In Vivo Imaging of Tumor Senescence with a novel beta-Galactosidase specific PET Tracer
27 March 2019 (online)
Senescence, a durable cell cycle arrest, is a stress response influencing the treatment outcome in cancer. Currently senescence-associated ß-galactosidase is the gold standard biomarker for ex vivo senescence detection. Here we developed the PET tracer [18F] FPyGal for in vivo detection of senescent cells in cancer patients.
In vitro, senescence was induced in HCT116, in a liver progenitor cell and in two liver carcinoma (LC) cell lines. The tracer uptake was assessed in a gamma-counter. For in vivo experiments, the previously described cell lines were injected s.c. in mice. For senescence induction, the animals were appropriately treated with doxorubicin, doxycycline or RCI. The tracer was injected i.v., after which PET/MR scans were performed. Finally, the tracer uptake in the tumors and tumor-to-muscle ratios were calculated. After toxicology studies in rats, a pilot first-in-man study was performed in a colorectal cancer patient with liver metastases treated with senescence inducing Alisertib.
In all four cell lines, the in vitro tracer uptake was significantly increased compared to the control cells. The strongest uptake was observed in one of the LC cell lines with a factor of > 3. In vivo, remarkable tracer uptake was observed in all tumor models. The highest uptake was measured again in the LC model with an increase by a factor of ˜2 compared to non-senescent tumors. Ex vivo immunohistology and ß-gal staining confirmed the senescence induction. The compound passed the toxicology tests. A first patient study revealed heterogeneous tracer uptake in a liver metastasis, in line with expected induction of senescence in parts of the tumor. Unfortunately, a liver biopsy of the areas with high uptake was technically unsuccessful.
Owing to the low toxicity, the increased uptake of [18F]FPyGal in vitro and in vivo in senescent cells and tumors, as well as the promising first-in-man study, clinical trials including histological validation are currently being prepared.