Gene Therapy for Treatment of Pancreatic Cancer

Review Article

Austin Therapeutics. 2014;1(1): 10.

Gene Therapy for Treatment of Pancreatic Cancer

Mishra B* and Patel RR

Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu Univeristy), Varanasi, India.

*Corresponding author: Mishra B, Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu Univeristy), Varanasi - 221005, UP, India

Received: August 05, 2014; Accepted: September 16, 2014; Published: September 16, 2014

Abstract

Pancreatic cancer is one of the most dreadful disease having high morbidity and mortality rate with limited success in treatment option. Even after chemotherapy, radiotherapy and surgical interventions, long-term survival remains a remote possibility. The identification of appropriate targets for exploiting the novel modalities, an alternative to existing adjuvant therapies is the need of hour. The advancement in identification of genetic and molecular target controlling the critical pathways in pancreatic cancer provides deep insight for the development of newer strategies. Gene therapy approaches are currently being explored for the treatment and prevention of pancreatic cancer deaths by engineered novel delivery systems. In the present review, an overview of principles behind use of gene therapy including molecular targets, various delivery vectors and gene therapy approaches in context to pancreatic cancer, including in-vitro, in-vivo and clinical studies are discussed.

Keywords: Pancreatic cancer; Gene; Therapy; Delivery vector; Chemotherapy

Abbreviations

DNA: Deoxyribonucleic Acid; RNA: Ribonucleic Acid; GDP; Guanosine Diphosphate; GTP: Guanosine Triphosphate; INK4: Inhibitor of cyclin-dependent kinase 4; CDK; Cyclin-Dependent Kinase; TGF-β: Tumor Growth Factor-β; EGFR: Epidermal Growth Factor Receptor; FGF: Fibroblast Growth Factors; CAR: Coxsackie- Adenovirus Receptor; AAVs: Adeno-Associated Viruses; PLL: Poly- L-Lysine; PEI; Polyethyleneimine;

MSCs: Mesenchymal Stem Cells; TSPs: Tumor-Specific Promoters; hTRET: Human Telomerase Reverse Transcriptase; GDEPT: Gene-Directed Enzyme Prodrug Activation Therapy; HSVtk: Herpes Simplex Virus Thymidine Kinase; IL: Interleukins; APCs: Antigen Presenting Cells; TIMP: Tissue Inhibition of Matrix Metalloproteinases; TRAIL: Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand

Introduction

Pancreatic cancer is one of the most ravaging diseases prevalent in today’s time, ranked as fourth common cause of cancer deaths and tenth in new cancer cases. The treatment and management of this disease by using existing conventional therapies has faced difficulties in providing complete cure [1]. Despite advancements in the diagnostic techniques, early stage cancer prognosis is still one of the most challenging and grave problems; with a post-diagnosis 5 year survival rate of only 4%. Hence, introduction of new modalities in the treatment option is necessary [2]. The identified precursor for pancreatic cancer is the multiple genetic mutations which result in disinherited growth, evasion of host immune response, sustained angiogenesis and avoidance of apoptosis and metastasis that can effectively be targeted for the therapeutic interventions [3]. Chemotherapeutic treatment option has been proven to be effective in palliative treatment only. However, overall outcome is poor due to development of resistance with median survival of less than 3 to 5 months [4,5]. Most of the patients suffer from locally advanced or metastatic cancer. Among them, limited numbers of patients are suitable for surgical resection which provides the opportunity for a long-term disease-free state but not promised. These shortcomings of existing treatment options indicate the need of novel therapies.

Recent progress in the molecular research provides an insight in pancreatic cancer associated genes with their expression profiles and mutation in cancer cells as well as genetic targets for development of novel therapeutic strategies, either alone or in combination with existing conventional cytotoxic chemotherapies. These allow improvement in treatment outcomes and also reduce toxicity as well as problem of cross-resistance, which generally happens with standard radiotherapy and chemotherapy.

Gene therapy treatment approach is based on the delivery of genetic material i.e., exogenous nucleic acid into cancer cells of a patient, to eradicate the cause of cancer by manipulating intracellular genetic material. The gene linked with regulatory DNA sequences is carried by vectors, either viral or non-viral to transport into the target cells where it expresses. The transgene expression might occur in every transfected cell or selectively targeted cells, where specific activated transcription factors are present, which interact with tissue selective or tumor selective promoter/enhancer elements [4,6]. The theoretical basis for gene therapy is the assumption that expression, restoration, elimination or inhibition of the activity of a particular gene of interest will reverse the malignant phenotype and hence, the growth of cancer cells will be prevented or inhibited. The effectiveness of gene therapy involves the technical ability to inhibit or restore gene products in most of the tumour cells [7,8]. The key elements of the efficient gene therapy are shown in Figure 1.