Scientists in Barcelona, Spain, have designed a new strategy for getting genetically modified viruses to selectively attack tumor cells without affecting healthy tissues, according to an article published in Nature Communications.
Conventional cancer treatment may cause adverse effects as a result of poor tissue selectivity. To avoid these outcomes, it is important that new therapies can efficiently remove cancer cells and preserve the healthy ones, according to the researchers. A new approach in cancer therapy is based on the development of oncolytic viruses that have been modified to infect only tumor cells. In recent years, several studies have examined viruses created by genetic engineering to maximize their anticancer effect. These studies have found, however, that as the potency of oncolytic viruses increases, so does their associated toxicity.
In their article, investigators at Barcelona’s August Pi i Sunyer Biomedical Research Institute and the Institute for Research in Biomedicine describe how they developed a new approach to providing adenoviruses with high specificity against tumor cells. “We have taken advantage of the different expression of a type of protein––CPEBs [cytoplasmic polyadenylation element binding proteins]––in normal and tumor tissues,” explained co-lead investigator Dr. Raúl Méndez.
CPEBs comprise 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 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 pathologic 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 [to be] 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 attacks only cells with high levels of CPEB4 and low CPEB1. That means that it affects only tumor cells, ignoring the healthy tissues,” Méndez said.
Co-lead investigator Dr. Cristina Fillat added: “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.” To do this, she explained, it was necessary to modify the genome of these viruses. In their study, the researchers inserted sequences that recognized CPEB proteins in key regions for the control of viral proteins. Their activity was checked in in vitro models of pancreatic cancer, and the control of tumor growth was observed in murine models.
The oncoselective viruses created in this study were very sophisticated, being activated by CPEB4 but repressed by CPEB1, the researchers point out. “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,” Fillat said. She added that “this new approach is very interesting since it is a therapy selectively amplified in the tumor.”
Since CPEB4 is overexpressed in several tumors, the investigators’ new oncoselective strategy may be valid for other solid tumors, they say. They are now working to combine their oncolytic viral treatment with therapies that are already being used in clinical practice or that are in an advanced stage of development to find synergies that will make the viruses more effective.
Source: EurekAlert; March 16, 2017.