Our laboratory is interested in the development of herpes simplex virus (HSV) vectors for cancer therapy, with the long-term goal of translating these vectors to the clinic, and strategies to target cancer stem cells. Oncolytic (replication-competent) viruses target tumor cells for destruction, yet are non-pathogenic to normal tissue. An important goal is to identify mutations in viral genes that confer oncolytic activity and tumor selectivity, and study their mechanism of action. An alternative strategy for tumor selectivity is to transcriptionally-target HSV, so its replication is dependent upon a cancer specific regulatory sequence. The host immune response plays a complex role in therapeutic efficacy, both positive and negative, and is an area of study. For example, we are; exploring the interactions between HSV infection and dendritic cell function and how they can be exploited for therapy, 'arming' oncolytic HSV with transgenes to modulate/enhance the immune response, and modifying innate or adaptive immune responses that might acutely inhibit virus spread. Tumors contain a range of cell types, in addition to cancer cells, that are important for therapy. 'Armed' oncolytic HSV vectors are a useful strategy for this, combining direct tumor cell killing with expression of therapeutic transgenes to target tumor stroma and vasculature. Like most cancer therapies, oncolytic HSV is likely to be most effective in combination with other therapies. We have been investigating synergistic interactions between oncolytic HSV and chemotherapeutic or small molecule inhibitor drugs.

Oncolylic HSV is effective against most solid tumors. We have recently focused our attention on primary brain tumors like glioblastoma and neural tumors arising in neurofibromatosis type 1, and cancer stem cells that reside in these tumors. Cancer stem cells have properties in common with normal stem cells, in particular self-renewal and are thought to be critical in tumor progression, metastasis, and recurrence. Understanding the biology of these cancer stem cells is important for developing therapies that target these cells and representative tumor models for preclinical studies. We are isolating and characterizing cancer stem cells from patient specimens and studying their susceptibility to different oncolytic HSV vectors.