Virology Faculty Member - Samuel Rabkin

Samuel Rabkin

Associate Professor of Surgery (Neurosurgery)

Massachusetts General Hospital
Brain Tumor Research Ctr, Simches, CPZN-3800
185 Cambridge St
Boston, MA 02114
Tel: 617-726-6817
Fax: 617-643-3422
Email: rabkin@helix.mgh.harvard.edu
Visit my lab page here.



We are developing HSV vectors as therapeutic agents for cancer, studying HSV interactions with cancer and normal cells, with the long-term goal being the clinical application of these vectors to patients. Our research centers on oncolytic (replication-competent) HSV vectors, which target tumor cells for destruction, yet are non-pathogenic to normal tissue. Tumor selectivity is achieved by mutating HSV genes that are: necessary for the virus to replicate in non-dividing cells; involved in pathogenicity/virulence; and/or blocking innate cellular responses or apoptosis. Many of these viral mutants are 'complemented' by cellular proteins with homologous activities, and agents that alter their expression, such as induction of DNA repair, can enhance oncolytic HSV activity. We are developing new oncolytic HSV vectors and combination strategies to take advantage of cancer cell physiology and improve efficacy. Characterizing virus-tumor and –host interactions, including both anti-tumor efficacy and host pathogenicity, in animal models is an important element of these studies.

We have also developed transcriptionally-targeted vectors, whose 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. In addition to the bulk tumor cells, the tumor microenvironment is composed of an array of cell types including; cancer stem-like or initiating cells, endothelial cells of the neovasculature, inflammatory cells, and fibroblasts in the stroma that are important for therapy. 'Armed' oncolytic HSV vectors are a useful strategy for this, combining direct tumor cell killing with expression of transgenes to target tumor stroma and vasculature. Our research is continually informed by the clinical situation and preclinical studies to support clinical translation are an important component.



Last Update: 10/22/2013



Publications

Wakimoto, H, Kesari, S, Farrell, CJ, Curry, WT Jr, Zaupa, C, Aghi, M, Kuroda, T, Stemmer-Rachamimov, A, Shah, K, Liu, T-C, Jeyaretna, DS, Debasitis, J, Pruszak, J, Martuza, RL, and Rabkin, SD. (2009) Human glioblastoma-derived cancer stem cells: Establishment of invasive glioma models and treatment with oncolytic herpes simplex virus vectors. Cancer Res 69: 3472-3481.

Kanai R, Zaupa C, Sgubin D, Antoszczyk SJ, Martuza RL, Wakimoto H, and Rabkin SD. (2012) Effect of gamma34.5 deletions on oncolytic herpes simplex virus activity in brain tumors. J Virol. 86: 4420-31.

Kanai R, and Rabkin SD. (2013) Combinatorial strategies for oncolytic herpes simplex virus therapy of brain tumors. CNS Oncol. 2: 129-42

Cheema TA, Wakimoto H, Fecci PE, Ning J, Kuroda T, Jeyaretna DS, Martuza RL, and Rabkin SD. (2013) Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model. Proc Natl Acad Sci U S A. 110: (in press).



© 2013 by the President and Fellows of Harvard College