Targeting PARP-1 with Alpha-Particles Is Potently Cytotoxic to Human Neuroblastoma in Preclinical Models

Abstract

Alpha-emitters can be pharmacologically delivered for irradiation of single cancer cells, but cellular lethality could be further enhanced by targeting alpha-emitters directly to the nucleus. PARP-1 is a druggable protein in the nucleus that is overexpressed in neuroblastoma compared with normal tissues and is associated with decreased survival in high-risk patients. To exploit this, we have functionalized a PARP inhibitor (PARPi) with an alpha-emitter astatine-211. This approach offers enhanced cytotoxicity from conventional PARPis by not requiring enzymatic inhibition of PARP-1 to elicit DNA damage; instead, the alpha-particle directly induces multiple double-strand DNA breaks across the particle track. Here, we explored the efficacy of [ 211 At]MM4 in multiple cancers and found neuroblastoma to be highly sensitive in vitro and in vivo. Furthermore, alpha-particles delivered to neuroblastoma show antitumor effects and durable responses in a neuroblastoma xenograft model, especially when administered in a fractionated regimen. This work provides the preclinical proof of concept for an alphaemitting drug conjugate that directly targets cancer chromatin as a therapeutic approach for neuroblastoma and perhaps other cancers.

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

“…Antitumor effects were observed using an astatinated PARP inhibitor in a mouse model of neuroblastoma. Favorable uptake was observed in the tumor after 2 h. A single dose of the alpha-emitting drug was able to significantly delay tumor growth and prolong survival against a control group (Makvandi et al, 2019) ( Figures 3F, G).…”

“…Reprinted by permission from Springer Nature: Springer Molecular Imaging and Biology (Carney et al, 2016) (Non-invasive PET imaging of PARP1 expression in glioblastoma models, Carney, B, G Carlucci, B Salinas, V Di Gialleonardo, S Kossatz, A Vansteene, VA Longo, A Bolaender, G Chiosis, KR Keshari, WA Weber, and T Reiner), copyright (2016). kBq not significant, (G) and single high dose of 1,480 kBq vs. a fractionated dose of 370 kBq twice weekly for a cumulative dose of 1,480 kBq (control vs. fractionated mixed linear model p < 0.0001, fractionated vs. high dose not significant; survival Mantel-Cox test high dose vs. control p < 0.0001, fractionated vs. control p < 0.03 (Makvandi et al, 2019).…”

“…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 compounds with the best pharmacokinetics were radioiodinated and evaluated in culture and orthotopic mouse models of human glioblastoma for PARP1 specificity (Salinas et al, 2015). 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).…”

“…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).…”