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Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage
Published on: August 21, 2021
Medulloblastoma and the DNA Damage Response
Leon F McSwain1, Kiran K Parwani2,3, Shubin W Shahab2
1Department of Pediatrics, Emory University, Atlanta, GA, United States.
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.
Insights
Targeting DNA damage repair proteins offers a promising strategy for treating medulloblastoma (MB), the most common pediatric brain cancer. This approach could provide broad impact across all molecular subgroups of MB.
Area of Science:
- Pediatric Oncology
- Cancer Genomics
- Molecular Biology
Background:
- Medulloblastoma (MB) is the most common malignant pediatric brain tumor.
- Current treatments include surgery, radiation, and chemotherapy, often guided by histology rather than molecular profile.
- Four distinct molecular subgroups (WNT, SHH, Group 3, Group 4) have been identified, yet treatment stratification remains limited.
Purpose of the Study:
- To explore the potential of targeting DNA damage response (DDR) pathways in medulloblastoma.
- To discuss the molecular basis of genomic instability in MB.
- To identify novel therapeutic strategies for MB irrespective of molecular subgroup.
Main Methods:
- Review of molecular underpinnings of genomic instability in medulloblastoma.
- Analysis of DNA damage response (DDR) pathways relevant to cancer therapy.
- Exploration of DDR inhibitors as potential therapeutic agents for MB.
Main Results:
- Genomic instability is a key feature of medulloblastoma.
- DNA damage response (DDR) proteins are critical for cancer cell survival.
- DDR inhibitors show promise as monotherapy or in combination for various cancers.
Conclusions:
- Targeting DNA damage repair mechanisms presents a viable therapeutic strategy for medulloblastoma.
- Inhibitors of DDR proteins could offer a broad-impact approach across all MB molecular subgroups.
- Further research into DDR inhibition is warranted for developing novel MB treatments.
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