Imaging the effects of treatment with TERT and EGFR inhibitors on glioblastoma: An MR study.

BACKGROUND

Telomerase reverse transcriptase (TERT) promoter mutations are observed in most glioblastoma (GBM) tumors, leading to TERT expression, which is crucial for tumor growth. Accordingly, inhibiting TERT or its upstream tumor-specific transcription factor GA-binding protein transcription factor subunit beta 1 (GABPB1) was shown to inhibit tumor growth. In addition, epidermal growth factor receptor (EGFR) was shown to signal upstream of TERT and GABPB1 and to control TERT expression, and EGFR inhibition also inhibits GBM growth.

METHODS

This study investigated the individual as well as combined effects of EGFR, TERT, and GABPB1 inhibition on cell and orthotopic rat models. We assessed cell proliferation, animal survival, tumor size, H magnetic resonance spectroscopy (MRS)-detectable steady-state lactate, and C MRS-detectable hyperpolarized (HP) lactate production.

RESULTS

When TERT or GABPB1 were inhibited simultaneously with EGFR, the combination treatment resulted in enhanced inhibition of cell and tumor growth as well as animal survival compared not only to controls but also to any of the single treatments. Our study also found that steady-state H MRS-detectable lactate and HP C MRS-detectable lactate production dropped following every treatment, and the drop was significantly greater following combination treatments. Furthermore, the metabolic changes occurred prior to changes in tumor size, and a reversal of these metabolic biomarkers was associated with tumor recurrence.

CONCLUSION

Our study points to the value of steady-state H MRS-detectable lactate and HP C MRS-detectable lactate as potential biomarkers of response to combination EGFR/TERT inhibition.