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- 1. Targeting the DDR in High Risk Neuroblastoma BY DANIEL HARRISON
- 2. Neuroblastoma Sympathetic Nervous System 8% Childhood Malignancies MYCN 5 Year Survival Rate Low Risk Medium Risk High 95% 90%< 40%-50%
- 3. Why target the DNA Damage Response? C-myc has been transcriptionally and non-transcriptionally implicated in having a role in DNA replication Increased levels of DNA Damage and replication stress has been reported Is this a vulnerability that could be exploited within the context of MYCN?
- 4. Hypothesis MYCN expression will correlate with increased endogenous levels of replication stress, DNA damage, DDR and repair activity MYCN expressing/amplified cells will be more sensitive to an inhibitor of DNA repair (PARPi)
- 5. Sheptet21N
- 6. MYCN Expression Correlates with Increased DNA Damage
- 7. MYCN Expression Correlates with Increased DNA Damage H2ax 53BP1 Western confirming MYCN expression KD in sheptet21 - DK
- 8. MYCN Expression Correlates with Increased DDR Pathway Activity Rad51 DNA-Pkcs
- 9. MYCN Expression Correlates with Increased DDR Pathway Activity Rad51 DNA-Pkcs
- 10. Why was DNA Damage associated with MYCN Expression? ROS – Variable effects DNA Fibre Assay Cdc45 Replication Characteristic Result when MYCN Expressed (OFF vs ON) Mean Fork Speed kb/min 0.743 vs 0.5359 CIdU 0.8959 vs 0.668 Idu Fork Asymmetry FPR <0.75 20% vs 72%** New Origins 19% vs 33%* Stalled/Collapsed forks 7.8% vs 16.8%*** N=7 N=4
- 11. Summary so far… MYCN Replication StressDNA Damage Other (ROS?) DDR and repair Survival
- 12. Summary so far… MYCN Replication StressDNA Damage Other (ROS?) DDR and repair SurvivalDeath
- 13. Rationale for Targeting the DDR Could MYCN be more sensitive to DDRi? Replication Stress DNA Damage DDR Repair Pathways PARP-1 High Expression correlates with poor prognosis DNA Repair A Bulwark vs Replication Stress Shown Efficacy in different Cancers
- 14. PARPi Drug Target Validation
- 15. Is MYCN more sensitive to PARPi?
- 16. Why are MYCN Expressing more sensitive to PARPi?
- 17. Conclusions MYCN Expression Correlates with – Increased DNA Damage & DNA repair Olaparib treatment increases DNA damage and more fork stalling/collapse when MYCN expressed Survival and viability assays confirm MYCN expressing are more sensitive to PARPi PARP is a potentially viable drug target in high risk neuroblastoma and warrants further research