A new type of therapy using modified viruses can help destroy cancer cells, according to The Guardian. The newspaper said that a technique has been developed to optimise therapies that use viruses to seek out and destroy cancer cells.
The research tested the use of a type of protein that can be combined with viruses to help them attach to cancer cells. The researchers hoped these proteins would give the viruses a greater ability to enter and attack the tumour cells as part of a targeted therapy. Their results showed that mixing these proteins with viruses could significantly increase their ability to enter tumour cells (described as the tumour cells’ uptake of the virus), with an 18-fold increase in uptake with one particular protein.
This experimental technique on cells in a laboratory was part of very preliminary research and, as such, needs further study and testing. However, the study may open up further avenues for research and improve the use of viruses targeting cancer cells and gene therapies.
Where did the story come from?
The study was conducted by Dr TJ Harvey and colleagues from St James University Hospital in Leeds, The Mayo Clinic in the US and the University of Bradford. The study was funded by Cancer Research UK and published in the peer-reviewed medical journal Gene Therapy.
This research was covered well by The Guardian, which highlighted its preliminary nature.
What kind of research was this?
This laboratory study tested a technique to potentially improve gene therapy targeted at cancer cells. The researchers looked at how gene therapies using adenoviruses could be improved. Adenoviruses are types of viruses can enter cells, where their DNA can be activated. It is possible to insert human DNA sequences into the viruses’ genetic material, so that the human DNA will also be carried into the cell and “transcribed” into a substance called RNA. The instructions carried in this RNA can then be “translated” into proteins. In principal, it is possible to target specially tailored adenoviruses so that they enter cancer cells and weaken them. However, the cancer cells’ uptake of these adenoviruses can be limited, so the researchers investigated new ways to increase adenovirus uptake.
The researchers say that this adenovirus-mediated cancer gene therapy is yet to fulfil its clinical potential and suggest some reasons for this. For example, the immune system may clear the viruses that contain the inserted DNA, some of the adenovirus may not reach the tumour when delivered though the bloodstream, the adenovirus may reach the tumour but may not be able to pass through multiple cells to get to the core of the tumour, or a lack of tumour-specific proteins on the surface of tumour cells may not allow the adenovirus to enter the cell.
The authors say that, in the past, attention has focussed on how to target adenoviruses to tumour cells rather than normal cells. They also say that one of the proteins on the surface of cells that takes up adenoviruses (called hCAR) is found on a wide variety of normal cells but at lower concentrations on some cancer cells. The researchers focussed on another protein, called the epidermal growth factor receptor (EGFR), which is found in higher concentrations on many cancer tumours than on normal cells, and a receptor called the urokinase-type plasminogen receptor (uPAR), which is related to the spread (metastasis) of cancer.
This researchers made a “fusion protein”, a type of protein designed to increase the adenovirus uptake by cancer cells. This protein had part of the protein sequence of hCAR as well as the protein sequence recognised by EGFR and a protein sequence recognised by the uPAR receptor. The researchers could then combine this protein with the adenovirus with the aim of improving its targeted uptake by tumour cells.
What did the research involve?
The researchers made a number of fusion proteins containing combinations of hCAR and EGFR sequences or hCAR and uPAR sequences. They mixed these proteins with an adenovirus and compared how well it was taken up into various cancer cells compared with an adenovirus that had not been mixed with the fusion protein. The adenoviruses also contained the DNA sequence for a protein called beta–galactosidase. This protein could be measured when it was made inside the cell, which provided a way to test adenovirus uptake rates.
The researchers used the adenoviruses to transfect (infect) cell lines derived from cervical cancer cells (HeLa) and ovarian cancer cells (SKOV3), and assessed how much of the virus ended up inside the cell, as well as the activity of beta-galactosidase that they had introduced into the cell. They also assessed the viruses in a variety of bladder tumour cell lines.
The researchers also made viruses that would allow the DNA sequence for proteins that could kill the cancer cells to be carried into the cells.
What were the basic results?
In the SKOV3 ovarian cancer cell line, there was an 18-fold increase in the uptake of the targeted hCAR/EGFR adenovirus compared with an untargeted adenovirus.
The researchers found that a panel of bladder cell lines had highly variable amounts of hCAR and EGFR on their surface, and that the amount of non-targeted adenovirus uptake was dependent on the amount of hCAR on the cell surface. Using the targeted hCAR/EGFR adenovirus improved uptake in cell lines that are normally difficult to infect with the virus, and the cell lines with the greatest EGFR/hCAR ratios took up the targeted virus most efficiently. They also found that viruses targeting the hCAR/uPAR receptors had improved uptake in bladder cancer cells.
The researchers found that there was a delay in the growth of tumours in mice injected with adenoviruses containing the DNA sequence for proteins that can kill cancer cells. This effect was increased by mixing the fusion protein with these viruses before injecting them into the tumour.
How did the researchers interpret the results?
The researchers say that their approach “represents an opportunity to improve adenoviral gene therapy strategies, in multiple cancer types”. They believe that their technique can be used with existing and future adenovirus-mediated gene therapy strategies to increase the action of the DNA introduced to the cancer cells.
They suggest that taking a biopsy of a patient’s tumour could allow them to assess the patient’s suitability for fusion protein gene therapy, either in the form of an “individualised therapy” or as a “cocktail” of fusion proteins to target a single adenovirus to a tumour.
This study has developed a method to increase the targeting of adenoviruses to tumour cells by mixing them with fusion proteins. Although this is preliminary research, animal studies showed that injecting targeted adenoviruses into a tumour slowed its growth compared to untargeted adenoviruses. The researchers suggest that their strategy is amenable to testing in clinical trials of tumours that have low amounts of hCAR and are less readily accessible to adenovirus-mediated gene therapy.
In the present study, the researchers only looked at uptake of the virus into cancerous cells rather than normal cells. The ideal situation would be that patients could receive gene therapy through an injection into the bloodstream rather than an injection into a tumour, which may be inaccessible. Further research and improvement of this technique are needed to ensure that gene therapy is only taken up by cancer cells. This is promising research, which moves this type of therapy a step further towards more individualised approaches to cancer therapy.
Analysis by Bazian
Edited by NHS Website
Links to the headlines
The Guardian, 23 April 2010
Links to the science
Gene Therapy, April 22 2010