Oral Presentation Australian Society for Medical Research Annual Scientific Meeting 2016

Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma (#16)

Belamy B. Cheung 1 , Daniel R. Carter 1 , Jayne Murray 1 , Murray D. Norris 1 , Michelle Haber 1 , Glenn M. Marshall 1 2
  1. Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of NSW, Randwick , NSW , Australia
  2. Kids Cancer Centre, Sydney Children’s Hospital, Randwick, , Sydney, NSW, Australia

Neuroblastoma tumour initiation is characterised by transient repression of cell-deletion signals, causing embryonal neuroblasts to persist postnatally as cancer-prone lesions1. Mechanisms that escalate MYCN expression to very high levels are required to support this pre-malignant phenotype2. We now have evidence that the Facilitates Chromatin Transcription (FACT) protein complex, a histone chaperone made up of two subunits, SSRP1 and SPT16, has a crucial regulatory role with MYCN at tumour initiation3. FACT and MYCN participated in a positive feedback regulatory loop where MYCN directly bound the both the SSRP1 or SPT16 promoter in ChIP assays and FACT regulated MYCN at two levels, transcriptionally and post-translationally. Chemical inhibition of FACT with CBL0137 recapitulated the repressive effects upon MYCN expression, suggesting that targeting FACT may have therapeutic potential in MYC(N)-driven cancers. Expression of SSRP1 and SPT16 were strong biomarkers of prognosis in primary neuroblastoma samples, strongly associating with poor overall and event free survival, and showing markedly elevated expression in patients with known clinical indicators of poor prognosis. Therapeutic targeting of FACT with CBL0137 showed promising signs in TH-MYCN preclinical testing, where single agent intravenous administration caused rapid and prolonged regression of primary tumours in >75% of mice. Tumour regression was associated with direct on-target effects, including downregulation of MYCN expression, suggesting that CBL0137 has an indirect inhibitory effect on MYCN by targeting the FACT/MYCN positive feedback loop in vivo.  The cooperation between MYCN and FACT also unexpectedly created a synthetic lethality when conventional DNA damaging chemotherapy was administered with CBL0137. Low dose CBL0137 enhanced the cytopathic effects of cyclophosphamide, vincristine, etoposide and cisplatin in TH-MYCN mice. Thus targeting the FACT/MYCN positive feedback loop with CBL0137 provided the mechanistic basis for an entirely new combination anti-cancer therapy approach.

 

  1. Calao M, et al. Direct effects of Bmi1 on p53 protein stability inactivates oncoprotein stress responses in embryonal cancer precursor cells at tumour initiation. Oncogene, 2013, 32, 3616–3626. 2. Marshall GM, et al. The prenatal origins of cancer. Nature Reviews Cancer., 2014, 14: 277-289. 3. Carter DR, et al. Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma. Science Translational Medicine. 2015, Vol 7, Issue 312, 312ra176.