Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Targeted cancer therapies aim to eliminate tumor cells while minimizing damage to healthy tissues.
• The von Hippel-Lindau (VHL) tumor suppressor gene loss is prevalent in renal cell carcinomas (RCCs).
• Many cancers, including RCCs, exhibit the Warburg effect, relying on aerobic glycolysis for ATP production, partly due to increased glucose transporter 1 (GLUT1) expression.

Purpose of the Study:

• To identify novel compounds that selectively target cancer cells with VHL gene loss.
• To investigate the potential of targeting the Warburg effect and GLUT1 dependence in RCCs.

Main Methods:

• A high-throughput chemical synthetic lethal screen was employed to identify compounds targeting VHL-deficient RCCs.
• The efficacy of identified compounds, specifically the 3-series exemplified by STF-31, was evaluated.
• Mechanism of action involving direct binding to GLUT1 and inhibition of glucose uptake was assessed.
• In vivo studies and micro-positron emission tomography (micro-PET) imaging using [(18)F]fluorodeoxyglucose were utilized.

Main Results:

• A class of compounds, the 3-series (e.g., STF-31), was identified that selectively kills RCCs.
• STF-31 directly targets and inhibits glucose uptake through GLUT1, crucial for RCC survival.
• Treatment with STF-31 demonstrated inhibition of RCC growth in vivo without observable toxicity to normal tissues.
• The therapeutic activity of STF-31 in experimental renal tumors could be monitored using micro-PET imaging.

Conclusions:

• The Warburg effect in tumor cells presents unique vulnerabilities that can be therapeutically exploited.
• STF-31 represents a promising targeted therapy for RCCs by selectively inhibiting GLUT1-mediated glucose uptake.
• This targeted approach offers a potential clinical strategy for treating VHL-deficient RCCs with minimal side effects.