3496 - Tumor-Induced Metabolic Stress and Subclinical Cardiac Injury in Tumor-Bearing Mice and Its Modulation by TEPP-46

Purpose/Objective(s):

Cardiac disease remains a concern in patients treated with chemoradiation for locally advanced NSCLC, and emerging evidence suggests that pre-existing metabolic stress may contribute to cardiac toxicity before and during treatment. This preliminary animal study evaluated whether presence of tumor is associated with systemic metabolic alterations and subclinical cardiac injury, and whether these effects can be modulated by the anti-glycolytic TEPP-46.

Materials/Methods:

Fifteen C57BL/6 mice were enrolled: ten implanted subcutaneously with Lewis lung carcinoma (LLC1) cells and five non-tumor-bearing mice serving as healthy controls. Among the tumor-bearing mice, five received the anti-glycolytic agent TEPP-46 given 50 mg/kg twice-daily, which was reduced to 50 mg/kg once-daily due to toxicity resulting in three deaths by day 10. Tumor volumes were measured daily. Blood was collected when the tumors approached the humane endpoint of 2 cm³. Cardiac troponin T levels were measured in the plasma with ELISA as the primary endpoint. Untargeted metabolomic profiling was performed on plasma samples using high-resolution mass spectrometry, with relative abundance of metabolites (e.g., L-lactate) serving as the secondary endpoint. Metabolomics was analyzed using one-way ANOVA with FDR-corrected pairwise comparisons and principal component analysis (PCA) was used to assess group-level metabolic differences. Troponin T levels were analyzed using one-way ANOVA with Bonferroni-adjusted post-hoc test (a = 0.05).

Results:

Plasma cardiac troponin T was significantly elevated in tumor-bearing mice compared with healthy controls (18.2 pg/mL vs. 2.2 pg/mL, p < 0.0001). TEPP-46 treatment prevented this increase, with troponin T levels not differing significantly from controls (p = 0.99). Metabolomics showed significant upregulation of multiple tumor-associated metabolites in untreated tumor-bearing mice, including elevated L-lactate (p = 0.01). TEPP-46 reduced relative abundance of L-Lactate in the plasma (p < 0.0001). Principal component analysis demonstrated distinct metabolic clustering of untreated tumor-bearing mice relative to controls, whereas TEPP-46–treated mice showed a metabolic profile shifted toward the healthy control group.

Conclusion:

These preliminary findings suggest that presence of tumor is associated with systemic metabolic stress and subclinical cardiac injury in mice. Elevated plasma lactate and increased cardiac troponin T in tumor-bearing mice support a potential link between tumor-related metabolic alterations and cardiac vulnerability. TEPP-46 reduced both metabolic abnormalities and troponin T elevations, indicating metabolic modulation may mitigate these effects. A definitive study is planned to validate these observations and further explore the role of tumor-associated metabolic stress in cardiac injury.