Leptin, BMI, and a Metabolic Gene Expression Signature Associated with Clinical Outcome to VEGF Inhibition in...

Area of Science:

• Oncology
• Molecular Biology
• Clinical Trials

Background:

• Vascular Endothelial Growth Factor (VEGF) inhibitors are crucial in cancer therapy, but effective patient selection remains difficult.
• Identifying predictive biomarkers is essential for optimizing anti-angiogenic treatment strategies.

Purpose of the Study:

• To identify patient physiological and tumor biological factors that predict response to VEGF receptor inhibitor cediranib in metastatic colorectal cancer.
• To correlate metabolic and angiogenic gene expression profiles with clinical outcomes in patients treated with cediranib.

Main Methods:

• Analysis of samples from a Phase III clinical trial comparing chemotherapy with chemotherapy plus cediranib.
• Assessment of circulating leptin levels, Body Mass Index (BMI), and tumor gene expression profiles.
• Validation of findings in pre-clinical tumor xenograft models.

Main Results:

• Circulating leptin levels, BMI, and a specific tumor metabolic/angiogenic gene signature predicted improved outcomes with cediranib.
• Patients with glycolytic and hypoxic/angiogenic profiles showed greater benefit from cediranib.
• Patients with lipogenic, oxidative phosphorylation, and serine biosynthesis profiles did not benefit from cediranib.

Conclusions:

• Patient physiology and tumor biology are linked to response to anti-angiogenic therapy.
• Metabolic profiling can identify patients likely to benefit from VEGF pathway inhibitors.
• These findings may guide future patient selection for VEGF-targeted therapies.