Mutant KRAS is a druggable target for pancreatic cancer

被引：237

作者：

Khvalevsky, Elina Zorde ^{[1
]}

Gabai, Racheli ^{[1
]}

Rachmut, Itzhak Haim ^{[1
]}

Horwitz, Elad ^{[1
]}

Brunschwig, Zivia ^{[1
]}

Orbach, Ariel ^{[1
]}

Shemi, Adva ^{[1
]}

Golan, Talia ^{[3
]}

Domb, Abraham J. ^{[4
,5
]}

Yavin, Eylon ^{[4
,5
]}

Giladi, Hilla ^{[2
]}

Rivkin, Ludmila ^{[2
]}

Simerzin, Alina ^{[2
]}

Eliakim, Rami ^{[10
]}

Khalaileh, Abed ^{[6
]}

Hubert, Ayala ^{[7
]}

Lahav, Maor ^{[10
]}

Kopelman, Yael ^{[8
]}

Goldin, Eran ^{[11
]}

Dancour, Alan ^{[9
]}

Hants, Yael ^{[9
]}

Arbel-Alon, Sagit ^{[9
]}

Abramovitch, Rinat ^{[2
]}

Shemi, Amotz ^{[1
]}

Galun, Eithan ^{[2
]}

机构：

[1] Silenseed LTD, IL-91120 Jerusalem, Israel

[2] Hadassah Hebrew Univ, Med Ctr, Goldyne Savad Inst Gene Therapy, IL-91120 Jerusalem, Israel

[3] Tel Aviv Univ, Sackler Sch Med, Chaim Sheba Med Ctr, Oncol Inst, IL-91120 Tel Aviv, Israel

[4] Hebrew Univ Jerusalem, Ctr Nanosci & Nanotechnol, Fac Med, Inst Drug Res,Sch Pharm, IL-91120 Jerusalem, Israel

[5] Hebrew Univ Jerusalem, Alex Grass Ctr Drug Design & Synth, IL-91120 Jerusalem, Israel

[6] Hadassah Hebrew Univ, Med Ctr, Dept Surg, IL-91120 Jerusalem, Israel

[7] Hadassah Hebrew Univ, Med Ctr, Sharett Inst Oncol, IL-91120 Jerusalem, Israel

[8] Hadassah Hebrew Univ, Med Ctr, Gastroenterol Inst, IL-91120 Jerusalem, Israel

[9] Hadassah Hebrew Univ, Med Ctr, Dept Obstet & Gynecol, IL-91120 Jerusalem, Israel

[10] Chaim Sheba Med Ctr, Dept Gastroenterol, IL-91120 Tel Aviv, Israel

[11] Shaare Zedek Med Ctr, Digest Dis Inst, IL-91120 Jerusalem, Israel

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2013年 / 110卷 / 51期

关键词：

targeted therapy; gene therapy; K-RAS; CELL-MIGRATION; IN-VITRO; ADDICTION; MUTATIONS;

D O I：

10.1073/pnas.1314307110

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：20723 / 20728

页数：6

共 23 条

[1]

Molecular biology of pancreatic cancer [J].