Targeting PARP-1 with alpha-particles is potently cytotoxic to human neuroblastoma in pre-clinical models

• Published in: Molecular cancer therapeutics Vol. 18; no. 7; pp. 1195 - 1204
• Main Authors: Makvandi, Mehran, Lee, Hwan, Puentes, Laura N., Reilly, Sean W., Rathi, Komal S., Weng, Chi-Chang, Chan, Ho Sze, Hou, Catherine, Raman, Pichai, Martinez, Daniel, Xu, Kuiying, Carlin, Sean D., Greenberg, Roger A., Pawel, Bruce R., Mach, Robert H., Maris, John M., Pryma, Daniel A.
• Format: Journal Article
• Language: English
• Published: 09.05.2019
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-18-0837

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. Poly(ADP-ribose) polymerase (PARP) 1 is a druggable protein in the nucleus that is overexpressed in neuroblastoma compared with normal pediatric tissues and is associated with decreased survival in high-risk patients. To exploit this, we have functionalized a PARP inhibitor with an alpha-emitter astatine-211. This approach offers enhanced cytotoxicity from conventional PARP inhibitors 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 pre-clinical proof-of-concept for an alpha-emitting drug conjugate that directly targets cancer chromatin as a therapeutic approach for neuroblastoma and perhaps other cancers.