PPARγ targeted oral cancer treatment and additional utility of genomics analytic techniques

Abstract

Objective Peroxisome proliferator-activated receptor γ (PPARγ) agonists have been shown to have anti-proliferative, anti-angiogenic, and pro-apoptotic effects, leading to interest in their use as cancer therapeutics. Pioglitazone, an FDA approved type II diabetes medication and PPARγ agonist, may have a role in adjuvant HNSCC treatment or prevention. Therefore, the purpose of this study was: 1) to treat oral cavity cancer cells with the PPARγ activator, pioglitazone, to analyze gene expression changes and 2) to compare those changes with our pre-existing genomic data for development of hypothesis driven additional basic and clinical studies. Study Design Prospective in vitro Methods We utilized microarray technology, as well as, OCPlus and Ingenuity Pathway Analysis to analyze differential gene expression in tumor and pioglitazone-treated tumor cells on a genome wide level to demonstrate the feasibility of such an approach and determine appropriate sample size for future investigations. Results We found approximately 35 samples are required to adequately power future studies. We next discovered pioglitazone significantly affects iCOS-iCOSL and type II Diabetes Mellitus pathways as a putative anti-cancer mechanism. Conclusions Genome wide analysis is possible for exploration of differential pathway modulation and rapid hypothesis generation. Both inflammation and type II diabetes pathways were significantly altered and therefore might provide unique hypothesis-driven pharmacodynamic parameters for future in vitro or in vivo studies utilizing thiazolidinediones. These techniques could be applied to microarray or other high throughput data from a variety of hypothesis-generating research scenarios in otolaryngology (e.g. middle ear proteomics, sinus microbiome studies, etc.). Level of Evidence NA

Association between pioglitazone use and head and neck cancer: Population‐based case‐control study

“…To our knowledge, this is the first epidemiological study using population‐based case‐control methodology to assess the association between pioglitazone use among patients with type 2 DM and the subsequent occurrence of HNC. Our findings contradict previous laboratory research findings, two phase II clinical trials, and a prospective cohort study, which suggested a chemoprotective effect of pioglitazone in oral/head and neck cancers. Notably our study not only showed no protective effect but, on the contrary, shows increased odds of oral cavity and HNC cancer with pioglitazone use.…”

“…PPARγ agonists as a chemoprevention agent for HNC have been established in many laboratory studies . There remains a paucity of human clinical studies, specifically whether PPARγ agonists such as pioglitazone used in patients with type 2 DM could be preventive against HNC .…”

Preclinical evidence for pioglitazone and bexarotene combination in oral cancer chemoprevention

“…The low micromolar dose range we employed for the experiments of 1–10 μM is certainly within a range that one could achieve clinically. These results alongside other published studies 4,7,16,24,25 support the rationale that using pioglitazone and bexarotene (alone and in combination) could be a strategy for cancer preventative treatment of oral preneoplastic lesions. Therefore, we have achieved potential preclinical validation that pioglitazone/bexarotene could be useful as a prevention or even treatment strategy in both premalignancy and cancer.…”

“…Head and neck squamous cell carcinoma (HNSCC) 5‐year survival rates have slowly improved over the past 50 years 1 ; however, the incidence of oropharyngeal cancer remains unacceptably high at more than 450 000 worldwide 2 with 10 750 estimated deaths annually in the United States alone 3–5 . It is hypothesized that the morbidity and mortality associated with HNSCC (34.9%) is largely due to late diagnoses, particularly for stage III and IV, as well as poor biomarkers and stagnant treatment methodologies 6–8 .…”

Development and Clinical Validation of a Novel 5 Gene Signature Based on Fatty Acid Metabolism-Related Genes in Oral Squamous Cell Carcinoma

“…Uma et al discovered that downregulation of FA-binding proteins (FABPs) was associated with metastasis of squamous cell carcinoma of the tongue [ 12 ]. Considerable evidence suggested that peroxisome proliferator-activated receptors (PPARs), which mediate lipid biosynthesis, are considered a therapeutic target in head and neck cancer [ 13 , 14 ]. In addition, increased gene and protein expression of the FA family of transport proteins has been found in the tumor microenvironment [ 15 ].…”