Abstract
Targeted thorium-227 conjugates (TTCs) represent a novel class of therapeutic radiopharmaceuticals for the treatment of cancer. TTCs consist of the alpha particle emitter thorium-227 complexed to a 3,2-hydroxypyridinone chelator conjugated to a tumor-targeting monoclonal antibody. The high energy and short range of the alpha particles induce potent and selective anti-tumor activity driven by the induction of DNA damage in the target cell. Methods: The efficacy of human epidermal growth factor receptor 2 (HER2)-TTC was tested in combination in vitro and in vivo with the poly ADP ribose polymerase (PARP) inhibitor (PARPi), olaparib, in the human colorectal adenocarcinoma isogenic cell line pair DLD-1 and the knockout variant DLD-1 BRCA2 -/- Results: The in vitro combination effects were determined to be synergistic in DLD-1 BRCA2 -/- and additive in DLD-1 parental cell lines. Similarly, the in vivo efficacy of the combination was determined to be synergistic only in the DLD-1 BRCA2 -/- xenograft model, with statistically significant tumor growth inhibition at a single TTC dose of 120 kBq/kg body weight (bw) and 50 mg/kg bw olaparib (daily, i.p. for 4 weeks), demonstrating comparable tumor growth inhibition to a single TTC dose of 600 kBq/kg bw. Conclusions: This study supports the further investigation of DNA damage response inhibitors in combination with TTCs as a new strategy for the effective treatment of mutation-associated cancers.
Highlights
Targeted alpha therapy (TAT) takes advantage of the combination of the highly potent radiobiological properties of an alpha particle emitting payload and a tumor-targeting moiety such as a monoclonal antibody
In this study we investigated whether the inhibition of the DNA repair proteins poly ADP ribose polymerase 1 (PARP-1) and poly ADP ribose polymerase 2 (PARP-2) might be synergistic in combination with the DNA damage inducer targeted thorium-227 conjugates (TTCs)
The radiochemical purity (RCP) and radiochemical yield was determined by instant thin-layer chromatography and high-purity germanium detector (HPGe) for each experiment and was shown to be consistently ≥ 95%
Summary
Targeted alpha therapy (TAT) takes advantage of the combination of the highly potent radiobiological properties of an alpha particle emitting payload and a tumor-targeting moiety such as a monoclonal antibody. Radium-223 is a calcium-mimetic that selectively targets hydroxyapatite in areas of high bone turnover such as bone metastases, exerting a cytotoxic effect on adjacent tumor cells through the induction of complex DNA double-strand breaks (DSBs) [4]. The studies presented included combination therapy with the PARP-1/2 inhibitor olaparib, which is FDA approved for treatment of BRCA-mutated ovarian and breast cancer. The human colorectal cancer isogenic cell line pair DLD-1 parental and DLD-1 BRCA2 -/-, the latter harboring a defect in the DNA double strand repair gene, was used. Both in vitro and in vivo experiments revealed a significant synergistic effect in the BRCA2 deficient model.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
