Targeted brain tumor radiotherapy using an Auger emitter

Abstract

One Sentence Summary:A novel PARP1-targeted Auger radiotherapeutic shows translational potential as a theranostic tool for imaging and killing cancer cells, resulting in tumor delineation and prolonged survival in a glioblastoma model. AbstractGlioblastoma 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. 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 cells' DNA. 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. Taken together, these results represent the first full characterization of an Auger-emitting PARP inhibitor, demonstrate a survival benefit in mouse models of GBM, and confirm the high potential of 123 I-MAPi for clinical translation.

Preclinical and first-in-human-brain-cancer applications of [18F]poly-(ADP-ribose) polymerase inhibitor PET/MR

“…A recently published study demonstrated promising results using a theragnostic Auger emitting PARP inhibitor (123I-MAPi) in a preclinical model. Taking advantage of the physical properties of Auger emission, dependent on the proximity of the electron emitter to the DNA to cause cellular damage, along with the biological expression of PARP1/2, much higher in cancer when compared to normal cells, it was possible to achieve lethal cancer doses with limited normal tissue toxicity ( 30 ).…”

Poly(ADP-Ribose)Polymerase (PARP) Inhibitors and Radiation Therapy

“…Several PARP inhibitors have also been labeled with therapeutic isotopes (Salinas et al, 2015;Jannetti et al, 2018;Reilly et al, 2018;Makvandi et al, 2019;Pirovano et al, 2019). The pharmacokinetic profiles of several iodinated PARP inhibitors based on olaparib were explored in human glioblastoma models in vitro and in vivo.…”

“…The rucaparib scaffold was also leveraged in the design and synthesis of alpha-and auger-emitting radiotherapeutics using copper-catalyzed halogenation of boronic esters (Reilly et al, 2018;Makvandi et al, 2019). The efficacy of PARP-targeted radiotherapeutics was first published in subcutaneous mouse models of glioblastoma, and later in orthotopic models of human glioblastoma (Jannetti et al, 2018;Pirovano et al, 2019). Intratumoral injections were implemented to mimic Convection Enhanced Delivery (CED).…”

“…The efficacy of combination therapies employing PARP inhibitors and external beam radiation has been demonstrated in the clinic, and several phase I clinical trials based on this approach have been completed at the time of writing (NCT00770471, NCT00649207, NCT01264432, NCT01477489, NCT01514201, NCT01657799), with results being available for some of them (Russo et al, 2009;Tangutoori et al, 2015;Dréan et al, 2016). The use of PARP inhibitors as scaffolds for radiopharmaceuticals has also blossomed in recent years (Irwin et al, 2014;Salinas et al, 2015;Carney et al, 2016;Carney et al, 2017;Jannetti et al, 2018;Reilly et al, 2018;Makvandi et al, 2019;Pirovano et al, 2019). To wit, several clinical trials of PARPinhibitor-based diagnostic imaging agents are currently in progress or have been completed ([ 18 F]FluorThanatrace (Michel et al, 2017), PARPi-FL (Kossatz et al, 2019)), and [ 18 F]PARPi (Schöder et al, 2019)) and a number of therapeutic radiopharmaceuticals based on PARP inhibitors have been employed in preclinical animal models (Kossatz et al, 2016;Michel et al, 2017;Sander Effron et al, 2017).…”

Use of radioiodine in nuclear medicine—A brief overview

“…Radioiodinated UdRs are effective as they covalently bind to DNA hence the Auger emissions are in perfect range to damage the DNA of the cancer cells. 123 I‐labelled Meitner ‐ Auger PARP1 (Figure 12) is an inhibitor used to treat a form of brain cancer known as Glioblastoma multiforme 114 . Not only can the gamma ray emission treat this type of cancer utilising Auger electrons but can also be used to image the patient and track therapeutic response and tumour advancement.…”