IDIBAPS and IRB Barcelona researchers show the effectiveness of a new strategy to achieved genetically modified viruses that infect only tumor cells, thus preserving healthy tissues.
It is an innovative approach that exploits the different expression profiles of certain proteins between tumor and healthy cells, thus allowing the virus to infect only the former.
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 achieve genetically modified viruses that selectively attack tumor cells without affecting healthy tissues. Published today by the journal Nature Communications, the study is part of Eneko Villanueva’s work for his PhD thesis and is co-led by Cristina Fillat, head of the Gene Therapy and Cancer Group at IDIBAPS, and Raúl Méndez, ICREA researcher at IRB Barcelona.
Conventional cancer treatment can cause undesirable side effects as a result of poor selectivity. To avoid them, it is important that new therapies efficiently remove cancer cells while preserving healthy ones. One of the new approaches in cancer therapy is based on the development of oncolytic viruses, that is to say, viruses modified to infect only tumor cells. In recent years several studies have focused on the development of genetically engineered viruses to maximize their anticancer effect; however, as their potency increases, so does associated toxicity. Limiting this effect on healthy cells is now the key to the application of this promising therapy.
In the study published in the journal Nature Communications, researchers from IDIBAPS and IRB Barcelona have developed an innovative approach to provide an 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 regulate the expression of hundreds of genes and maintain 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 demonstrate to be highly expressed in cancer cells and necessary for tumor growth. And, on the other hand, there is CPEB1, which is expressed in normal tissue and lost in cancer cells. We have taken advantage of this imbalance to develop a virus that attacks only cells with high levels of CPEB4 and low levels of CPEB1, which means that it affects only tumor cells, ignoring 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, and also conjunctivitis and gastroenteritis but which have features that make them very attractive for tumor treatment," explains Cristina Fillat. To do this, it is necessary to modify the genome of these viruses. In the study, researchers 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 oncoselective viruses developed 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 tumor cells they replicated their genome and, when leaving , they destroyed the cell and released more viral particles with the potential to infect more cancer cells," says Fillat. She adds that, “this new approach is very interesting since it is a therapy that is 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 used in clinical practice or that are in a very advanced stage of development, with the aim to find synergies that make them more effective.
This technology is patent protected and ready for out-license.
This study has received funding from the Spanish Association Against Cancer (AECC) and Fundación Botín and Banco Santander, through Santander Universidades.
Eneko Villanueva, Pilar Navarro, María Rovira-Rigau, Annarita Sibilio, Raúl Méndez, Cristina Fillat
Translational reprogramming in tumor cells can generate oncoselectivity in viral therapies
Nature Communications. DOI: 10.1038/NCOMMS14833