title: Functional cloning of recurrence-specific antigens identifies molecular targets to treat tumor relapse.
abstract: Aggressive regrowth of recurrent tumors following treatment-induced dormancy represents a major clinical challenge for treatment of malignant disease. We reported previously that recurrent prostate tumors, which underwent complete macroscopic regression followed by aggressive regrowth, could be cured with a vesicular stomatitis virus (VSV)-expressed cDNA library derived from recurrent tumor cells. By screening the protective, recurrence-derived VSV-cDNA library, here we identify topoisomerase-IIα (TOPO-IIα) as a recurrence-specific tumor antigen against which tolerance can be broken. Tumor recurrences, in two different types of tumor (prostate and melanoma), which had evaded two different frontline treatments (immunotherapy or chemotherapy), significantly overexpressed TOPO-IIα compared with their primary tumor counterparts, which conferred a novel sensitivity to doxorubicin (DOX) chemotherapy upon the recurrent tumors. This was exploited in vivo using combination therapies to cure mice, which would otherwise have relapsed, after suboptimal primary therapy in both models. Our data show that recurrent tumors-across histologies and primary treatments-express distinct antigens compared with the primary tumor which can be identified using the VSV-cDNA library technology. These results suggest that it may be possible to design a few common second-line therapies against a variety of tumor recurrences, in some cases using agents with no obvious activity against the primary tumor.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boisgerault
authors.forename: Timothy
authors.initials: T
authors.lastname: Kottke
authors.forename: Jose
authors.initials: J
authors.lastname: Pulido
authors.forename: Jill
authors.initials: J
authors.lastname: Thompson
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Diaz
authors.forename: Diana
authors.initials: D
authors.lastname: Rommelfanger-Konkol
authors.forename: Addie
authors.initials: A
authors.lastname: Embry
authors.forename: Dyana
authors.initials: D
authors.lastname: Saenz
authors.forename: Eric
authors.initials: E
authors.lastname: Poeschla
authors.forename: Hardev
authors.initials: H
authors.lastname: Pandha
authors.forename: Kevin
authors.initials: K
authors.lastname: Harrington
authors.forename: Alan
authors.initials: A
authors.lastname: Melcher
authors.forename: Peter
authors.initials: P
authors.lastname: Selby
authors.forename: Richard
authors.initials: R
authors.lastname: Vile
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology*; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000276:immunology; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D015723:Gene Library; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology; D012008:Recurrence; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology; D019139:Tumor Escape / Q000235:genetics / Q000276:immunology; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D000939:Epitopes; D059005:Topoisomerase II Inhibitors; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II