Aurora Kinase A inhibition enhances DNA damage and tumor cell death with 131I-MIBG therapy in high-risk neuroblastoma

Prerna Kumar; Jessica Koach; Erin Nekritz; Sucheta Mukherjee; Benjamin S Braun; Steven G DuBois; Nicole Nasholm; Daphne Haas-Kogan; Katherine K Matthay; William A Weiss; Clay Gustafson; Youngho Seo

doi:10.1186/s13550-024-01112-7

Aurora Kinase A inhibition enhances DNA damage and tumor cell death with ¹³¹I-MIBG therapy in high-risk neuroblastoma

EJNMMI Res. 2024 Jun 13;14(1):54. doi: 10.1186/s13550-024-01112-7.

Authors

Prerna Kumar^#^{1

2}, Jessica Koach^#³, Erin Nekritz³, Sucheta Mukherjee³, Benjamin S Braun^{3

4}, Steven G DuBois⁵, Nicole Nasholm³, Daphne Haas-Kogan⁶, Katherine K Matthay^{3

4}, William A Weiss^{3

7

4}, Clay Gustafson^#^{3

4}, Youngho Seo^#^{8

4}

Affiliations

¹ Department of Pediatrics, University of Illinois College of Medicine at Peoria, 530 NE Glen Oak Ave, Peoria, IL, 61637, USA. prerna@uic.edu.
² Department of Pediatrics, University of California, San Francisco, CA, USA. prerna@uic.edu.
³ Department of Pediatrics, University of California, San Francisco, CA, USA.
⁴ Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, CA, USA.
⁵ Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.
⁶ Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Departments of Neurology, Neurosurgery, and Brain Tumor Research Center, University of California San Francisco, San Francisco, CA, USA.
⁸ Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.

^# Contributed equally.

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.

Keywords: 131I-MIBG; Aurora Kinase A inhibitors; Metaiodobenzylguanidine; Neuroblastoma; Radiopharmaceutical.

Abstract

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