Related Experiment Video
Updated: May 1, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
SGI-110 and entinostat therapy reduces lung tumor burden and reprograms the epigenome
Carmen S Tellez1, Marcie J Grimes, Maria A Picchi
1Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM.
Abstract:
The DNA methyltransferase (DNMT) inhibitor vidaza (5-Azacytidine) in combination with the histone deacetylase inhibitor entinostat has shown promise in treating lung cancer and this has been replicated in our orthotopic lung cancer model. However, the effectiveness of DNMT inhibitors against solid tumors is likely impacted by their limited stability and rapid inactivation by cytidine deaminase (CDA) in the liver. These studies were initiated to test the efficacy of SGI-110, a dinucleotide containing decitabine that is resistant to deamination by CDA, as a single agent and in combination with entinostat. Evaluation of in vivo plasma concentrations and pharmacokinetic properties of SGI-110 showed rapid conversion to decitabine and a plasma half-life of 4 hr. SGI-110 alone or in combination with entinostat reduced tumor burden of a K-ras/p53 mutant lung adenocarcinoma cell line (Calu6) engrafted orthotopically in nude rats by 35% and 56%, respectively. SGI-110 caused widespread demethylation of more than 300 gene promoters and microarray analysis revealed expression changes for 212 and 592 genes with SGI-110 alone or in combination with entinostat. Epigenetic therapy also induced demethylation and expression of cancer testis antigen genes that could sensitize tumor cells to subsequent immunotherapy. In the orthotopically growing tumors, highly significant gene expression changes were seen in key cancer regulatory pathways including induction of p21 and the apoptotic gene BIK. Moreover, SGI-110 in combination with entinostat caused widespread epigenetic reprogramming of EZH2-target genes. These preclinical in vivo findings demonstrate the clinical potential of SGI-110 for reducing lung tumor burden through reprogramming the epigenome.
Insights
SGI-110, a novel DNA methyltransferase inhibitor, effectively reduces lung tumor burden in preclinical models. Combined with entinostat, it shows enhanced efficacy by reprogramming the epigenome for potential immunotherapy sensitization.
Area of Science:
- Oncology
- Epigenetics
- Pharmacology
Background:
- DNA methyltransferase (DNMT) inhibitors show promise for lung cancer but face stability issues.
- Cytidine deaminase (CDA) rapidly inactivates DNMT inhibitors in the liver, limiting efficacy against solid tumors.
Purpose of the Study:
- To evaluate the efficacy of SGI-110, a deamination-resistant decitabine prodrug, as a single agent and in combination with entinostat.
- To assess the pharmacokinetic properties and in vivo anti-tumor activity of SGI-110 in a lung cancer model.
Main Methods:
- Orthotopic lung adenocarcinoma xenograft model (Calu6) in nude rats.
- Administration of SGI-110 alone and in combination with entinostat.
- Evaluation of plasma concentrations, tumor burden, gene promoter methylation, gene expression (microarray), and epigenetic reprogramming.
Main Results:
- SGI-110 demonstrated favorable pharmacokinetics with a 4-hour plasma half-life.
- SGI-110 alone and with entinostat reduced tumor burden by 35% and 56%, respectively.
- Widespread gene demethylation, altered expression of over 500 genes, induction of p21 and BIK, and reprogramming of EZH2-target genes were observed.
Conclusions:
- SGI-110 exhibits preclinical efficacy in reducing lung tumor burden through epigenetic reprogramming.
- The combination of SGI-110 and entinostat shows enhanced anti-tumor activity and broad epigenetic modulation.
- SGI-110 holds clinical potential for lung cancer treatment, potentially sensitizing tumors to immunotherapy.
