Polyamine pathway inhibition as a novel therapeutic approach to treating neuroblastoma
Polyamines are highly regulated essential cations that are elevated in rapidly proliferating tissues, including diverse cancers. Expression analyses in neuroblastomas suggest that upregulation of polyamine pro-synthetic enzymes and downregulation of catabolic enzymes is associated with poor prognosi...
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doaj-de2d901897dc4c3d92f85300445c39002020-11-24T21:20:10ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2012-11-01210.3389/fonc.2012.0016234394Polyamine pathway inhibition as a novel therapeutic approach to treating neuroblastomaLaura Dawn Gamble0Michael D Hogarty1Xuenyuan eLiu2David S Ziegler3David S Ziegler4Glenn M Marshall5Glenn M Marshall6Murray D Norris7Michelle eHaber8Children’s Cancer Institute Australia for Medical ResearchThe Children's Hospital of Philadelphia, Perelman School of Medicine at the University of PennsylvaniaThe Children's Hospital of Philadelphia, Perelman School of Medicine at the University of PennsylvaniaChildren’s Cancer Institute Australia for Medical ResearchSydney Children's HospitalChildren’s Cancer Institute Australia for Medical ResearchSydney Children's HospitalChildren’s Cancer Institute Australia for Medical ResearchChildren’s Cancer Institute Australia for Medical ResearchPolyamines are highly regulated essential cations that are elevated in rapidly proliferating tissues, including diverse cancers. Expression analyses in neuroblastomas suggest that upregulation of polyamine pro-synthetic enzymes and downregulation of catabolic enzymes is associated with poor prognosis. Polyamine sufficiency may be required for MYCN oncogenicity in MYCN amplified neuroblastoma, and targeting polyamine homeostasis may therefore provide an attractive therapeutic approach. ODC1, an oncogenic MYCN target, is rate-limiting for polyamine synthesis, and is overexpressed in many cancers including neuroblastoma. Inhibition of ODC1 by difluoromethylornithine (DFMO) decreased tumour penetrance in TH-MYCN mice treated pre-emptively, and extended survival and synergized with chemotherapy in treating established tumours in both TH-MYCN and xenograft models. Efforts to augment DFMO activity, or otherwise maximally reduce polyamine levels, are focused on antagonizing polyamine uptake or augmenting polyamine export or catabolism. Since polyamine inhibition appears to be clinically well tolerated, these approaches, particularly when combined with chemotherapy, have great potential for improving neuroblastoma outcome in both MYCN amplified and non-MYCN amplified neuroblastomas.http://journal.frontiersin.org/Journal/10.3389/fonc.2012.00162/fullNeuroblastomaPolyaminesMYCNODC1DFMO |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Laura Dawn Gamble Michael D Hogarty Xuenyuan eLiu David S Ziegler David S Ziegler Glenn M Marshall Glenn M Marshall Murray D Norris Michelle eHaber |
spellingShingle |
Laura Dawn Gamble Michael D Hogarty Xuenyuan eLiu David S Ziegler David S Ziegler Glenn M Marshall Glenn M Marshall Murray D Norris Michelle eHaber Polyamine pathway inhibition as a novel therapeutic approach to treating neuroblastoma Frontiers in Oncology Neuroblastoma Polyamines MYCN ODC1 DFMO |
author_facet |
Laura Dawn Gamble Michael D Hogarty Xuenyuan eLiu David S Ziegler David S Ziegler Glenn M Marshall Glenn M Marshall Murray D Norris Michelle eHaber |
author_sort |
Laura Dawn Gamble |
title |
Polyamine pathway inhibition as a novel therapeutic approach to treating neuroblastoma |
title_short |
Polyamine pathway inhibition as a novel therapeutic approach to treating neuroblastoma |
title_full |
Polyamine pathway inhibition as a novel therapeutic approach to treating neuroblastoma |
title_fullStr |
Polyamine pathway inhibition as a novel therapeutic approach to treating neuroblastoma |
title_full_unstemmed |
Polyamine pathway inhibition as a novel therapeutic approach to treating neuroblastoma |
title_sort |
polyamine pathway inhibition as a novel therapeutic approach to treating neuroblastoma |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Oncology |
issn |
2234-943X |
publishDate |
2012-11-01 |
description |
Polyamines are highly regulated essential cations that are elevated in rapidly proliferating tissues, including diverse cancers. Expression analyses in neuroblastomas suggest that upregulation of polyamine pro-synthetic enzymes and downregulation of catabolic enzymes is associated with poor prognosis. Polyamine sufficiency may be required for MYCN oncogenicity in MYCN amplified neuroblastoma, and targeting polyamine homeostasis may therefore provide an attractive therapeutic approach. ODC1, an oncogenic MYCN target, is rate-limiting for polyamine synthesis, and is overexpressed in many cancers including neuroblastoma. Inhibition of ODC1 by difluoromethylornithine (DFMO) decreased tumour penetrance in TH-MYCN mice treated pre-emptively, and extended survival and synergized with chemotherapy in treating established tumours in both TH-MYCN and xenograft models. Efforts to augment DFMO activity, or otherwise maximally reduce polyamine levels, are focused on antagonizing polyamine uptake or augmenting polyamine export or catabolism. Since polyamine inhibition appears to be clinically well tolerated, these approaches, particularly when combined with chemotherapy, have great potential for improving neuroblastoma outcome in both MYCN amplified and non-MYCN amplified neuroblastomas. |
topic |
Neuroblastoma Polyamines MYCN ODC1 DFMO |
url |
http://journal.frontiersin.org/Journal/10.3389/fonc.2012.00162/full |
work_keys_str_mv |
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