"My research goal is to develop novel therapeutic approaches for cancer by using virotherapy (oncolytic virus, OV), molecular-targeted therapeutics and chemotherapy through targeting DNA damage responses (DDR) in cancer cells and the immune system. For postdoc training, I joined the lab of the Brain Tumor Research Center (BTRC) at Massachusetts General Hospital supervised by Robert Martuza, MD, and Samuel David Rabkin, PhD, who have been developing oncolytic herpes simplex virus (oHSV) therapies for cancer with a particular emphasis on brain tumors, represented by glioblastoma, a fatal brain tumor with median survival of 15 months. Cancer stem cell is one of the primary reasons causing the poor diagnosis. I have had an opportunity to use a panel of patient-derived glioblastoma stem cells (GSCs) as a lab resource that recapitulate the characteristics of patient tumors and generate orthotopic mouse models for therapeutic testing."
In 2013, my colleagues and I found that an oHSV armed with an immunomodulatory cytokine, interleukin 12, significantly inhibited the growth of murine GSC-generated intracerebral tumors in syngeneic mice. The survival benefit resulted from not only direct oHSV oncolysis of GSCs, but also increased IFN-Y release, inhibition of angiogenesis and reduction of the number of regulatory T cells in the tumor. This work demonstrated multifaceted oncolytic virus therapy for glioblastoma-targeting tumor cells, tumor microenvironment and the immune system."
My major research interest is to explore DDR in cancer to gain selective therapeutic effects. I led the recently published study that combined oHSV and poly(ADP-ribose) polymerase inhibitor (PARPi) for the treatment of GSCs. I found the combination treatment synergistically killed GSCs, irrespective of their PARPi sensitivity, and significantly increased DNA damage and apoptosis in vitro and in vivo. The synergy is caused by oHSV manipulation of DDR by degrading the key homologous recombination repair (HR) protein Rad51 and inhibiting HR. This was the first report of PARPi + oHSV combination therapy in cancer stem cells. OHSV antagonism of DDR provides a novel strategy for combination therapy with drugs inhibiting DDR pathways, like PARPi, in GBM and other tumors. This work establishes oHSV as a unique PARPi partner to overcome the current clinical limitations of PARPi such as resistance. To further expand the use of PARPi in cancers, I screened a variety of DDR targeting agents in combination with PARPi. I discovered that ATR inhibitor sensitized GSCs to PARPi and the combination therapy prolonged survival of mice bearing brain tumors derived from PARPi-sensitive and -resistant GSCs. Furthermore, my investigation identified the specific mechanisms that underlie the cancer-selective cytotoxicity of this approach and new biomarkers for PARPi-response in cancer cells."
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