The viral tropism of two distinct oncolytic viruses, reovirus and myxoma virus, is modulated by cellular tumor suppressor gene status

Abstract

Replication-competent oncolytic viruses hold great potential for the clinical treatment of many cancers. Importantly, many oncolytic virus candidates, such as reovirus and myxoma virus, preferentially infect cancer cells bearing abnormal cellular signaling pathways. Reovirus and myxoma virus are highly responsive to activated Ras and Akt signaling pathways, respectively, for their specificity for viral oncolysis. However, considering the complexity of cancer cell populations, it is possible that other tumor-specific signaling pathways may also contribute to viral discrimination between normal versus cancer cells. Because carcinogenesis is a multistep process involving the accumulation of both oncogene activations and the inactivation of tumor suppressor genes, we speculated that not only oncogenes but also tumor suppressor genes may have an important role in determining the tropism of these viruses for cancer cells. It has been previously shown that many cellular tumor suppressor genes, such as p53, ATM and Rb, are important for maintaining genomic stability; dysfunction of these tumor suppressors may disrupt intact cellular antiviral activity due to the accumulation of genomic instability or due to interference with apoptotic signaling. Therefore, we speculated that cells with dysfunctional tumor suppressors may display enhanced susceptibility to challenge with these oncolytic viruses, as previously seen with adenovirus. We report here that both reovirus and myxoma virus preferentially infect cancer cells bearing dysfunctional or deleted p53, ATM and Rb tumor suppressor genes compared to cells retaining normal counterparts of these genes. Thus, oncolysis by these viruses may be influenced by both oncogenic activation and tumor suppressor status.

Myxoma virus suppresses proliferation of activated T lymphocytes yet permits oncolytic virus transfer to cancer cells

“…[8][9][10] MYXV is a viral oncolytic agent that is nonpathogenic to humans and mice but has natural tropism for a variety of human cancers. [11][12][13] In the course of developing MYXV as an ex vivo purging agent for transplant, we serendipitously discovered that NSG mice receiving human HCT xenografts treated ex vivo with MYXV developed no GVHD, lived longer, and yet still exhibited robust human hematopoietic engraftment in the recipient bone marrow. 14 We hypothesized that MYXV impaired the GVHD capacity of alloreactive donor T lymphocytes.…”

Molecular Determinants for the Inactivation of the Retinoblastoma Tumor Suppressor by the Viral Cyclin-dependent Kinase UL97

“…Many viruses modulate the Rb pathway, presumably to improve viral fitness (8 -10). The mechanisms through which viruses inactivate the Rb pathway are of interest in terms of developing potential antiviral and anticancer therapeutics (11), designing oncolytic viruses as treatments for human cancers (12)(13)(14), and furthering our molecular understanding of cancer cell biology (15).…”

Herpes Simplex Type 1 for Use in Cancer Gene Therapy: Looking Backward to Move Forward

“…et al, 1999). Reovirus and MYXV replicate to higher levels in cancer cells with reduced expression of p53, and although this is not the major determinant dictating their selective replication in tumor cells, it enhances efficiency of infection (Kim et al, 2010 (Platanias, 2005;Everts & van der Poel, 2005). A well characterized ISG involved in blocking viral replication is PKR, as discussed previously (Sadler & Williams, 2008;Everts & van der Poel, 2005).…”