Cancer

Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma

Glioblastoma (GBM) is a highly aggressive brain tumor with limited effective treatment options. Despite the known role of glucose and glutamine in fueling GBM growth, few therapies have targeted these fuels as a treatment strategy.

This study investigated the therapeutic benefit of combining a calorically restricted ketogenic diet (KD-R) with the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) in two mouse models of late-stage GBM.

The rationale of the study was as follows:

• The KD-R reduces glucose availability and increases levels of ketone bodies, which cannot be used by GBM cells.
• DON inhibits glutaminolysis, depriving the tumor of another key fuel source.

Key findings:

•  Tumor control: The combination of KD-R and DON effectively reduced tumor growth (60-70% for 0.5 mg/kg DON; near complete resolution for DON 1 mg/kg) and reduced disease symptoms.
• Improved survival: The combination of KD-R and DON significantly improved overall survival in both mouse models of GBM (mice survival until day 40 and onwards, vs untreated mice who died between day 15 and 18).
• Reduced complications: Treatment led to a reduction in tumor-associated edema, hemorrhage, and inflammation.
• Enhanced drug delivery: The KD-R diet improved the delivery of DON to the brain, allowing a lower dosage to achieve therapeutic effects.

These findings suggest that targeting glucose and glutamine metabolism by combining a calorie-restricted ketogenic diet and DON could be an effective approach to managing GBM.