ondrey
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2024
Award: $103,823
Funding agency: National Cancer Institute
Project Summary/Abstract
With stagnant cure rates, there is a severe unmet need for strategies to improve oral and all other types
of aerodigestive cancer survival. There are no robust chemoprevention drugs or other treatments for high
risk oral precancerous conditions or field carcinogenesis despite 40 years of clinical trial research. High
risk oral precancerous conditions (such as leukoplakia) represent a standard target for chemoprevention
interventions. Type II anti-diabetic agents, including pioglitazone and metformin, are promising cancer
prevention drugs for oral cavity preneoplasia that we have used in NCI sponsored clinical trials. They
have adequate safety and moderate efficacy in human trials, however, individually are likely not sufficient
to advance to large scale clinical trials. These agents have differing mechanisms of action which each
attack different events in oral carcinogenesis. In this project, we propose to conduct a phase IIa 12 week
clinical trial with combination BID pioglitazone-metformin (15mg-500mg) in oral preneoplasia patients.
We have assembled a consortium of clinics in Minneapolis/St. Paul MN for efficient accrual to this trial.
We will examine pharmacodynamic endpoints in specimens based on both the mechanisms of the
agents and how they may affect T cell subsets before and after treatment. Further, we will also analyze
leukoplakia specimens and adjacent normal mucosa specimens by RNA-Seq before and after treatment,
which will shed light on effects of the drugs as well as any putative “off target” effects. At the completion
of this project, we will have a better understanding of pioglitazone and metformin effects on oral
carcinogenesis, as well as, an early stage clinical trial which could be expanded to larger randomized
trials with a promising cancer prevention strategy for oral preneoplasia or other tobacco-associated
malignancies.
Terms: <1-Phosphatidylinositol 3-Kinase><2,4-thiazolidinedione><ATRA><Affect><After Care><After-Treatment><Aftercare><Animal Model><Animal Models and Related Studies><Anti-diabetic Agents><Anti-diabetic Drugs><Apopain><Apoptosis><Apoptosis Pathway><Apoptosis-Related Cysteine Protease Caspase 3><Arachidonic Acid Cyclooxygenase><B7-H1><B7H1><Biguanides><Buccal Cavity><Buccal Cavity Head and Neck><CASP-3><CASP3><CASP3 gene><CD274><CD8><CD8B><CD8B1><CD8B1 gene><CPP-32><CPP32><CPP32 protein><CPP32B><CPP32beta><Cancer Induction><Cancer Patient><Cancers><Carcinoma><Cavitas Oris><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Line><Cell Signaling><CellLine><Chemoprevention><Chemopreventive><Chemopreventive Agent><Clinic><Clinical><Clinical Chemoprevention><Clinical Trials><Combined Modality Therapy><Cyclo-Oxygenase><Cyclooxygenase><Cysteine Protease CPP32><Cysteine Protease CPP32 Gene><Data><Development><Dimethylbiguanidine><Dimethylguanylguanidine><Dose><Drug Combinations><Drugs><EGCG><EGCG cpd><Early-Stage Clinical Trials><Epigallocatechin Gallate><Epigallocatechingallate><Epithelial cancer><Event><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Fatty Acid Cyclo-Oxygenase><Fortification><Funding><Gene Expression><Glitazones><Green Tea Extract><Green Tea Polyphenols><Head and Neck Cancer><Head and Neck Carcinoma><Healthcare><Histologic><Histologically><Human><Hydroperoxide Cyclase><Immunoglobulin Enhancer-Binding Protein><Individual><Inflammation><Inflammatory><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Keratotic Plaque><LYT3><Lesion><Leukoplakia><Link><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><Malignant Head and Neck Neoplasm><Malignant Neoplasms><Malignant Oral Cavity Neoplasm><Malignant Oral Cavity Tumor><Malignant Oral Neoplasm><Malignant Tumor><Mechanistic Target of Rapamycin><Medication><Metformin><Modern Man><Mouth><Mouth Cancer><Mouth Leukoplakia><Mucosa><Mucosal Tissue><Mucous Membrane><Multimodal Therapy><Multimodal