Abstract 3921: Poly(ADP-ribose) polymerase 1 (PARP-1) targeting radionuclides are highly cytotoxic across a panel of 20 neuroblastoma cell lines
Authors: Hwan Lee, Adam Mansfield, Minu Samanta, Sean W. Reilly, Kuiying Xu, Sean D. Carlin, John M. Maris, Robert H. Mach, Mehran Makvandi, Daniel A. Pryma
Journal: Cancer Research (2019)

Abstract Introduction: Neuroblastoma is the most common extracranial solid malignancy in childhood, with only up to 50% 5-year survival in high-risk cases. It overexpresses the nuclear enzyme PARP-1, which can be targeted for specific delivery of radionuclides to DNA. Two such novel radiolabeled small molecule therapeutics are [211At]MM4, containing an alpha particle-emitting astatine-211, and [125I]KX1, containing an Auger electron-emitting iodine-125. Methods: Twenty human neuroblastoma cell lines were screened in vitro for sensitivity to [211At]MM4 and [125I]KX1, with non-targeted radionuclides and non-radioactive PARP-1 inhibitors as controls. Next, one sensitive and one resistant cell line was chosen for dosimetry based on radiopharmacology and cellular geometry properties measured specific to each therapeutic and cell line. Monte Carlo simulation was then performed to calculate the radiation dose to the cell nucleus at 50% cell kill. Relative biological effectiveness (RBE) of alpha and Auger particles against gamma irradiation was determined. Finally, the mechanism responsible for differential radiosensitivity across the twenty cell lines was examined by correlation with PARP-1 mRNA level. Results: [211At]MM4 and [125I]KX1 showed closely correlated (R2=0.93) cytotoxicity across the twenty neuroblastoma cell lines. [211At]MM4 demonstrated 102-103 times and 108-109 times greater cytotoxic potency compared to unbound 211At and its non-radioactive PARP-1 inhibitor analog respectively. More sensitive cell lines demonstrated greater sensitivity to [211At]MM4 even when normalized against their sensitivity to alpha radiation (R2=0.40, p&amp;lt;0.01). [125I]KX1 also showed 104-106 times greater potency than its non-radioactive analog. No cell kill by biochemical inhibition of PARP-1 was seen at therapeutic doses of [211At]MM4 and [125I]KX1.The sensitive and resistant cell lines had similar PARP-1 binding of [211At]MM4 and [125I]KX1, but only the sensitive cell line had significantly higher RBE of alpha (9.2) and Auger (4.2) radiation compared to external gamma irradiation. RBE of alpha against Auger therapy was similar in both sensitive (2.2) and insensitive (1.9) cell lines. Cytotoxic sensitivity to PARP-1 targeted radiopharmaceutical was not correlated with PARP-1 mRNA level (R2=0.10, p=0.17). Conclusion: Delivery of alpha and Auger emitters directly to neuroblastoma nuclear DNA by radiolabeled PARP-1 inhibitors results in enhanced cytotoxicity without requiring enzymatic PARP-1 inhibition. Sensitivity to radiolabeled PARP-1 inhibitors is characterized by increased RBE against gamma irradiation and only partially explained by inherent radiosensitivity, warranting further investigation of underlying biological factors. This promising efficacy in vitro can be examined in vivo and in other cancer types for broader application. Citation Format: Hwan Lee, Adam Mansfield, Minu Samanta, Sean W. Reilly, Kuiying Xu, Sean D. Carlin, John M. Maris, Robert H. Mach, Mehran Makvandi, Daniel A. Pryma. Poly(ADP-ribose) polymerase 1 (PARP-1) targeting radionuclides are highly cytotoxic across a panel of 20 neuroblastoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3921.