From scourge to cure: tumour-selective viral pathogenesis as a new strategy against cancer

Abstract

Tumour mutations corrupt cellular pathways, and accumulate to disrupt, dysregulate, and ultimately avoid mechanisms of cellular control. Yet the very changes that tumour cells undergo to secure their own growth success also render them susceptible to viral infection. Enhanced availability of surface receptors, disruption of antiviral sensing, elevated metabolic activity, disengagement of cell cycle controls, hyperactivation of mitogenic pathways, and apoptotic avoidance all render the malignant cell environment highly supportive to viral replication. The therapeutic use of oncolytic viruses (OVs) with a natural tropism for infecting and subsequently lysing tumour cells is a rapidly progressing area of cancer research. While many OVs exhibit an inherent degree of tropism for transformed cells, this can be further promoted through pharmacological interventions and/or the introduction of viral mutations that generate recombinant oncolytic viruses adapted to successfully replicate only in a malignant cellular environment. Such adaptations that augment OV tumour selectivity are already improving the therapeutic outlook for cancer, and there remains tremendous untapped potential for further innovation.

Figure 1. Tumour Evolution.

A hypothetical pathway of tumour evolution from a normal cell to an advanced-stage cancer. Mutations in key regulatory genes lead to changes in cell physiology that favour tumour growth. Over time, these genetic defects accumulate to confer many of the known hallmarks of cancer . The sequence of these events and the timing represented here is only one example of how this might occur.

Figure 2. Oncolytic Viruses Are Designed to Grow in the Tumour Niche.

There are at least six key critical features of tumour cell growth that can be targeted by oncolytic viruses. These include changes in the expression of viral-host cell receptors, the antiviral response, nucleotide and protein synthesis, cell proliferation, and apoptosis. A number of engineered or selected oncolytic viruses exist that can exploit one or more of these malignant characteristics.