Measuring mTORC1 Signaling with Non-Invasive (89)Zr-Transferrin PET
- Author(s): Hsiao, Jeffrey Chieh
- Advisor(s): Evans, Michael J
- et al.
The diagnosis and management of the phenotypically heterogeneous and progressive disorders tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM) is a significant clinical challenge owing to a lack of disease specific biomarkers. Because the genetic mutations in TSC1 and/or TSC2 characteristic of TSC and LAM activate mTORC1 signaling, we hypothesized that disease burden could be measured with PET using 89Zr-transferrin (Tf). Toward this goal, we show that spontaneous renal cystadenomas arising in a genetically engineered mouse model heterozygous for Tsc2 were readily detectable with 89Zr-Tf PET. Moreover, subcutaneous implants of TSC and LAM cell line models consistently harbored high avidity for 89Zr-Tf in vivo. Deeper mechanistic studies showed that transferrin receptor expression and Tf biology were mTORC1 regulated in TSC and LAM models. Finally, the early treatment effects of clinically approved and experimental systemic therapies for TSC and LAM were interpretable using 89Zr-Tf PET. In summary, these data advance a translatable molecular imaging strategy that may be capable of detecting and longitudinally monitoring whole body TSC and LAM disease burden.