A redox-responsive prodrug for tumor-targeted glutamine restriction

Area of Science:

• Biochemistry
• Oncology
• Immunology

Background:

• Cancer immunotherapy is enhanced by modulating cancer and immune cell metabolism within the tumor microenvironment.
• Glutamine metabolism is crucial for cancer cells, but non-specific inhibition causes toxicity.
• Targeted glutamine inhibition offers a strategy to overcome these limitations.

Purpose of the Study:

• To synthesize and evaluate a redox-responsive prodrug, redox-6-Diazo-5-oxo-L-norleucine (redox-DON), for targeted glutamine inhibition.
• To assess the antitumor efficacy and safety profile of redox-DON compared to existing prodrugs.
• To investigate the synergistic effects of redox-DON with checkpoint blockade antibodies in cancer therapy.

Main Methods:

• Synthesis of a redox-responsive prodrug (redox-DON) based on 6-Diazo-5-oxo-L-norleucine.
• In vivo evaluation of redox-DON in mice bearing CT26 colon carcinoma.
• Comparison of redox-DON with the established prodrug JHU083 regarding efficacy and toxicity.
• Assessment of combination therapy with redox-DON and checkpoint blockade antibodies.

Main Results:

• Redox-DON demonstrated comparable antitumor efficacy to JHU083 in CT26 tumor-bearing mice.
• Redox-DON exhibited a significantly improved safety profile, especially in spleen and gastrointestinal tract.
• Combination therapy with redox-DON and checkpoint blockade antibodies resulted in durable cures.
• The redox-responsive prodrug approach showed potential for reducing off-target toxicity.

Conclusions:

• Redox-DON is a safe and effective therapeutic for targeted glutamine inhibition, improving metabolic modulatory immunotherapy.
• Reversible chemical modification of drugs can mitigate toxicity and enhance therapeutic outcomes.
• This strategy holds promise for developing safer and more effective cancer metabolic therapies.