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Potential of Bezafibrate for Combination with Nivolumab in Treatment of Advanced Non-Small Cell Lung Cancer

ABSTRACT: Background. Novel combination therapies with PD-1/PD-L1 inhibitors are needed to overcome resistance to these drugs. Bezafibrate, a ligand of PGC-1a/PPAR complexes, has shown a synergistic antitumor effect with PD-1 blockade in mice that is mediated by activation of mitochondria in T cells. We have therefore now performed a phase I trial of bezafibrate with nivolumab in previously treated patients with advanced non-small cell lung cancer. The primary end point was the percentage of patients who experience dose-limiting toxicity, and this combination regimen was found to be well tolerated. Preplanned comprehensive analysis of plasma metabolites and gene expression in peripheral cytotoxic T cells indicated that bezafibrate promoted T cell function through upregulation of mitochondrial metabolism including fatty acid oxidation and may thereby have prolonged the duration of response. This combination strategy targeting T cell metabolism thus has the potential to maintain antitumor activity of immune checkpoint inhibitors and warrants further validation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE202417 | GEO | 2025/05/06

REPOSITORIES: GEO

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Potential of Bezafibrate for Combination with Nivolumab in Treatment of Advanced Non-Small Cell Lung Cancer

Project description:Potential of Bezafibrate for Combination with Nivolumab in Treatment of Advanced Non-Small Cell Lung Cancer

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Expression data from (bezafibrate treated-wild type, Clock mutant, and PPARalpha-null) mouse liver

Project description:A functional interaction between peroxisome proliferator-activated receptor alpha (PPARalpha) and components of the circadian clock has been suggested; however, it remains to be clarified whether those transcriptional factors interact with each other to regulate the expression of their target genes. In this study, we used a ligand of PPARalpha, bezafibrate, to search the PPARalpha-regulated genes that express in a CLOCK-dependent circadian manner. Microarrays analyses using hepatic RNA isolated from bezafibrate treated-wild type, Clock mutant (Clk/Clk), and PPARalpha-null mice revealed that 136 genes are transcriptionally regulated by PPARalpha in a CLOCK-dependent manner. Clk/Clk mutant mice with Jcl:ICR background, wild-type mice with the same strain, and PPARalpha-null mice aged 6-12 weeks were housed under a 12 h light-12 h dark cycle [LD 12:12; lights on at Zeitgeber time (ZT) 0]. For chronic treatment of bezafibrate, mice were provided with either a normal diet or the same diet containing 0.5% w/w bezafibrate for 5 days. A white fluorescent lamp provided light (300 - 500 lux at cage level) during the day. To examine the transient effect of bezafibrate injection on hepatic gene expression, bezafibrate was dissolved in warm (~40 C) sterile corn oil (Sigma) at a concentration of 10 mg/ml and administered intraperitoneally (i.p.) in a single dose of 100 mg/kg body weight at ZT2. To examine the PPARalpha-regulated genes that express in a CLOCK-dependent manner in mice, we performed oligonucleotide microarray analysis at ZT14, when CLOCK/BMAL1 transcriptional activity is maximal, using RNA isolated from wild-type (n = 3), Clock mutant (n = 3), and PPARalpha-null mice (n = 3) treated with bezafibrate for 5 days, and control wild-type mice (n = 3). Livers were collected and frozen in liquid nitrogen. Total RNA (250 ng) was extracted using RNAiso.

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