title: Translational development of difluoromethylornithine (DFMO) for the treatment of neuroblastoma.
abstract: Neuroblastoma is a childhood tumor in which MYC oncogenes are commonly activated to drive tumor progression. Survival for children with high-risk neuroblastoma remains poor despite treatment that incorporates high-dose chemotherapy, stem cell support, surgery, radiation therapy and immunotherapy. More effective and less toxic treatments are sought and one approach under clinical development involves re-purposing the anti-protozoan drug difluoromethylornithine (DFMO; Eflornithine) as a neuroblastoma therapeutic. DFMO is an irreversible inhibitor of ornithine decarboxylase (Odc), a MYC target gene, bona fide oncogene, and the rate-limiting enzyme in polyamine synthesis. DFMO is approved for the treatment of Trypanosoma brucei gambiense encephalitis ("African sleeping sickness") since polyamines are essential for the proliferation of these protozoa. However, polyamines are also critical for mammalian cell proliferation and the finding that MYC coordinately regulates all aspects of polyamine metabolism suggests polyamines may be required to support cancer promotion by MYC. Pre-emptive blockade of polyamine synthesis is sufficient to block tumor initiation in an otherwise fully penetrant transgenic mouse model of neuroblastoma driven by MYCN, underscoring the necessity of polyamines in this process. Moreover, polyamine depletion regimens exert potent anti-tumor activity in pre-clinical models of established neuroblastoma as well, in combination with numerous chemotherapeutic agents and even in tumors with unfavorable genetic features such as MYCN, ALK or TP53 mutation. This has led to the testing of DFMO in clinical trials for children with neuroblastoma. Current trial designs include testing lower dose DFMO alone (2,000 mg/m(2)/day) starting at the completion of standard therapy, or higher doses combined with chemotherapy (up to 9,000 mg/m(2)/day) for patients with relapsed disease that has progressed. In this review we will discuss important considerations for the future design of DFMO-based clinical trials for neuroblastoma, focusing on the need to better define the principal mechanisms of anti-tumor activity for polyamine depletion regimens. Putative DFMO activities that are both cancer cell intrinsic (targeting the principal oncogenic driver, MYC) and cancer cell extrinsic (altering the tumor microenvironment to support anti-tumor immunity) will be discussed. Understanding the mechanisms of DFMO activity are critical in determining how it might be best leveraged in upcoming clinical trials. This mechanistic approach also provides a platform by which iterative pre-clinical testing using translational tumor models may complement our clinical approaches.
authors.affiliation: 1 Division of Infectious Diseases, The Children's Hospital of Philadelphia, Philadelphia, USA ; 2 Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA ; 3 Children's Cancer Institute Australia, Sydney, Australia ; 4 Lankenau Institute for Medical Research, Wynnewood, USA ; 5 Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA.
authors.forename: Hamid
authors.initials: H
authors.lastname: Bassiri
authors.affiliation: 1 Division of Infectious Diseases, The Children's Hospital of Philadelphia, Philadelphia, USA ; 2 Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA ; 3 Children's Cancer Institute Australia, Sydney, Australia ; 4 Lankenau Institute for Medical Research, Wynnewood, USA ; 5 Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Benavides
authors.affiliation: 1 Division of Infectious Diseases, The Children's Hospital of Philadelphia, Philadelphia, USA ; 2 Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA ; 3 Children's Cancer Institute Australia, Sydney, Australia ; 4 Lankenau Institute for Medical Research, Wynnewood, USA ; 5 Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Haber
authors.affiliation: 1 Division of Infectious Diseases, The Children's Hospital of Philadelphia, Philadelphia, USA ; 2 Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA ; 3 Children's Cancer Institute Australia, Sydney, Australia ; 4 Lankenau Institute for Medical Research, Wynnewood, USA ; 5 Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Gilmour
authors.affiliation: 1 Division of Infectious Diseases, The Children's Hospital of Philadelphia, Philadelphia, USA ; 2 Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA ; 3 Children's Cancer Institute Australia, Sydney, Australia ; 4 Lankenau Institute for Medical Research, Wynnewood, USA ; 5 Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA.
