期刊
COMMUNICATIONS BIOLOGY
卷 5, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s42003-022-04209-8
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资金
- DOE-NP Isotope Program award [DE-SC0021066]
- NIH/NCI [R01CA219006, R35CA220500]
- Giulio D'Angio Endowement
- U.S. Department of Energy (DOE) [DE-SC0021066] Funding Source: U.S. Department of Energy (DOE)
The efficacy and toxicity of the PARP inhibitor parthanatine, radiolabeled with the alpha particle emitter astatine-211, in 11 patient derived neuroblastoma murine xenografts is investigated.
Astatine-211-parthanatine ([At-211]PTT) is an alpha-emitting radiopharmaceutical therapeutic that targets poly(adenosine-diphosphate-ribose) polymerase 1 (PARP1) in cancer cells. High-risk neuroblastomas exhibit among the highest PARP1 expression across solid tumors. In this study, we evaluated the efficacy of [At-211]PTT using 11 patient-derived xenograft (PDX) mouse models of high-risk neuroblastoma, and assessed hematological and marrow toxicity in a CB57/BL6 healthy mouse model. We observed broad efficacy in PDX models treated with [At-211]PTT at the maximum tolerated dose (MTD 36 MBq/kg/fraction x4) administered as a fractionated regimen. For the MTD, complete tumor response was observed in 81.8% (18 of 22) of tumors and the median event free survival was 72 days with 30% (6/20) of mice showing no measurable tumor >95 days. Reversible hematological and marrow toxicity was observed 72 hours post-treatment at the MTD, however full recovery was evident by 4 weeks post-therapy. These data support clinical development of [At-211]PTT for high-risk neuroblastoma. The efficacy and toxicity of the PARP inhibitor parthanatine, radiolabeled with the alpha particle emitter astatine-211, in 11 patient derived neuroblastoma murine xenografts is investigated.
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