Medulloblastoma and the DNA Damage Response

• Type of Material: Article
• Authors: Leon F McSwain, Emory University; Kiran K Parwani, Emory University; Shubin Shahab, Emory University; Dolores Hambardzumyan, Emory University; Tobey MacDonald, Emory University; Jennifer Spangle, Emory University; Anna Kenney, Emory University
• Language: English
• Date: 2022-06-07
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2022 McSwain, Parwani, Shahab, Hambardzumyan, MacDonald, Spangle and Kenney
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fonc.2022.903830
• Title of Journal or Parent Work: FRONTIERS IN ONCOLOGY
• Volume: 12
• Start Page: 903830
• End Page: 903830
• Grant/Funding Information: JS is supported by NCI 4R00CA204601. AK is supported by NINDS R01NS110386 and Alex’s Lemonade Stand Foundation for Childhood Cancer Research. Dr.s JS and AK are members of the Winship Cancer Institute (P30 Center Grant CA138292).
• Keywords: Life Sciences & Biomedicine; therapeutic targeting; HOMOLOGOUS RECOMBINATION; Oncology; P53 GENE-MUTATIONS; MOLECULAR SUBGROUPS; SUPPRESS MEDULLOBLASTOMA; radiation oncology; APURINIC/APYRIMIDINIC ENDONUCLEASE ACTIVITY; Science & Technology; pediatrics; CHILDHOOD MEDULLOBLASTOMA; p53 status; medulloblastoma; IONIZING-RADIATION; REPAIR PATHWAYS; WIP1 PHOSPHATASE; EXCISION-REPAIR
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in children with standard of care consisting of surgery, radiation, and chemotherapy. Recent molecular profiling led to the identification of four molecularly distinct MB subgroups – Wingless (WNT), Sonic Hedgehog (SHH), Group 3, and Group 4. Despite genomic MB characterization and subsequent tumor stratification, clinical treatment paradigms are still largely driven by histology, degree of surgical resection, and presence or absence of metastasis rather than molecular profile. Patients usually undergo resection of their tumor followed by craniospinal radiation (CSI) and a 6 month to one-year multi-agent chemotherapeutic regimen. While there is clearly a need for development of targeted agents specific to the molecular alterations of each patient, targeting proteins responsible for DNA damage repair could have a broader impact regardless of molecular subgrouping. DNA damage response (DDR) protein inhibitors have recently emerged as targeted agents with potent activity as monotherapy or in combination in different cancers. Here we discuss the molecular underpinnings of genomic instability in MB and potential avenues for exploitation through DNA damage response inhibition.