Oncolytic Viruses in Pancreatic Adenocarcinoma Treatment

Although cancer-related medical research has been developed for many years, pancreatic cancer is a highly lethal disease that is extremely difficult to detect and treat. Complete surgical resection is still the only chance of long-term disease-free survival. Unfortunately, 80% of patients will develop locally advanced or metastatic disease, which makes it impossible to perform resection after diagnosis. The majority of patients undergoing surgical treatment have only a slight improvement in survival rate, and almost all patients will relapse. Therefore, the treatment of pancreatic cancer has recently focused on multimodal treatment through surgery, chemotherapy and radiation. The development of pancreatic cancer-targeted drugs and chemotherapy only has a moderate impact on clinical outcomes, and has not changed its 5-year survival rate. Fortunately, the genetic and molecular mechanisms of pancreatic cancer are being quickly discovered and provide opportunities for new targeted therapies. Oncolytic virus (OV) therapy is currently one of the most promising targeted drugs for the treatment of pancreatic cancer.

Biologic features of pancreatic cancer. Fig.1 Biologic features of pancreatic cancer. (Ryan, 2014)

Difficulties of Treatment for Pancreatic Cancer

Oncogenic transformation in the pancreas is currently considered to be a multistage process involving the accumulation of inherited and acquired mutations in specific cancer-related genes in precancerous tumors, following a multistep progression from preneoplastic to infiltrating carcinoma, characterized by an increased degree of morphological and cytological atypia. The most common situation is to start with activating mutations of the KRAS gene, followed by somatic mutations of one or more tumor suppressor genes TP53, p16/CDKN2A and SMAD4. About 10% of cases can be partially attributed to one of several germline mutations. The development of metastatic cancer requires both KRAS mutations and the deletion of tumor suppressor genes. Targeting these molecular pathways has become one of the methods of customizing oncolytic viruses and targeted therapies for pancreatic cancer.

The Potential of OV in the Treatment of Pancreatic Cancer

OV itself has tumor selectivity and the ability to cause cancer cell lysis, and is becoming more and more popular in the treatment of many different forms of cancer. OV can prevent its binding and replication in normal cells through genetic engineering, and can add foreign genes that directly and/or indirectly cause cell death to selectively target tumor cells. These viruses usually also can replicate. Therefore, replication in tumor cells produces infectious progeny, which may further spread and kill the tumor mass. The efficacy of oncolytic viruses depends on direct tumor lysis, the ability of the virus to spread to surrounding cancer cells, and the ability of the virus to spread. At present, the main types of viruses used in the treatment of pancreatic cancer are the following:

  • Poxviruses. The modified vaccinia virus GLV-1h68 can express the endostatin-angiostatin fusion protein, which has been shown to inhibit angiogenesis in pancreatic cancer, and it has significant antitumor efficacy against pancreatic cancer in vivo.
  • Oncolytic herpes virus. Herpes simplex virus (HSV) HSV-1 and HSV-2 are large enveloped viruses with double-stranded DNA. In the wild, they can cause self-limiting infections, usually causing ulcers of the mouth, lips, or genitals, and can form potential infections in the ganglia. As an oncolytic virus, HSV has been genetically modified to replicate only in cancer cells, and it has proved to be a promising drug in the treatment of pancreatic cancer virus.
  • Adenovirus. Adenovirus is one of the most commonly used gene therapy vectors. ONYX-15 is an improved adenovirus that deletes the necessary viral genes needed to replicate normal cells. It is only allowed to replicate in cancer cells and is the first oncolytic virus used in clinical trials for pancreatic cancer. In phase I/II clinical trials, it was found that the combined use of ONYX-15 and gemcitabine has a good therapeutic effect on pancreatic cancer.
  • Parvovirus. Parvoviruses are not pathogenic to animals and humans, but have shown tumor-suppressing effects in animal models. It can cause both direct oncolytic and immunomodulatory effects. When Gemcitabine is administered, H-1PV can show reduced tumor growth in vivo, prolonged animal survival, and no metastasis in computed tomography. This shows that parvovirus can be used as a useful adjuvant drug for multimodal therapy of pancreatic cancer.

Reference

  1. Ryan, D. P.; et al. Pancreatic adenocarcinoma. New England Journal of Medicine. 2014, 371.11: 1039-1049.
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