Mutant KRAS is a druggable target for pancreatic cancer
| العنوان: | Mutant KRAS is a druggable target for pancreatic cancer |
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| المؤلفون: | Elad Horwitz, Ludmila Rivkin, Hilla Giladi, Eylon Yavin, Abed Khalaileh, Zivia Brunschwig, Yael Hants, Rami Eliakim, Ayala Hubert, Maor Lahav, Amotz Shemi, Elina Zorde Khvalevsky, Eithan Galun, Yael Kopelman, Rinat Abramovitch, Adva Shemi, Ariel Orbach, Eran Goldin, A Dancour, Sagit Arbel-Alon, Abraham J. Domb, Talia Golan, Itzhak Haim Rachmut, Alina Simerzin, Racheli Gabai |
| المصدر: | Proceedings of the National Academy of Sciences. 110:20723-20728 |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Genetic enhancement, medicine.medical_treatment, Drug Evaluation, Preclinical, Mice, SCID, Biology, medicine.disease_cause, Targeted therapy, Proto-Oncogene Proteins p21(ras), Mice, Drug Delivery Systems, In vivo, Cell Line, Tumor, Proto-Oncogene Proteins, Pancreatic cancer, Absorbable Implants, medicine, Animals, Humans, Gene silencing, Gene Silencing, RNA, Small Interfering, Cell Proliferation, Multidisciplinary, Oncogene, SiG12D LODER, Biological Sciences, medicine.disease, digestive system diseases, Pancreatic Neoplasms, Mutation, Immunology, ras Proteins, Cancer research, Female, KRAS, Carcinoma, Pancreatic Ductal |
| الوصف: | 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. |
| تدمد: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1314307110 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::468ac25207984b9a3d38b74651d74088 https://doi.org/10.1073/pnas.1314307110 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....468ac25207984b9a3d38b74651d74088 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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| DOI: | 10.1073/pnas.1314307110 |