title: Cancer screening by systemic administration of a gene delivery vector encoding tumor-selective secretable biomarker expression.
abstract: Cancer biomarkers facilitate screening and early detection but are known for only a few cancer types. We demonstrated the principle of inducing tumors to secrete a serum biomarker using a systemically administered gene delivery vector that targets tumors for selective expression of an engineered cassette. We exploited tumor-selective replication of a conditionally replicative Herpes simplex virus (HSV) combined with a replication-dependent late viral promoter to achieve tumor-selective biomarker expression as an example gene delivery vector. Virus replication, cytotoxicity and biomarker production were low in quiescent normal human foreskin keratinocytes and high in cancer cells in vitro. Following intravenous injection of virus >90% of tumor-bearing mice exhibited higher levels of biomarker than non-tumor-bearing mice and upon necropsy, we detected virus exclusively in tumors. Our strategy of forcing tumors to secrete a serum biomarker could be useful for cancer screening in high-risk patients, and possibly for monitoring response to therapy. In addition, because oncolytic vectors for tumor specific gene delivery are cytotoxic, they may supplement our screening strategy as a "theragnostic" agent. The cancer screening approach presented in this work introduces a paradigm shift in the utility of gene delivery which we foresee being improved by alternative vectors targeting gene delivery and expression to tumors. Refining this approach will usher a new era for clinical cancer screening that may be implemented in the developed and undeveloped world.
authors: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors: Andrew W
authors: AW
authors: Browne
authors: Jennifer L
authors: JL
authors: Leddon
authors: Mark A
authors: MA
authors: Currier
authors: Jon P
authors: JP
authors: Williams
authors: Jason S
authors: JS
authors: Frischer
authors: Margaret H
authors: MH
authors: Collins
authors: Chong H
authors: CH
authors: Ahn
authors: Timothy P
authors: TP
authors: Cripe
references: J Nucl Med. 2011 Apr;52(4):625-633
references: 21421727
references: Nat Biotechnol. 2008 Dec;26(12):1373-8
references: 19029914
references: Nat Protoc. 2009;4(4):582-91
references: 19373229
references: Cancer Gene Ther. 2010 Aug;17(8):550-8
references: 20379224
references: Gene Ther. 2003 Aug;10(17):1458-64
references: 12900760
references: Proc Natl Acad Sci U S A. 1997 Feb 4;94(3):843-8
references: 9023344
references: Adv Enzyme Regul. 2001;41:189-207
references: 11384745
references: Oncogene. 2008 Jul 10;27(30):4249-54
references: 18345032
references: Mol Ther. 2009 Jan;17(1):199-207
references: 18957964
references: Mol Ther. 2008 May;16(5):879-85
references: 18388918
references: J Control Release. 2007 Nov 6;123(2):109-15
references: 17894942
references: Gene Ther. 2005 Jan;12(1):87-94
references: 15385953
references: Mol Ther. 2005 Mar;11(3):435-43
references: 15727940
references: Science. 2010 May 21;328(5981):1031-5
references: 20378772
references: Cancer Res. 2008 Feb 15;68(4):1170-9
references: 18281493
references: AJR Am J Roentgenol. 2010 Aug;195(2):341-9
references: 20651188
references: Proc Natl Acad Sci U S A. 1980 Jul;77(7):4030-4
references: 6933450
references: J Gen Virol. 2011 Jun;92(Pt 6):1279-1291
references: 21325477
references: Nat Med. 2002 May;8(5):527-31
references: 11984600
references: Lab Chip. 2008 Apr;8(4):542-9
references: 18369508
references: Pediatr Blood Cancer. 2006 Jun;46(7):745-54
references: 16124003
references: Biosens Bioelectron. 2011 Apr 15;26(8):3647-53
references: 21388801
references: Nucleic Acids Res. 2004 Mar 16;32(5):e48
references: 15026537
references: Biomaterials. 2011 Jun;32(18):4306-16
references: 21429576
references: Gene Ther. 2006 Apr;13(8):705-14
references: 16421599
references: J Am Chem Soc. 2006 Jul 5;128(26):8378-9
references: 16802785
references: J Virol. 1994 Dec;68(12):7774-89
references: 7966567
references: Int Immunopharmacol. 2003 Mar;3(3):319-28
references: 12639809
references: Nat Methods. 2008 Feb;5(2):171-3
references: 18204457
references: Curr Cancer Drug Targets. 2011 Jan;11(1):111-22
references: 21062239
references: Mol Ther. 2009 Aug;17(8):1395-403
references: 19471250
references: Blood. 2003 Oct 15;102(8):2819-27
references: 12829586
references: Anal Chim Acta. 2008 Mar 17;611(1):17-30
references: 18298963
references: Adv Drug Deliv Rev. 2004 Sep 22;56(11):1649-59
references: 15350294
references: J Invest Dermatol. 1983 Jul;81(1 Suppl):33s-40s
references: 6345690
references: J Control Release. 2007 Jul 16;120(1-2):18-26
references: 17509712
references: J Clin Invest. 2003 Jun;111(12):1823-33
references: 12813018
references: Cancer Gene Ther. 2006 Nov;13(11):975-92
references: 16604059
references: Mol Ther. 2000 Oct;2(4):387-93
references: 11020355
references: Cancer Res. 2006 Jul 1;66(13):6732-40
references: 16818648
references: J Neurovirol. 2003 Aug;9(4):477-88
references: 12907392
references: J Pediatr Hematol Oncol. 2002 Aug-Sep;24(6):447-53
references: 12218591
references: Mol Cancer Ther. 2007 Feb;6(2):742-51
references: 17308070
references: Clin Cancer Res. 2009 Sep 15;15(18):5840-51
references: 19737950
references: J Clin Invest. 2000 Apr;105(7):841-6
references: 10749560
references: Nat Biotechnol. 2004 Aug;22(8):969-76
references: 15258594