title: Mutant KRAS is a druggable target for pancreatic cancer.
abstract: Pancreatic ductal adenocarcinoma (PDA) represents an unmet therapeutic challenge. PDA is addicted to the activity of the mutated KRAS oncogene which is considered so far an undruggable therapeutic target. We propose an approach to target KRAS effectively in patients using RNA interference. To meet this challenge, we have developed a local prolonged siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against the mutated KRAS (siG12D LODER). The siG12D LODER was assessed for its structural, release, and delivery properties in vitro and in vivo. The effect of the siG12D LODER on tumor growth was assessed in s.c. and orthotopic mouse models. KRAS silencing effect was further assessed on the KRAS downstream signaling pathway. The LODER-encapsulated siRNA was stable and active in vivo for 155 d. Treatment of PDA cells with siG12D LODER resulted in a significant decrease in KRAS levels, leading to inhibition of proliferation and epithelial-mesenchymal transition. In vivo, siG12D LODER impeded the growth of human pancreatic tumor cells and prolonged mouse survival. We report a reproducible and safe delivery platform based on a miniature biodegradable polymeric matrix, for the controlled and prolonged delivery of siRNA. This technology provides the following advantages: (i) siRNA is protected from degradation; (ii) the siRNA is slowly released locally within the tumor for prolonged periods; and (iii) the siG12D LODER elicits a therapeutic effect, thereby demonstrating that mutated KRAS is indeed a druggable target.
authors.affiliation: Silenseed LTD, and Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Elina
authors.initials: E
authors.lastname: Zorde Khvalevsky
authors.forename: Racheli
authors.initials: R
authors.lastname: Gabai
authors.forename: Itzhak Haim
authors.initials: IH
authors.lastname: Rachmut
authors.forename: Elad
authors.initials: E
authors.lastname: Horwitz
authors.forename: Zivia
authors.initials: Z
authors.lastname: Brunschwig
authors.forename: Ariel
authors.initials: A
authors.lastname: Orbach
authors.forename: Adva
authors.initials: A
authors.lastname: Shemi
authors.forename: Talia
authors.initials: T
authors.lastname: Golan
authors.forename: Abraham J
authors.initials: AJ
authors.lastname: Domb
authors.forename: Eylon
authors.initials: E
authors.lastname: Yavin
authors.forename: Hilla
authors.initials: H
authors.lastname: Giladi
authors.forename: Ludmila
authors.initials: L
authors.lastname: Rivkin
authors.forename: Alina
authors.initials: A
authors.lastname: Simerzin
authors.forename: Rami
authors.initials: R
authors.lastname: Eliakim
authors.forename: Abed
authors.initials: A
authors.lastname: Khalaileh
authors.forename: Ayala
authors.initials: A
authors.lastname: Hubert
authors.forename: Maor
authors.initials: M
authors.lastname: Lahav
authors.forename: Yael
authors.initials: Y
authors.lastname: Kopelman
authors.forename: Eran
authors.initials: E
authors.lastname: Goldin
authors.forename: Alan
authors.initials: A
authors.lastname: Dancour
authors.forename: Yael
authors.initials: Y
authors.lastname: Hants
authors.forename: Sagit
authors.initials: S
authors.lastname: Arbel-Alon
authors.forename: Rinat
authors.initials: R
authors.lastname: Abramovitch
authors.forename: Amotz
authors.initials: A
authors.lastname: Shemi
authors.forename: Eithan
authors.initials: E
authors.lastname: Galun
mesh_terms: D020341:Absorbable Implants; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016503:Drug Delivery Systems / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D005260:Female; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology*; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: gene therapy; targeted therapy