title: A heparan sulfate-targeted conditionally replicative adenovirus, Ad5.pk7-Delta24, for the treatment of advanced breast cancer.
abstract: Conditionally replicating adenoviruses (CRAds) that replicate in tumor but less in normal cells are promising anticancer agents. A major determinant of their potency is their capacity for infecting target cells. The primary receptor for serotype 5 adenovirus (Ad5), the most widely used serotype in gene therapy, is the coxsackie-adenovirus receptor (CAR). CAR is expressed variably and often at low levels in various tumor types including advanced breast cancer. We generated a novel p16/retinoblastoma pathway-dependent CRAd, Ad5.pK7-Delta24, with a polylysine motif in the fiber C-terminus, enabling CAR-independent binding to heparan sulfate proteoglycans (HSPG). Ad5.pK7-Delta24 mediated effective oncolysis of all breast cancer cell lines tested. Further, we utilized noninvasive, fluorescent imaging for analysis of antitumor efficacy in an orthotopic model of advanced hormone refractory breast cancer. A therapeutic benefit was seen following both intratumoral and intravenous delivery. Murine biodistribution similar to Ad5, proven safe in trials, suggests feasibility of clinical safety testing. Interestingly, upregulation of CAR was seen in low-CAR M4A4-LM3 breast cancer cells in vivo, which resulted in better than expected efficacy also with an isogenic CRAd with an unmodified capsid. These results suggest utility of Ad5.pK7-Delta24 and the orthotopic model for further translational studies.
authors.affiliation: Cancer Gene Therapy Group, Rational Drug Design Program and Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: T
authors.initials: T
authors.lastname: Ranki
authors.forename: A
authors.initials: A
authors.lastname: Kanerva
authors.forename: A
authors.initials: A
authors.lastname: Ristimäki
authors.forename: T
authors.initials: T
authors.lastname: Hakkarainen
authors.forename: M
authors.initials: M
authors.lastname: Särkioja
authors.forename: L
authors.initials: L
authors.lastname: Kangasniemi
authors.forename: M
authors.initials: M
authors.lastname: Raki
authors.forename: P
authors.initials: P
authors.lastname: Laakkonen
authors.forename: S
authors.initials: S
authors.lastname: Goodison
authors.forename: A
authors.initials: A
authors.lastname: Hemminki
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001943:Breast Neoplasms / Q000628:therapy*; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D005434:Flow Cytometry; D015870:Gene Expression; D018390:Gene Targeting; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006497:Heparan Sulfate / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D023421:Models, Animal; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy / Q000379:methods*; D011485:Protein Binding; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic / Q000379:methods; D014779:Virus Replication
chemical_list: D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D049452:Green Fluorescent Proteins; D006497:Heparan Sulfate; D011991:Receptors, Virus; C568771:CLMP protein, human; C568772:CLMP protein, mouse