Gene Therapy Using Nanocarriers for Pancreatic Ductal Adenocarcinoma: Applications and Challenges in Cancer Therapeutics.

Young-Seok Cho,Tae-Jong Yoon,Hyeji Park,Eun-Jeong Won

doi:10.3390/pharmaceutics14010137

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide, and its incidence is increasing. PDAC often shows resistance to several therapeutic modalities and a higher recurrence rate after surgical treatment in the early localized stage. Combination chemotherapy in advanced pancreatic cancer has minimal impact on overall survival. RNA interference (RNAi) is a promising tool for regulating target genes to achieve sequence-specific gene silencing. Here, we summarize RNAi-based therapeutics using nanomedicine-based delivery systems that are currently being tested in clinical trials and are being developed for the treatment of PDAC. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) genome editing has been widely used for the development of cancer models as a genetic screening tool for the identification and validation of therapeutic targets, as well as for potential cancer therapeutics. This review discusses current advances in CRISPR/Cas9 technology and its application to PDAC research. Continued progress in understanding the PDAC tumor microenvironment and nanomedicine-based gene therapy will improve the clinical outcomes of patients with PDAC.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer related deaths in the Unites States and the seventh leading cause worldwide
Mutational inactivation of tumor suppressor genes, including cyclin-dependent kinase inhibitor 2A, tumor protein 53 (TP53), and SMAD family member 4 (SMAD4), are frequently detected in type 2 and 3 lesions. These findings suggest that KRAS mutations are associated with tumor initiation, and subsequent gene mutations are a rate-limiting step for tumor progression [2,9]
We present RNA interference (RNAi)-based therapeutics using nanomedicine-based delivery systems that are currently being investigated in clinical trials for the treatment of PDAC

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer related deaths in the Unites States and the seventh leading cause worldwide. Mutational inactivation of tumor suppressor genes, including cyclin-dependent kinase inhibitor 2A, tumor protein 53 (TP53), and SMAD family member 4 (SMAD4), are frequently detected in type 2 and 3 lesions These findings suggest that KRAS mutations are associated with tumor initiation, and subsequent gene mutations are a rate-limiting step for tumor progression [2,9]. We present RNA interference (RNAi)-based therapeutics using nanomedicine-based delivery systems that are currently being investigated in clinical trials for the treatment of PDAC. We developed a novel therapeutic strategy that targets KRAS and TP53 mutations at same time via liposome delivery of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), ribonucleoprotein (RNP) complexes, and single-guide RNA (sgRNA) to overcome drugresistance of PDAC, and this treatment significantly enhanced the anti-tumor activity of gemcitabine [15]. We provide our perspective on the development of gene therapy using nanotechnology for future clinical translation

RNAi Therapy for Pancreatic Cancer

CRISPR-Cas Gene Editing

Findings

Conclusions and Future Perspectives