Abstract
A recent death projection has placed pancreatic ductal adenocarcinoma as the second cause of death by cancer in 2030. The prognosis for pancreatic cancer is very poor and there is a great need for new treatments that can change this poor outcome. Developments of therapeutic innovations in combination with conventional chemotherapy are needed urgently. Among innovative treatments the gene therapy offers a promising avenue. The present review gives an overview of the general strategy of gene therapy as well as the limitations and stakes of the different experimental in vivo models, expression vectors (synthetic and viral), molecular tools (interference RNA, genome editing) and therapeutic genes (tumor suppressor genes, antiangiogenic and pro-apoptotic genes, suicide genes). The latest developments in pancreatic carcinoma gene therapy are described including gene-based tumor cell sensitization to chemotherapy, vaccination and adoptive immunotherapy (chimeric antigen receptor T-cells strategy). Nowadays, there is a specific development of oncolytic virus therapies including oncolytic adenoviruses, herpes virus, parvovirus or reovirus. A summary of all published and on-going phase-1 trials is given. Most of them associate gene therapy and chemotherapy or radiochemotherapy. The first results are encouraging for most of the trials but remain to be confirmed in phase 2 trials.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of cancer-related death in Western countries, and its incidence has increased over the last 40 years [1]
Even if promising innovative treatments based on patient genetics (PARP inhibitor), or targeting the tumor microenvironment, are currently being evaluated in early phase clinical trials, the prognosis for PDAC is still very poor and there is great need for new treatments that can change this poor outcome [7,8,9]
In the past few years, several teams and we have developed innovative approaches based on therapeutic gene transfer namely gene therapy
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of cancer-related death in Western countries, and its incidence has increased over the last 40 years [1]. The prognostic remains poor and a recent death projection of the “top cancer killers” due to demographic changes has placed PDAC as the second cause of death by cancer in 2030 behind the pulmonary carcinoma [2]. A vast majority (85%) of patients are diagnosed with locally advanced tumors and/or metastases because of lack specific symptoms and early markers for this dismal disease. For these patients, palliative armamentarium consists of conventional chemotherapeutic agents such as gemcitabine and, more recently, FOLFIRINOX (protocol 5-FU, Folinic Acid, Irinotecan, Oxaliplatin) and nab-paclitaxel, which offer marginal survival benefits [3,4,5,6]. Even if promising innovative treatments based on patient genetics (PARP inhibitor), or targeting the tumor microenvironment (hyaluronidase, sonic hedgehog inhibitors), are currently being evaluated in early phase clinical trials, the prognosis for PDAC is still very poor and there is great need for new treatments that can change this poor outcome [7,8,9]
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