Treatment><N,N-dimethyl-imidodicarbonimidic diamide><NF-kB><NF-kappa B><NF-kappaB><NFKB><Neoplasms><Nuclear><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Oral><Oral Cancer><Oral Cavity Leukoplakia><Oral Keratosis><Oral Leukoplakia><Oral cavity><PARP Cleavage Protease><PARP Cleavage Protease Gene><PD 1><PD-1><PD-L1><PD1><PDL-1><PDL1><PGH Synthase><PGH2 Synthetase><PI-3 Kinase><PI3-Kinase><PI3CG><PI3KGamma><PI3k><PIK3><PIK3CG><PIK3CG gene><PPAR gamma><PPAR-g><PPAR-γ><PPARgamma><PPARγ><Pathway interactions><Patients><Peroxisome Proliferative Activated Receptor Gamma><Peroxisome Proliferator-Activated Receptor gamma><Peroxisome Proliferator-Activated Receptor γ><Pharmaceutical Preparations><Pharmacodynamics><Phase><Phase 1 Clinical Trials><Phase I Clinical Trials><Phosphatidylinositol 3-Kinase><Phosphatidylinositol-3-OH Kinase><Phosphoinositide 3-Hydroxykinase><Physiologic><Physiological><Pioglitazone><Population><Precancerous Conditions><Premalignant Condition><Premalignant State><Preventative intervention><Preventative strategy><Prevention strategy><Prevention trial><Preventive strategy><Programmed Cell Death><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Prostaglandin Cyclo-Oxygenase><Prostaglandin Cyclooxygenase><Prostaglandin Endoperoxide Synthetase><Prostaglandin G-H Synthase><Prostaglandin H Synthase><Prostaglandin H2 Synthetase><Prostaglandin Synthase><Prostaglandin Synthetase><Prostaglandin-Endoperoxide Synthase><PtdIns 3-Kinase><RAFT1><RNA Seq><RNA sequencing><RNAseq><Randomization trial><Recurrence><Recurrent><Research><Research Specimen><Retinoic Acid><Risk><SCA-1><SCA-1 Gene><SREBP Cleavage Activity 1><SREBP Cleavage Activity 1 Gene><Safety><Series><Signal Transduction><Signal Transduction Systems><Signaling><Specimen><Staining method><Stains><Stem Cell like><Strains Cell Lines><T-Cell Subsets><T-Lymphocyte Subsets><Tea catechin><Testing><Thiazolidinedione Receptor><Thiazolidinediones><Tobacco><Tobacco-Associated Carcinogen><Toxic effect><Toxicities><Trans Vitamin A Acid><Transcription Factor NF-kB><Tretinoin><Tretinoinum><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><Vitamin A Acid><Work><Yama><Yama protein><all-trans-Retinoic Acid><all-trans-Vitamin A acid><antagonism><antagonist><anti-cancer><anti-carcinogenic><anti-diabetic><anticarcinogenic><biological signal transduction><cancer prevention><cancer survival><carcinogenesis><caspase-3><cellular differentiation><chemoprevention agent><cohort><combination therapy><combined modality treatment><combined treatment><cultured cell line><cysteine protease P32><developmental><drug/agent><epigallo-catechin gallate><epigallocatechin-3-gallate><epithelial carcinoma><experience><head/neck cancer><health care><high risk><improved><indexing><intervention for prevention><interventional strategy><kappa B Enhancer Binding Protein><mTOR><malignancy><malignant head and neck tumor><malignant mouth neoplasm><malignant mouth tumor><mammalian target of rapamycin><model of animal><multi-modal therapy><multi-modal treatment><neoplasia><neoplasm/cancer><neoplastic growth><non-diabetic><nondiabetic><nuclear factor kappa beta><oral cancer prevention><oral carcinogenesis><oral cavity cancer><oral mucosa leukokeratosis><oral mucosa leukoplakia><oral precancer><oral premalignancy><pathway><pharmacodynamic biomarker><pharmacodynamic marker><phase I protocol><post treatment><precancer><precancerous><precancerous state><premalignant><prevent><preventing><prevention clinical trial><prevention intervention><preventional intervention strategy><preventive intervention><programmed cell death 1><programmed cell death ligand 1><programmed cell death protein 1><programmed cell death protein ligand 1><programmed death 1><protein death-ligand 1><randomized trial><response><sle2><stem cell characteristics><stemness><systemic lupus erythematosus susceptibility 2><thiazolidinedione><tobacco carcinogen><tobacco related carcinogen><tobacco specific carcinogen><trans-Retinoic Acid><transcriptome sequencing><transcriptomic sequencing>