Abstract
Breast cancer is a leading cause of cancer death and source of brain metastases (BM) among women in the US. With a dismal two year survival of 2%, novel treatment modalities are essential. Chondroitin sulfate proteoglycan (CSPG) expression has been directly associated with metastatic potential in breast cancer. The Chondroitinase ABC (Chase) enzyme is able to digest CSPGs, thereby disrupting critical extracellular matrix interactions. We recently generated an oncolytic virus expressing Chase which resulted in some efficacy in mice bearing intracranial gliomas. Here, we developed a second generation Chase mutant (ChaseM) vector, which results in optimal enzymatic expression and function in mammalian cells. ChaseM decreases neurosphere formation in vitro, akin to the phenotype observed with pharmacologic blockade of CSPG assembly. In nude mice bearing glioma xenografts, OV-ChaseM led to a significant increase in median survival over control virus treated animals (p = 0.005). CSPGs in the CNS are formed as an integral part of the glial scar and implicated in the sequestration of inflammation at the site of insult. Thus, we hypothesize that the dissolution of CSPGs by OV-ChaseM will facilitate the influx of immune cells into the tumor stroma, alleviate microglia suppression and elevate T-cell responses following viral therapy, resulting in long term responses. We generated a syngeneic model of BM to test the ability of OV-ChaseM to facilitate these effects. Intracranial implantation of DB7 breast cancer cells results in 100% tumor development and pathology akin to human BM disease. In this model, a single dose of OV-ChaseM resulted in a significant survival advantage compared to controls (p = 0.02). Ongoing studies are evaluating the contribution of host anti-tumor immune activation towards this survival efficacy. With this data, we aim to broaden the scope of treatment for brain cancer patients and provide therapeutic evidence for regiments to be implemented in the clinic.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