authors.forename: Murray D
authors.initials: MD
authors.lastname: Norris
authors.affiliation: 1 Division of Infectious Diseases, The Children's Hospital of Philadelphia, Philadelphia, USA ; 2 Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA ; 3 Children's Cancer Institute Australia, Sydney, Australia ; 4 Lankenau Institute for Medical Research, Wynnewood, USA ; 5 Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hogarty
keywords: MYCN; experimental therapeutics; immunotherapy; pre-clinical models; tumor microenvironment
references.citation: Nature. 2008 Oct 16;455(7215):975-8
references.pmid: 18923525
references.citation: Cell. 2006 Jan 27;124(2):263-6
references.pmid: 16439202
references.citation: Carcinogenesis. 2013 May;34(5):1081-8
references.pmid: 23349014
references.citation: Br J Cancer. 1997;76(3):365-70
references.pmid: 9252204
references.citation: Pediatr Blood Cancer. 2013 Jul;60(7):1135-40
references.pmid: 23281263
references.citation: Cancer Res. 2001 Aug 15;61(16):6185-93
references.pmid: 11507071
references.citation: Nat Immunol. 2008 May;9(5):495-502
references.pmid: 18425106
references.citation: Blood. 2011 Jun 23;117(25):6952-62
references.pmid: 21521781
references.citation: FASEB J. 2009 Sep;23(9):2888-97
references.pmid: 19417083
references.citation: Nature. 2008 Oct 16;455(7215):930-5
references.pmid: 18724359
references.citation: J Exp Med. 2007 Jan 22;204(1):49-55
references.pmid: 17210731
references.citation: Protein Sci. 2008 May;17(5):793-802
references.pmid: 18369191
references.citation: Nat Rev Cancer. 2010 Apr;10(4):301-9
references.pmid: 20332779
references.citation: Cell Death Dis. 2014 Mar 20;5:e1135
references.pmid: 24651438
references.citation: J Natl Cancer Inst. 2006 Sep 6;98(17):1193-203
references.pmid: 16954472
references.citation: Science. 1984 Jun 8;224(4653):1121-4
references.pmid: 6719137
references.citation: Nat Med. 2010 Sep;16(9):974-5
references.pmid: 20823880
references.citation: Nature. 2009 May 7;459(7243):118-21
references.pmid: 19424157
references.citation: J Immunol. 2003 Aug 1;171(3):1232-9
references.pmid: 12874210
references.citation: J Natl Cancer Inst. 1972 Jan;48(1):165-72
references.pmid: 4652370
references.citation: Nat Med. 2013 Nov;19(11):1423-37
references.pmid: 24202395
references.citation: Nat Genet. 2013 Mar;45(3):279-84
references.pmid: 23334666
references.citation: PLoS One. 2012;7(12):e51297
references.pmid: 23284678
references.citation: Pediatr Hematol Oncol. 2014 Nov;31(8):717-22
references.pmid: 24684178
references.citation: Cancer Cell. 2014 Feb 10;25(2):139-51
references.pmid: 24525231
references.citation: Nat Genet. 2013 Jan;45(1):12-7
references.pmid: 23202128
references.citation: Int J Cancer. 2006 May 1;118(9):2344-9
references.pmid: 16331620
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12664-9
references.pmid: 15314226
references.citation: Genome Biol. 2008 Oct 13;9(10):R150
references.pmid: 18851746
references.citation: Cancer Res. 2013 Nov 1;73(21):6504-15
references.pmid: 24030976
references.citation: Oncoimmunology. 2014 Jan 1;3(1):e27360
references.pmid: 24711956
references.citation: Nat Rev Drug Discov. 2007 May;6(5):373-90
references.pmid: 17464296
references.citation: J Biol Chem. 2003 Apr 4;278(14):12563-73
references.pmid: 12529326
references.citation: Int J Cancer. 2010 Sep 1;127(5):1141-50
references.pmid: 20039320
references.citation: N Engl J Med. 1985 Oct 31;313(18):1111-6
references.pmid: 4047115
references.citation: Cancer Prev Res (Phila). 2008 Jun;1(1):32-8
references.pmid: 18841250
references.citation: Clin Cancer Res. 2004 Feb 15;10(4):1299-305
references.pmid: 14977828
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4194-9
references.pmid: 17360499
