Viruses Created to Selectively Attack Tumor Cells

The image shows tumor cells infected by the virus, which expresses a fluorescent protein. Over the days (in the image fifth day), the virus multiplies, generating new virus that infect more cancer cells

It is an innovative approach that takes advantage of the different expression profiles of certain proteins between tumor and healthy cells that make the virus to only infect the first ones.

Scientists at the IDIBAPS Biomedical Research Institute and at the Institute for Research in Biomedicine (IRB Barcelona) lead a study in which they have designed a new strategy to get genetically modified viruses to selectively attack tumor cells without affecting healthy tissues. The study, published today by the journal Nature Communications, is part of Eneko Villanueva's work for his PhD and it is co-lead by Cristina Fillat, head of the Gene Therapy and Cancer Group at IDIBAPS, and Raúl Méndez, ICREA researcher at IRB Barcelona.

Conventional cancer treatment may cause undesirable side effects as a result of poor selectivity. To avoid them it is important that new therapies can efficiently remove cancer cells and preserve the healthy ones. One of the new approaches in cancer therapy is based on the development of oncolytic viruses, ie, viruses modified to only infect tumor cells. In recent years several studies have been focused on the development of viruses created by genetic engineering to maximize their anticancer effect but, as their potency increases, so does the associated toxicity. Limiting this effect on healthy cells is now the key for the application of this promising therapy.



An innovative and specific approach
In the study published in the journal Nature Communications, researchers from IDIBAPS and IRB Barcelona have developed an innovative approach to provide adenovirus with high specificity against tumor cells. "We have taken advantage of the different expression of a type of protein, CPEBs, in normal and tumor tissues," explains Raúl Méndez from IRB Barcelona.

CPEB is a family of four RNA binding proteins (the molecules that carry information from genes to synthesize proteins) that control the expression of hundreds of genes and maintain the functionality and the ability to repair tissues under normal conditions. When CPEBs become imbalanced, they change the expression of these genes in cells and contribute to the development of pathological processes such as cancer. "We have focused on the double imbalance of two of these proteins in healthy tissues and tumors: on the one hand we have CPEB4, which in previous studies we have shown that it is highly expressed in cancer cells and necessary for tumor growth; and, on the other hand, CPEB1, expressed in normal tissue and lost in cancer cells. We have taken advantage of this imbalance to make a virus that only attacks cells with high levels of CPEB4 and low CPEB1, that means that it only affects tumor cells, ignoring the healthy tissues," says Méndez.



"In this study we have worked with adenoviruses, a family of viruses that can cause infections of the respiratory tract, the urinary tract, conjunctivitis or gastroenteritis but which have features that make them very attractive to be used in the therapy against tumors," explains Cristina Fillat. To do this, it is necessary to modify the genome of these viruses. In the study researchers have inserted sequences that recognize CPEB proteins in key regions for the control of viral proteins. Their activity was checked in in vitro models of pancreatic cancer and control of tumor growth was observed in mouse models.

The onco-selective viruses created in this study were very sophisticated, being activated by CPEB4 but repressed by CPEB1. Thus, researchers achieved attenuated viral activity in normal cells, while in tumor cells the virus potency was maintained or even increased. "When the modified viruses entered into tumor cells they replicated their genome and, when going out, they destroyed the cell and released more particles of the virus with the potential to infect more cancer cells," says Fillat. She adds that, "this new approach is very interesting since it is a therapy selectively amplified in the tumor."



Since CPEB4 is overexpressed in several tumors, this oncoselective strategy may be valid for other solid tumors. Researchers are now trying to combine this treatment with therapies that are already being used in clinical practice, or that are in a very advanced stage of development, to find synergies that make them more effective.
Source: Materials provided by the Institute for Research in Biomedicine (IRB Barcelona)

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Amazing Discovery: Viruses are Dominant Drivers of Human Evolution, Researchers Say

In a new study, scientists apply big-data analysis to reveal the full extent of viruses’ impact on the evolution of humans and other mammals. Their findings suggest 30% of all protein adaptations since humans’ divergence with chimpanzees have been driven by viruses.

When an environmental change occurs, species are able to adapt in response due to mutations in their DNA. Although these mutations occur randomly, by chance some of them make the organism better suited to their new environment. These are known as adaptive mutations.

In the past decade, scientists have discovered a large number of adaptive mutations in a wide variety of locations in the genome of humans and other mammals.



The fact that adaptive mutations are so pervasive is puzzling. What kind of environmental pressure could possibly drive so much adaptation in so many parts of the genome?

Viruses are ideal suspects since they are always present, ever-changing and interact with hundreds to thousands of proteins.

“When you have a pandemic or an epidemic at some point in evolution, the population that is targeted by the virus either adapts, or goes extinct,” said lead author Dr. David Enard, of Stanford University.

“We knew that, but what really surprised us is the strength and clarity of the pattern we found.”

Previous research on the interactions between viruses and proteins has focused on individual proteins that are directly involved in the immune response.

This is the first study to take a global look at all types of proteins.

“The big advancement here is that it’s not only very specialized immune proteins that adapt against viruses,” Dr. Enard said.

“Pretty much any type of protein that comes into contact with viruses can participate in the adaptation against viruses. It turns out that there is at least as much adaptation outside of the immune response as within it.”



The team’s first step was to identify all the proteins that are known to physically interact with viruses.

After reviewing tens of thousands of scientific abstracts, they culled the list to 1,256 proteins of interest.

“We identified 1,256 proteins that physically interact with viruses out of a total of 9,861 proteins with orthologs in the genomes of the 24 mammals included in the analysis,” the scientists said.

The next step was to build big-data algorithms to scour genomic databases and compare the evolution of virus-interacting proteins to that of other proteins.

The results revealed that adaptations have occurred three times as frequently in virus-interacting proteins compared with other proteins.

“We’re all interested in how it is that we and other organisms have evolved, and in the pressures that made us what we are,” said senior author Dr. Dmitri Petrov, also from Stanford University.

“The discovery that is in constant battle with viruses has shaped us in every aspect — not just the few proteins that fight infections, but everything — is profound.”



“All organisms have been living with viruses for billions of years; this work shows that those interactions have affected every part of the cell.”

Viruses hijack nearly every function of a host organism’s cells in order to replicate and spread, so it makes sense that they would drive the evolution of the cellular machinery to a greater extent than other evolutionary pressures such as predation or environmental conditions.

The study sheds light on some longstanding biological mysteries, such as why closely-related species have evolved different machinery to perform identical cellular functions, like DNA replication or the production of membranes.

Scientists previously did not know what evolutionary force could have caused such changes.
“This paper is the first with data that is large enough and clean enough to explain a lot of these puzzles in one fell swoop,” Dr. Petrov said.

Source: eLife

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