Preclinical Combination Studies of an FGFR2 Targeted Thorium-227 Conjugate and the ATR Inhibitor BAY 1895344

• DOI: 10.1016/j.ijrobp.2019.06.2508
• Publication Date: 2019-06-27T12:17:40Z
• Authors: Katrine Wickstroem; Urs B. Hagemann; Alexander Kristian; Christine Ellingsen; Anette Sommer; Heidrun Ellinger-...; Uta Wirnitzer; Else-Marie Hagelin; Aasmund Larsen; Roger Smeets; Roger M. Bjerke; Jenny Karlsson; Olav B. Ryan; Antje M. Wengner; Lars Linden; Dominik Mumberg; Alan S. Cuthbertson
• Keywords: 0301 basic medicine; Immunoconjugates; Cell Survival; Mice, Nude; Breast Neoplasms; Drug Synergism; Ataxia Telangiectasia Mutated Proteins; Radioimmunotherapy; Antibodies, Monoclonal, Humanized; 3. Good health; G2 Phase Cell Cycle Checkpoints; Histones; Drug Combinations; Mice; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; Molecular Targeted Therapy; Receptor, Fibroblast Growth Factor, Type 2; Protein Kinase Inhibitors; Chelating Agents; DNA Damage

Fibroblast growth factor receptor 2 (FGFR2) has been previously reported to be overexpressed in several types of cancer, whereas the expression in normal tissue is considered to be moderate to low. Thus, FGFR2 is regarded as an attractive tumor antigen for targeted alpha therapy. This study reports the evaluation of an FGFR2-targeted thorium-227 conjugate (FGFR2-TTC, BAY 2304058) comprising an anti-FGFR2 antibody, a chelator moiety covalently conjugated to the antibody, and the alpha particle-emitting radionuclide thorium-227. FGFR2-TTC was assessed as a monotherapy and in combination with the DNA damage response inhibitor ATRi BAY 1895344.The in vitro cytotoxicity and mechanism of action were evaluated by determining cell viability, the DNA damage response marker γH2A.X, and cell cycle analyses. The in vivo efficacy was determined using human tumor xenograft models in nude mice.In vitro mechanistic assays demonstrated upregulation of γH2A.X and induction of cell cycle arrest in several FGFR2-expressing cancer cell lines after treatment with FGFR2-TTC. In vivo, FGFR2-TTC significantly inhibited tumor growth at a dose of 500 kBq/kg in the xenograft models NCI-H716, SNU-16, and MFM-223. By combining FGFR2-TTC with the ATR inhibitor BAY 1895344, an increased potency was observed in vitro, as were elevated levels of γH2A.X and inhibition of FGFR2-TTC-mediated cell cycle arrest. In the MFM-223 tumor xenograft model, combination of the ATRi BAY 1895344 with FGFR2-TTC resulted in significant tumor growth inhibition at doses at which the single agents had no effect.The data provide a mechanism-based rationale for combining the FGFR2-TTC with the ATRi BAY 1895344 as a new therapeutic approach for treatment of FGFR2-positive tumors from different cancer indications.