Defining the role of cytomegalovirus in glioblastoma therapies

Brown University, Providence RI

Investigators

Linked publications & trials

Abstract

Summary: Glioblastoma (GBM) is an incurable brain tumor for which improved therapies are badly needed. There are roughly 10,000 cases diagnosed in the US each year, and median survival is ~14 months. Evidence has been accumulating over recent years linking cytomegalovirus (CMV) to GBM and other cancers. However, the role of CMV in GBM remains poorly defined. CMV is a prevalent virus in humans, where it resides lifelong in a latent state but can be reactivated under certain conditions. Several clinical trials targeting CMV using diverse approaches including immunotherapies and the anti-viral drug valganciclovir have shown very promising responses in GBM patients, but the underlying mechanisms are not clear. To improve our understanding of this area we have developed an immunocompetent murine model of intracranial GBM grown in the context of a systemic latent CMV infection. This consistently leads to significantly shortened survival compared with mock infected controls in multiple distinct murine GBM models. These effects can be reversed by treatment with anti- viral drugs. The goal of this study is to investigate the role of cytomegalovirus in therapeutic resistance in glioblastoma, building from our parent RO1 to design new combination approaches. As part of her PhD studies in the lab of Dr Lawler, Jasmine Clark will: 1) Identify anti-viral drugs for the most effective combination with standard of care (chemoirradiation), 2) investigate the role of altered vasculature/blood tumor barriers in therapeutic resistance, and 3) find molecular mechanisms involved in mediating resistance, using our mouse and human models of glioblastoma with CMV. Our goal is to develop improved therapeutic combinations.