Targeted Brain Tumor Radiotherapy Using an Auger Emitter.

Published on Feb 17, 2020in Clinical Cancer Research10.107
· DOI :10.1158/1078-0432.CCR-19-2440
Giacomo Pirovano9
Estimated H-index: 9
(MSK: Memorial Sloan Kettering Cancer Center),
Stephen A. Jannetti6
Estimated H-index: 6
(MSK: Memorial Sloan Kettering Cancer Center)
+ 9 AuthorsThomas Reiner39
Estimated H-index: 39
(Cornell University)
Purpose: Glioblastoma multiforme is a highly aggressive form of brain cancer whose location, tendency to infiltrate healthy surrounding tissue, and heterogeneity significantly limit survival, with scant progress having been made in recent decades. Experimental design: 123 I-MAPi (Iodine-123 Meitner-Auger PARP1 inhibitor) is a precise therapeutic tool composed of a PARP1 inhibitor radiolabeled with an Auger- and gamma-emitting iodine isotope. Here, the PARP inhibitor, which binds to the DNA repair enzyme PARP1, specifically targets cancer cells, sparing healthy tissue, and carries a radioactive payload within reach of the cancer cells9 DNA. Results: The high relative biological efficacy of Auger electrons within their short range of action is leveraged to inflict DNA damage and cell death with high precision. The gamma ray emission of 123 I-MAPi allows for the imaging of tumor progression and therapy response, and for patient dosimetry calculation. Here we demonstrated the efficacy and specificity of this small molecule radiotheranostic in a complex preclinical model. In vitro and in vivo studies demonstrate high tumor uptake and a prolonged survival in mice treated with 123 I-MAPi when compared to vehicle controls. Different methods of drug delivery were investigated to develop this technology for clinical applications, including convection enhanced delivery (CED) and intrathecal injection. Conclusions: Taken together, these results represent the first full characterization of an Auger-emitting PARP inhibitor which demonstrate a survival benefit in mouse models of GBM and confirm the high potential of 123 I-MAPi for clinical translation.
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