Targeting PARP-1 with Alpha-Particles Is Potently Cytotoxic to Human Neuroblastoma in Preclinical Models.
Mehran MakvandiHwan LeeLaura N PuentesSean W ReillyKomal S RathiChi-Chang WengHo Sze ChanCatherine HouPichai RamanDaniel MartinezKuiying XuSean D CarlinRoger A GreenbergBruce R PawelRobert H MachJohn M MarisDaniel A PrymaPublished in: Molecular cancer therapeutics (2019)
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 [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 preclinical proof of concept for an alpha-emitting drug conjugate that directly targets cancer chromatin as a therapeutic approach for neuroblastoma and perhaps other cancers.
Keyphrases
- dna damage
- dna repair
- oxidative stress
- newly diagnosed
- transcription factor
- ejection fraction
- stem cells
- radiation therapy
- squamous cell carcinoma
- papillary thyroid
- bone marrow
- fluorescent probe
- emergency department
- dna methylation
- small molecule
- single molecule
- drug delivery
- living cells
- high resolution
- circulating tumor cells
- protein protein
- anti inflammatory