Progression of bone-metastatic prostate cancer in a mouse model treated with a novel pan-class I GLUT inhibitor (DRB18)

Abstract

Aim: Bone-metastatic prostate cancer (PCa) is a debilitating disease with few therapeutic options once androgen independence and chemotherapeutic resistance develop. Advanced PCa has metabolic vulnerabilities involving glycolysis, which is mediated by class I glucose transporters (GLUTs1-4). We previously patented DRB18, a small molecule pan-class I GLUT inhibitor that successfully inhibited the growth of a human lung cancer xenograft in mice. The purpose of this study was to determine the sensitivity of advanced PCa to GLUT antagonism using DRB18.

Methods: Bioinformatics was performed on human and canine PCa datasets to determine the clinical expression of class I GLUTs. Glucose uptake and cell viability in response to DRB18 were measured in vitro. Tibias of athymic mice were inoculated with Ace-1 canine PCa cells and treated with DRB18. The combination of DRB18 with cytotoxic docetaxel was assessed in vitro.

Results: Expression of important class I GLUTs and glycolysis genes increased during PCa progression in men and dogs. DRB18 reduced cancer cell glucose uptake and cell viability in a dose-dependent manner. Half-maximal inhibitory concentrations (IC₅₀) ranged from 20-30 µM. DRB18 did not prevent intratibial PCa growth in vivo and had toxic effects at higher concentrations. DRB18 and docetaxel combination therapy and gene expression data from publicly available human PCa samples indicated docetaxel treatment does not stimulate glucose-related metabolic pathways.

Conclusion: GLUT1 inhibition alone or with combination therapy may not be appropriate for bone-metastasis inhibition. The results contribute to evidence that suggests bone metastatic PCa is not glucose dependent.

Keywords

Prostate cancer / bone metastasis / glycolysis / glucose transporter / DRB18 / Ace-1 / dog / preclinical model

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