Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer

Hadas Gibori,Emmanuelle Merquiol,Joo Sang Lee,Galia Blum,Adva Krivitsky,Talia Golan,Dikla Ben-Shushan,Galia Tiram,Eytan Ruppin,Iris Barshack,Shay Eliyahu,Limor Landsman,Rachel Blau,Paula Ofek,Ronit Satchi-Fainaro,Yana Epshtein

doi:10.1038/s41467-017-02283-9

Abstract

The heterogeneity of pancreatic ductal adenocarcinoma (PDAC) suggests that successful treatment might rely on simultaneous targeting of multiple genes, which can be achieved by RNA interference-based therapeutic strategies. Here we show a potent combination of microRNA and siRNA delivered by an efficient nanocarrier to PDAC tumors. Using proteomic-microRNA profiles and survival data of PDAC patients from TCGA, we found a novel signature for prolonged survival. Accordingly, we used a microRNA-mimic to increase miR-34a together with siRNA to silence PLK1 oncogene. For in vivo dual-targeting of this combination, we developed a biodegradable amphiphilic polyglutamate amine polymeric nanocarrier (APA). APA-miRNA–siRNA polyplexes systemically administered to orthotopically inoculated PDAC-bearing mice showed no toxicity and accumulated at the tumor, resulting in an enhanced antitumor effect due to inhibition of MYC oncogene, a common target of both miR-34a and PLK1. Taken together, our findings warrant this unique combined polyplex’s potential as a novel nanotherapeutic for PDAC.

Highlights

The heterogeneity of pancreatic ductal adenocarcinoma (PDAC) suggests that successful treatment might rely on simultaneous targeting of multiple genes, which can be achieved by RNA interference-based therapeutic strategies
Based on The Cancer Genome Atlas (TCGA) data obtained from 180 pancreatic cancer patients, whose survival status was available, we found that patients with high miR-34a/low PLK1 expression levels had a significantly longer overall survival (OS) time compared to patients with low miR-34a/high PLK1 (
Since high miR-34a and low PLK1 expression levels correlated with favorable outcomes, we hypothesized that restoration of miR-34a together with silencing of PLK1 could improve the therapeutic response and prolong survival

Summary

Introduction

The heterogeneity of pancreatic ductal adenocarcinoma (PDAC) suggests that successful treatment might rely on simultaneous targeting of multiple genes, which can be achieved by RNA interference-based therapeutic strategies. One of the miRNAs that was associated with good prognosis in PDAC patients[10,11] and holds a great therapeutic potential[12] is miR-34a It is a tumor suppressor miRNA downregulated in PDAC13 which inhibits malignant growth by repressing genes involved in various cellular signaling pathways, such as proliferation, cell cycle, and senescence[14]. We rationalized to combine miR-34a and PLK1-siRNA in order to attack distinct molecular defects in this cancer while inhibiting MYC, a common target of PLK118 and miR-34a19. We hypothesized that this approach will lead to a synergistic anticancer effect against PDAC. We have recently synthesized a library of aminated polyglutamates for small oligonucleotides complexation[23], out of which a fully aminated polyglutamate backbone was used in vivo for the treatment of ovarian cancer showing promising results[22]

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