Poster Presentation Advances in Neuroblastoma Research Congress 2016

Targeting the polyamine pathway in combination with conventional chemotherapy for the treatment of childhood neuroblastoma (#290)

Laura D. Gamble 1 , Jayne Murray 1 , Georgina Eden 1 , Sophie Allan 1 , Asel Biktasova 1 , Angelika Kosciolek 1 , Glenn M. Marshall 1 2 , David S. Ziegler 2 , Michael D. Hogarty 3 , Murray D. Norris 1 , Michelle Haber 1
  1. Children's Cancer Institute Australia, Randwick, NSW, Australia
  2. Sydney Chilren's Hospital, Sydney, Australia
  3. The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

Introduction

Polyamines are highly regulated essential cations that are elevated in rapidly proliferating tissues. We have previously shown that the MYCN/MYC transcriptional target ornithine decarboxylase (ODC1), the rate-limiting enzyme for polyamine biosynthesis, is a therapeutic target for neuroblastoma (Cancer Res 68:9735, 2008).  In addition, we found that each member of the polyamine pathway is regulated by MYCN and that their expression is prognostic of outcome. We have shown that the FDA-approved ODC1 suicide inhibitor, difluoromethylornithine (DFMO), represents a potentially powerful treatment strategy when combined with chemotherapy. Based on our research, a NANT Phase I clinical trial combining DFMO with conventional chemotherapy and an inducer of catabolic SAT1, Celebrex, is currently underway, with early results showing promising responses. We have now investigated combining DFMO with other polyamine depletion agents to further improve this form of therapy.

Methods

Cytotoxicity assays, colony assays, and determination of synergy were performed with combinations of polyamine depletion compounds and chemotherapeutic agents as previously described (Sci Transl Med 7(32):312 2015). The TH-MYCN transgenic mouse model was used to study the most effective combinations in vivo.

Results

We investigated a range of compounds targeting various components of the polyamine pathway including blocking polyamine synthesis (DFMO, 4MCHA, APCHA), promoting polyamine catabolism (Celebrex), blocking polyamine uptake (AMXT-1501) and polyamine analogues (CGC-11047, CGC-11093, CGC-11144, ANTMHSpd). Amongst these agents, CGC-11093, which has been studied in a phase I clinical trial for the treatment of cancer, was found to be highly synergistic with both DFMO and chemotherapy. Moreover, the combination of DFMO and AMXT-1501 is also proving to be effective at inhibiting tumour progression in TH-MYCN mice, particularly when combined with conventional chemotherapy.

Conclusions

These data highlight the therapeutic potential of treating neuroblastoma by targeting multiple steps in the polyamine pathway in combination with conventional chemotherapy.