Oncolytic viral therapy is an up-and-coming anti-tumor therapeutic approach that adopts oncolytic viruses (OVs) to kill cancer cells. Here, one major obstacle is to guarantee patient safety during OV treatment. This issue can be overcome by establishing oncoselectivity of the treatment, i.e., the selective elimination of cancer cells while rendering healthy tissue unaffected.
Raúl Méndez and Cristina Fillat, Institut d’Investigacions Biome`diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, and colleagues made use of the recent discovery that many different types of cancer cells reactivate programs in control of mRNA translation via cytoplasmic polyadenylation element-binding proteins (CPEBs). In general, CPEBs are known to regulate mRNA translation through cis-binding of the cytoplasmic polyadenylation element (CPE) present in mRNAs 3′-untranslated region (3′-UTR). To this end, the scientists inserted a CPE regulatory sequences in the 3′ UTR of the E1A viral gene supposedly activating E1A expression in cancer cells while promoting its translational repression in normal tissues. Several cell lines reflecting pancreatic adenocarcinomas, colorectal carcinomas, and malignant brain tumors were validated to upregulate CPE-mediated E1A expression and thus viral activity dependent on high levels of CBEP4 typical for those tumors. In contrast to control cell lines, e.g., human embryonic kidney (HEK), retinal pigment epithelial (RPE), human hepatocytes, and fibroblasts maintained high levels of CBEP1 mediating repression of CPE-containing mRNAs.
In vivo proof of principle for this methodology was provided using nude mice carrying subcutaneous pancreatic tumors and demonstrated reduced viral toxicity in healthy tissues and sustained oncolytic potency.
- Translational reprogramming in tumour cells can generate oncoselectivity in viral therapies,
E. Villanueva, P. Navarro, M. Rovira-Rigau, A. Sibilio, R. Méndez, C. Fillat,
Nature Communic. 2017.