title: Co-targeting EGFR and survivin with a bivalent aptamer-dual siRNA chimera effectively suppresses prostate cancer.
abstract: Current targeted therapies using small kinase inhibitors and antibodies have limited efficacy in treating prostate cancer (PCa), a leading cause of cancer death in American men. We have developed a novel strategy by engineering an RNA-based aptamer-siRNA chimera, in which a bivalent aptamer specifically binds prostate-specific membrane antigen (PSMA) via an antibody-like structure to promote siRNA internalization in PCa cells, and two siRNAs specific to EGFR and survivin are fused between two aptamers. The chimera is able to inhibit EGFR and survivin simultaneously and induce apoptosis effectively in vitro and in vivo. In the C4-2 PCa xenograft model, the treatment with the chimera significantly suppresses tumor growth and angiogenesis. The inhibition of angiogenesis is mediated by an EGFR-HIF1α-VEGF-dependent mechanism. Our results support that the bivalent aptamer-driven delivery of two siRNAs could be a new combination therapeutic strategy to effectively inhibit multiple and conventionally "undruggable" targets.
authors.affiliation: Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
authors.forename: Hong Yan
authors.initials: HY
authors.lastname: Liu
authors.affiliation: Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Yu
authors.affiliation: Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
authors.forename: Haitao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Georgia Cancer Center at Augusta University, and Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
authors.forename: Daqing
authors.initials: D
authors.lastname: Wu
authors.affiliation: Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
authors.forename: Jin-Xiong
authors.initials: JX
authors.lastname: She
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D017209:Apoptosis; D052157:Aptamers, Nucleotide / Q000627:therapeutic use; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000628:therapy; D011471:Prostatic Neoplasms / Q000628:therapy*; D034741:RNA, Small Interfering / Q000235:genetics; D000067492:RNAi Therapeutics / Q000379:methods*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D000077022:Survivin
chemical_list: D000954:Antigens, Surface; D052157:Aptamers, Nucleotide; C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000077022:Survivin; C541485:EGFR protein, mouse; D066246:ErbB Receptors; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II