Physical Poster + E-Poster Presentation 34th Lorne Cancer Conference 2022

Development of targeted epigenetic combination therapies for the treatment of neuroblastoma (#224)

DAENIKKA RAVINDRARAJAH 1 , JANITH A Seneviratne 1 , DANIEL R CARTER 1 2 , Glenn M Marshall 1 3 , BELAMY B CHEUNG 1 4
  1. Embryonal Cancer Therapy and Prevention, Children's Cancer Institute, Lowy Cancer Research Centre, Randwick, NSW, Australia
  2. School of Biomedical Engineering, University of Technology Sydney, Ultimo, NSW, Australia
  3. Kids Cancer Centre, Sydney Children’s Hospital, Randwick, NSW, Australia
  4. School of Women’s and Children’s Health, University of New South Wales Australia, Sydney, NSW, Australia

Drug resistance to induction chemotherapy agents represents an obstacle to improving neuroblastoma patient outcomes1. Targeted combination therapies represent a significant benefit for these drug-resistant patients, as they minimise the chance of acquiring further resistance2. Recent studies have exemplified that neuroblastoma tumours have a unique oncogenic dependency on epigenetic processes, and that their targeting with small molecule inhibitors results in highly efficacious anti-cancer activity in pre-clinical models3,4. The targeting of epigenetic regulators at the level of histones or DNA was of great interest given recent discoveries highlighting the importance of enhancer landscapes in defining phenotypic plasticity and dug sensitivity in neuroblastoma5-7. Drug inhibitors targeting these DNA regulatory processes in cancer have multiple targets including histone methyltransferases (HMTs) which modulate the cancerous gene transcription8. To identify novel targeted combination therapies in neuroblastoma, we performed a high-throughput combinatorial drug screen in the chemo-resistant neuroblastoma cell line. The combinatorial drug screening revealed strong anti-cancer synergy between histone methyltransferase EZH2 and DOT1L inhibitors: GSK343 and SGC0946, respectively. The chemical and genetic perturbation of specific HMTs in neuroblastoma, EZH2 and DOT1L, have previously been demonstrated to reduce neuroblastoma tumour growth. We found the combination of these two HMTs with their respective inhibitors resulted in synergistic cell death in vitro and anti-tumour effects in vivo. Molecular profiling of mRNA from the combination of GSK343 and SGC0946 treated neuroblastoma cells indicated that a several key genes in the endoplasmic reticulum stress (ER) pathway were also downregulated. ER stress signatures derived from SGC0946, and GSK343 combination therapy responses in vitro were found to associate with better neuroblastoma patient prognoses. This is the first reported occurrence of such synergy and the anti-tumour efficacy observed in neuroblastoma animal models also presents promising clinical translation in the future.

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