PLOS Pathogens: Preclinical Therapy of Disseminated HER-2+ Ovarian and Breast Carcinomas with a HER-2-Retargeted Oncolytic Herpesvirus

PLOS Pathogens: Preclinical Therapy of Disseminated HER-2+ Ovarian and Breast Carcinomas with a HER-2-Retargeted Oncolytic Herpesvirus

Introduction

The past decades have witnessed remarkable progresses in the ability to treat numerous cancers by means of surgery, chemio- and radiotherapy, or combinations thereof. Nonetheless, there remains a tremendous burden of tumors not sensitive or accessible to standard treatments. Oncolytic virotherapy exploits the intrinsic ability of viruses to kill the target cell and simultaneously to spread to other target cells. A key requirement is that the virus specifically targets cancer cells [1]. Herpes simplex virus- 1 (HSV-1) is being actively investigated in preclinical and phase 1–3 clinical studies as it lends itself to numerous genetic modifications that make it cancer-specific [2], [3].
The strategy pursued in our laboratories is to modify HSV-1 tropism, and efficiently retarget the virus to cancer-associated cell-surface molecules, such as the human epithelial growth factor receptor 2 (HER-2), a member of the tyrosine kinase receptors [4]–[9]. The clinical impact of the HER-2 oncogene stems from the fact that it is overexpressed in human breast and ovary carcinomas (>200,000 new cancer cases each year in the U.S.), and correlates with worsened prognosis. Because of these properties, HER-2 is currently the target of antibody-based (trastuzumab) therapies, or small molecule tyrosine kinase inhibitors.......