CBL0137, a novel NFkB suppressor and p53 activator, is highly effective in two independent pre-clinical mouse models of neuroblastoma — ASN Events
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CBL0137, a novel NFkB suppressor and p53 activator, is highly effective in two independent pre-clinical mouse models of neuroblastoma (#136)

Jayne Murray 1 , Michelle Haber 1 , Laura Gamble 1 , Ashleigh Carnegie-Clark 1 , Hannah Webber 1 , Michelle Ruhle 1 , Andrew Gifford 1 , Daniel Carter 1 , Andre Oberthuer 2 , Matthias Fischer 2 , David Ziegler 1 , Glenn Marshall 1 3 , Katerina Gurova 4 , Catherine Burkhart 5 , Andrei Purmal 5 , Andrei Gudkov 4 , Murray Norris 1
  1. Children's Cancer Institute, RANDWICK, NSW, Australia
  2. Department of Pediatric Oncology and Hematology and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
  3. Kids Cancer Centre, Sydney Children's Hospital, Sydney, Australia
  4. Roswell Park Cancer Institute, Buffalo, NY, USA
  5. Cleveland BioLabs, Inc., Buffalo, NY, USA

Background: CBL0137 is a carbazole-based anti-cancer agent with a unique mechanism of action. It is an indirect inhibitor of the chromatin remodeling complex FACT (Facilitates Chromatin Transcription). Inhibition of FACT by CBL0137 modulates the activity of several transcription factors involved in cancer: NF-kB and HSF1 are suppressed, while p53 is activated (1).

 

Methods: Expression profiles of650 primary untreated neuroblastomas were analyzed for the expression of two FACT subunits, SSRP1 and SPT16, and related to clinical outcome. Colony-forming assays were used to study the effect of CBL0137, either alone or combined with chemotherapeutic drugs in human MYCN-amplified neuroblastoma cell lines. Cohorts of tumour-bearing TH-MYCN transgenic mice or human neuroblastoma (BE(2)-C) xenografted nude mice, were treated with CBL0137, alone or combined with chemotherapeutic drugs.

Results: High levels of the FACT subunits SSRP1 and SPT16 were associated with MYCN amplification, and strongly predictive of poor neuroblastoma outcome (p<0.0001). Single agent CBL0137 administered iv had remarkable anti-tumour activity in both the TH-MYCN and xenograft mouse models. CBL0137 also synergized strongly with a variety of chemotherapeutic agents, including vincristine, cisplatin, etoposide and cyclophosphamide, both in vitro in colony forming assays and in vivo, in TH-MYCN tumour-bearing mice. Most dramatic results were observed when CBL0137 was combined with the standard neuroblastoma relapse protocol of cyclophosphamide/topotecan, a highly active therapy for relapsed neuroblastoma. Cyclophosphamide/topotecan plus CBL0137 resulted in cure of 90% of tumour-bearing MYCN-transgenic mice and a doubling of the lifespan of BE(2)-C xenografted nude mice. CBL0137 also synergized strongly with the alternate relapse backbone, irinotecan/temozolomide.

 

Conclusion: These results are superior to any combination chemotherapy regimens we have tested in these models, and a Phase I Children’s Oncology Group (USA) trial of CBL0137 in refractory pediatric cancer patients is currently being planned.

  1. Sci Transl Med. 2011 Aug 10;3(95):95ra74