title: U1 Adaptors Suppress theKRAS-MYCOncogenic Axis in Human Pancreatic Cancer Xenografts.
abstract: Targeting KRAS and MYC has been a tremendous challenge in cancer drug development. Genetic studies in mouse models have validated the efficacy of silencing expression of both KRAS and MYC in mutant KRAS-driven tumors. We investigated the therapeutic potential of a new oligonucleotide-mediated gene silencing technology (U1 Adaptor) targeting KRAS and MYC in pancreatic cancer. Nanoparticles in complex with anti-KRAS U1 Adaptors (U1-KRAS) showed remarkable inhibition of KRAS in different human pancreatic cancer cell linesin vitroandin vivoAs a nanoparticle-free approach is far easier to develop into a drug, we refined the formulation of U1 Adaptors by conjugating them to tumor-targeting peptides (iRGD and cRGD). Peptides coupled to fluorescently tagged U1 Adaptors showed selective tumor localizationin vivoEfficacy experiments in pancreatic cancer xenograft models showed highly potent (>90%) antitumor activity of both iRGD and (cRGD)2-KRAS Adaptors. U1 Adaptors targeting MYC inhibited pancreatic cancer cell proliferation caused by apoptosisin vitro(40%-70%) and tumor regressionsin vivoComparison of iRGD-conjugated U1 KRAS and U1 MYC Adaptorsin vivorevealed a significantly greater degree of cleaved caspase-3 staining and decreased Ki67 staining as compared with controls. There was no significant difference in efficacy between the U1 KRAS and U1 MYC Adaptor groups. Our results validate the value in targeting both KRAS and MYC in pancreatic cancer therapeutics and provide evidence that the U1 Adaptor technology can be successfully translated using a nanoparticle-free delivery system to target two undruggable genes in cancer.Mol Cancer Ther; 16(8); 1445-55. ©2017 AACR.
authors.affiliation: Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.|Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
authors.forename: Ashley T
authors.initials: AT
authors.lastname: Tsang
authors.affiliation: Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.|Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
authors.forename: Crissy
authors.initials: C
authors.lastname: Dudgeon
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
authors.forename: Lan
authors.initials: L
authors.lastname: Yi
authors.affiliation: Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.|Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.affiliation: Silagene Inc., Hillsborough, New Jersey.
authors.forename: Rafal
authors.initials: R
authors.lastname: Goraczniak
authors.affiliation: Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.
authors.forename: Kristen
authors.initials: K
authors.lastname: Donohue
authors.affiliation: Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.|Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.|Department of Pharmacology, Rutgers University, Piscataway, New Jersey.
authors.forename: Samuel
authors.initials: S
authors.lastname: Kogan
authors.affiliation: Silagene Inc., Hillsborough, New Jersey.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brenneman
authors.affiliation: Department of Biology, Lafayette College, Easton, Pennsylvania.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Ho
authors.affiliation: Silagene Inc., Hillsborough, New Jersey.|Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey.
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Gunderson
authors.affiliation: Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey. carpizdr@cinj.rutgers.edu.|Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.|Department of Pharmacology, Rutgers University, Piscataway, New Jersey.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Carpizo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D009841:Oligonucleotides / Q000494:pharmacology*; D009857:Oncogenes; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015203:Reproducibility of Results; D023041:Xenograft Model Antitumor Assays
chemical_list: C117307:KRAS protein, human; D009841:Oligonucleotides; D010455:Peptides; D016271:Proto-Oncogene Proteins c-myc; D016283:Proto-Oncogene Proteins p21(ras)