Monitoring rapamycin treatment response in lymphangioleiomyomatosis with [¹⁸F]fluoroethylcholine PET

Objectives: Lymphangioleiomyomatosis (LAM) is a proliferative and destructive lung disease caused by inactivating mutations in the tuberous sclerosis complex 1 or 2 genes that cause hyperactivation of the mammalian target of rapamycin complex 1 (mTORC1). Currently, there is no biomarker for early detection of LAM progression and monitoring response to treatment with mTORC1 inhibitor rapamycin. This study investigates the applicability of [¹⁸F]fluoroethylcholine ([¹⁸F]FEC) PET for direct non-invasive measurement of LAM cell metabolic activity as a biomarker of rapamycin-activity.

Methods: 13 immunodeficient mice were inoculated subcutaneously with rat leiomyoma-derived TSC2-deficient cells (V3ELT3) and received 40 min dynamic microPET/CT scans with [¹⁸F]FEC before and after treatment with 3 mg/kg/day doses of rapamycin (n=11) or control vehicle (n=2; 3 tumors): 6 were imaged after 24 hours (1 dose of rapamycin); 8 were imaged after 2 days (3 doses of rapamycin/vehicle). Time activity curves, expressed as standardized uptake value (SUV; activity concentration normalized by dose and body weight), pre and post treatment were compared. After post imaging, tumor tissue was extracted and histology was performed to confirm rapamycin activity. In addition, ¹⁹F NMR was performed on ELT3 cells treated with rapamycin.

Results: Tumor SUV measured at 30-40 min p.i. decreased significantly (p<0.01) after 3 doses of rapamycin (-50±21%; n=6) compared to an increase (+27±13%; n=2) for controls; histology confirmed rapamycin activity. After 1 dose of rapamycin, results were variable with decreased SUV for 4 mice (-13±6%) and increased SUV for 1 mouse (+15%); histological assessment is ongoing in this cohort. NMR confirmed a 20% decrease in [¹⁹F]FEC incorporation into lipids after 24 hour treatment with 20 nM rapamycin.

Conclusion: These results indicate that [¹⁸F]FEC PET is sensitive to rapamycin-activity and shows promise as a biomarker for LAM diagnostics and therapeutic evaluation. Research Support: Department of Defense W81XWH-13-1-0262; Tuberous Sclerosis Alliance Research Grant; LAM Foundation Biomarker Innovation Grant