The development of targeted drugs and chemotherapy for pancreatic cancer has only a certain impact on the clinical results, and has not changed the 5-year survival rate. Fortunately, the genetic and molecular mechanisms of pancreatic cancer are rapidly being discovered, providing opportunities for new targeted therapies. Oncolytic viral therapy (OVT) is one of the most promising targeted therapies for pancreatic cancer.
The pancreas is a gland located behind the stomach and in front of the spine. The pancreas produces digestive fluid and hormones that regulate blood sugar. Cells called exocrine pancreatic cells to produce digestive fluid, while cells called endocrine pancreatic cells produce hormones. Pancreatic cancer is a disease that forms malignant cells in pancreatic tissue and is the third leading cause of cancer death in the United States. Most pancreatic cancers begin with exocrine cells.
In the vast majority of cases, symptoms appear only after pancreatic cancer has grown and begun to spread. Due to the position of pancreas in the body, symptoms include jaundice, abdominal pain, weight loss, itching, backache, swelling, nausea, vomiting, etc.
According to a person's examination, laboratory test and symptom description, doctors usually require imaging tests: computed tomography (CT scan), magnetic resonance imaging (MRI), ultrasound, Positron emission tomography (PET scan). If a tumor is found in the pancreas by imaging, it can be diagnosed as pancreatic cancer only through biopsy-taking out the real tissue from the tumor.
Currently, the treatment of pancreatic cancer is based on the degree of cancer. Options may include surgery, chemotherapy, radiotherapy, novel immunotherapy, or a combination of them.
Fig.1 The pancreas in the digestive system.
Safety and effectiveness data from previous studies conducted in the past 10 years indicate that OVT may be a promising and innovative method for the treatment and management of pancreatic cancer. Nowadays, many types of oncolytic viruses (OVs) have been studied as therapeutic agents. OVs used in the treatment of pancreatic cancer in recent experimental and clinical work include adenoviruses (Ads), herpes simplex virus (HSV), and reoviruses (RVs).
|Adenoviruses are a kind of non-enveloped, linear, double-stranded DNA virus. Its genome size is about 38 kb. Ad E1B protein is necessary to prevent apoptosis of infected host cells. E1B gene deletion Ad can bind to p53, which can block the transcription activation mediated by p53 and achieve the effect of inhibiting cancer.|
ONYX-015 is probably the most famous replication OV, which is specially used in clinical trials of head and neck cancer. ONYX-015 is an E1B 55 kDa gene deletion adenovirus, which is specially used in clinical trials of head and neck cancer. It is believed that it depends on the change of the tumor suppressor pathway of p53, so that it can replicate efficiently in tumor cells. ONYX-015 has been tested in humans in phase I and phase II studies of pancreatic cancer. In the phase II clinical trial of ONYX-015 for recurrent head and neck cancer, the combination of the virus with chemotherapy (cisplatin and 5-fluorouracil) has proved particularly beneficial.
In addition, DF3 (Muc1) gene is mainly overexpressed in human breast cancer and pancreatic cancer. Since Ad.DF3-E1 has the E1A gene regulated by the DF3 promoter, the E1A gene is expressed only in Muc1 producing cells. The replication of this virus is limited to cancer cell lines that produce Muc1. The researchers confirmed that Ad.DF3-E1 selectively replicates in breast cancer, showing the effect of reducing breast cancer flanking tumors, and may have high potential for treating pancreatic cancer.
|Herpes simplex virus (HSV) is an enveloped double-stranded DNA virus with a genome size of 152 kb. The viral DNA is packaged in a complex T=16 icosahedral capsid, which is embedded in a proteinaceous layer known as the tegument that is surrounded by a host-derived lipid envelope. The envelope of the virus is covered with glycoproteins that regulate the attachment and entry of the virus.|
Some characteristics of HSV type-1 (HSV-1), including large exogenous gene capacity, neural sensitivity and high titer manufacturing, make it a candidate for virus delivery in cancer treatment. Through genetic engineering, at least eight different HSV-1 genes, including TK (UL23), ICP6 (UL39), ICP34.5, and Us3, can be deleted or mutated, and HSV-1 can be designed as a replication virus.
HF10 is a spontaneously mutated virus from HSV-1 HF strain. The deletion of 3.9-kb at the right end of UL and UL/IRL connection leads to the deletion of UL56 expression. A 2.3 kb deletion and extensive transformation rearrangement (UL52-UL55) were also observed at the left end of UL. It has been proved that injecting the virus into the peritoneal diffusion model of mice can successfully trigger the anti-tumor immunity of mice. At present, a phase I clinical trial using HF10 against an unresectable advanced pancreatic cancer has been approved by the ethics committee of the Nagoya University School of Medicine and is in progress.
NV1020 (r7020) originates from HSV-1, one of the missing TK genes, γ 34.5 (on IRL) and 15 kb over the region jointly shared between US and UL that includes ICP0, ICP4, and LATs. Under the regulation of HSV-1 α4 promoter, the 5.2 kb fragment of HSV-1 DNA and TK gene was inserted into the missing 15 kb region. NV1020 was originally developed as a human immune vaccine against HSV-1 and HSV-2 infection. In preclinical models of pancreatic cancer, it has been detected as a potential oncolytic agent.
Fig.2 Structure of NV1020. (Kasuya, 2005)
||RV is a member of the family Reoviridae. It is a non-enveloped double-stranded RNA virus, which is 85 nm wide and consists of two concentric icosahedral protein capsids, with the least pathogenicity to the human body.|
In general, 90% of pancreatic cancers have K-ras mutations. The replication of RV is related to the high activity of the ras gene, which is believed to prevent cell apoptosis and anoikis. Replication of the virus in normal cells is inhibited, but it can propagate in cells highly activated by Ras. When RV infects cells, the viral blocking pathway is activated by RNA activated protein kinase (PKR) and eIF2α pathway. Therefore, RV has great potential in the treatment of pancreatic cancer.
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