references.citation: J Biol Chem. 2010 Apr 23;285(17):12474-81
references.pmid: 20181941
references.citation: Proc Natl Acad Sci U S A. 2013 Jul 16;110(29):11988-93
references.pmid: 23803853
references.citation: Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19190-5
references.pmid: 23091029
references.citation: Nature. 2008 Dec 18;456(7224):971-5
references.pmid: 19011615
references.citation: Cancer Cell. 2005 May;7(5):433-44
references.pmid: 15894264
references.citation: Cancer Res. 2009 Jan 15;69(2):547-53
references.pmid: 19147568
references.citation: Clin Cancer Res. 2009 Oct 1;15(19):5956-61
references.pmid: 19789308
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14094-9
references.pmid: 18780787
references.citation: Nitric Oxide. 1997 Jun;1(3):268-72
references.pmid: 9704589
references.citation: Cancer Immunol Res. 2014 Mar;2(3):274-85
references.pmid: 24778323
references.citation: J Biochem. 2006 Jan;139(1):27-33
references.pmid: 16428316
references.citation: Cancer Cell. 2014 Nov 10;26(5):682-94
references.pmid: 25517749
references.citation: JAMA. 2012 Mar 14;307(10):1062-71
references.pmid: 22416102
references.citation: J Clin Oncol. 2012 Oct 1;30(28):3525-32
references.pmid: 22927533
references.citation: Int J Cancer. 2014 Mar 15;134(6):1335-45
references.pmid: 24038106
references.citation: Proc Natl Acad Sci U S A. 1968 Aug;60(4):1420-7
references.pmid: 4299947
references.citation: Cancer Res. 2003 Sep 1;63(17):5266-73
references.pmid: 14500357
references.citation: Anticancer Res. 1997 Mar-Apr;17(2A):1059-65
references.pmid: 9137449
references.citation: Ann Oncol. 2010 Oct;21(10):1944-1951
references.pmid: 20237004
references.citation: Oncogene. 2005 Aug 25;24(36):5606-18
references.pmid: 16007177
references.citation: Clin Cancer Res. 2003 Mar;9(3):981-90
references.pmid: 12631596
references.citation: EMBO J. 1997 Jun 2;16(11):2985-95
references.pmid: 9214616
references.citation: Cancer Res. 2008 Dec 1;68(23):9825-31
references.pmid: 19047162
references.citation: J Clin Pathol. 2008 Oct;61(10):1098-103
references.pmid: 18682419
references.citation: Int J Immunopharmacol. 1986;8(4):411-7
references.pmid: 3091515
references.citation: Lancet. 2007 Jun 23;369(9579):2106-20
references.pmid: 17586306
references.citation: J Immunol. 2005 Jul 1;175(1):237-45
references.pmid: 15972654
references.citation: Front Oncol. 2013 Jun 26;3:167
references.pmid: 23805414
references.citation: N Engl J Med. 2010 Sep 30;363(14):1324-34
references.pmid: 20879881
references.citation: J Immunol. 2004 Jan 15;172(2):989-99
references.pmid: 14707072
references.citation: Cancer Discov. 2013 Sep;3(9):1072-81
references.pmid: 23771434
references.citation: Cell. 1995 Jan 13;80(1):51-60
references.pmid: 7813017
references.citation: J Exp Clin Cancer Res. 2011 Oct 11;30:95
references.pmid: 21988863
references.citation: EMBO J. 2001 Mar 15;20(6):1383-93
references.pmid: 11250904
references.citation: Sci Transl Med. 2013 Aug 28;5(200):200ra116
references.pmid: 23986400
references.citation: Cancer Res. 2004 Aug 15;64(16):5839-49
references.pmid: 15313928
references.citation: Cancer Res. 2008 Dec 1;68(23):9735-45
references.pmid: 19047152
references.citation: Nat Immunol. 2013 Oct;14(10):1014-22
references.pmid: 24048123
references.citation: Int J Cancer. 1981 Nov 15;28(5):567-70
references.pmid: 6796528
references.citation: Anticancer Res. 1993 Jul-Aug;13(4):1027-33
references.pmid: 8352521
references.citation: Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2169-74
references.pmid: 23345430
references.citation: Nitric Oxide. 1999 Oct;3(5):409-18
references.pmid: 10534445
references.citation: Nat Rev Immunol. 2012 Mar 22;12(4):253-68
references.pmid: 22437938