Abstract
Background
Neuroblastoma is the most common extra-cranial pediatric solid tumor. 131I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical highly specific for neuroblastoma tumors, providing potent radiotherapy to widely metastatic disease. Aurora kinase A (AURKA) plays a role in mitosis and stabilization of the MYCN protein in neuroblastoma. We aimed to study the impact of AURKA inhibitors on DNA damage and tumor cell death in combination with 131I-MIBG therapy in a pre-clinical model of high-risk neuroblastoma.
Results
Using an in vivo model of high-risk neuroblastoma, we demonstrated a marked combinatorial effect of 131I-MIBG and alisertib on tumor growth. In MYCN amplified cell lines, the combination of radiation and an AURKA A inhibitor increased DNA damage and apoptosis and decreased MYCN protein levels.
Conclusion
The combination of AURKA inhibition with 131I-MIBG treatment is active in resistant neuroblastoma models.
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1 University of Illinois College of Medicine at Peoria, Department of Pediatrics, Peoria, USA (GRID:grid.35403.31) (ISNI:0000 0004 1936 9991); Department of Pediatrics, University of California, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)
2 Department of Pediatrics, University of California, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)
3 Department of Pediatrics, University of California, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); UCSF, Helen Diller Family Comprehensive Cancer Center, San Francisco, USA (GRID:grid.511215.3) (ISNI:0000 0004 0455 2953)
4 Harvard Medical School, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X)
5 Harvard Medical School, Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X)
6 Department of Pediatrics, University of California, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); University of California San Francisco, Departments of Neurology, Neurosurgery, and Brain Tumor Research Center, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); UCSF, Helen Diller Family Comprehensive Cancer Center, San Francisco, USA (GRID:grid.511215.3) (ISNI:0000 0004 0455 2953)
7 University of California, Department of Radiology and Biomedical Imaging, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); UCSF, Helen Diller Family Comprehensive Cancer Center, San Francisco, USA (GRID:grid.511215.3) (ISNI:0000 0004 0455 2953)