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

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 [211At]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.