Abstract 1146: [18F]FPyGal: A novel ß-galactosidase specific PET tracer forin vivoimaging of tumor senescence

Senescence influences treatment outcome in cancer. Therefore it is of great interest to develop a diagnostic tool to detect senescent cells in cancer patients. Here we describe the evaluation of the PET tracer FPyGal for non-invasive imaging of s-galactosidase as a surrogate marker for senescence. In vitro, we induced senescence in HCT116 cells by doxorubicin, in a liver progenitor cell line by p53-reactivation and in two liver carcinoma cell lines by a ribosomal checkpoint inhibitor (RCI). The cells were then incubated with FPyGal and tracer uptake was determined in a gamma-counter. For in vivo testing, the described cell lines were injected s.c. in mice. The tumor bearing mice were then treated appropriately to induce senescence. PET/MR scans were performed after i.v. injection of FPyGal for assessment of tracer uptake in the tumors. Ex vivo autoradiographies and X-Gal stainings were prepared to correlate intratumoral distribution of ⇓-galactosidase activity and tracer uptake. After toxicology studies, a pilot first-in-man study was performed in a cancer patient treated with Alisertib. Compared to the respective control cells, in vitro tracer uptake was significantly increased in all four cellular models tested. The strongest increase was observed in one of the liver carcinoma cell lines with a >3-fold increase in senescent cells. FPyGal tracer uptake increased in control HCT116 tumors from 1.1 to 1.7%ID/cc in senescent cells in in vivo PET/MRI studies and in the HRas model from 0.9 to 1.5 %ID/cc. In one of the liver tumor models we could observe a 2-fold increase in treated mice. Ex vivo ⇓-galactosidase staining and IHC of tumor tissue confirmed induction of senescence. Autoradiography and X-Gal staining showed an intratumoral correlation of ⇓-gal activity and FPyGal uptake. The compound passed the toxicology tests. A first patient study revealed high and heterogeneous tracer uptake in a liver metastasis. FPyGal shows increased in vitro and in vivo uptake in senescent cells and tumors. No toxicity of the compound could be detected and a first-in-man study showed promising results. Clinical trials including histological cross-validation are currently being prepared. Citation Format: Marcel A. Krueger, Jonathan M. Cotton, Benyuan Zhou, Katharina Wolter, Johannes Schwenck, Anna Kuehn, Kerstin Fuchs, Andreas Maurer, Christian La Fougere, Lars Zender, Bernd J. Pichler. [18F]FPyGal: A novel s-galactosidase specific PET tracer for in vivo imaging of tumor senescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1146.