Abstract
Treatment of aggressive glioblastoma brain tumors is challenging, largely due to diffusion barriers preventing efficient drug dosing to tumors. To overcome these barriers, bacterial carriers that are actively motile and programmed to migrate and localize to tumor zones were designed. These carriers can induce apoptosis via hypoxia-controlled expression of a tumor suppressor protein p53 and a pro-apoptotic drug, Azurin. In a xenograft model of human glioblastoma in rats, bacterial carrier therapy conferred a significant survival benefit with 19% overall long-term survival of >100 days in treated animals relative to a median survival of 26 days in control untreated animals. Histological and proteomic analyses were performed to elucidate the safety and efficacy of these carriers, showing an absence of systemic toxicity and a restored neural environment in treated responders. In the treated non-responders, proteomic analysis revealed competing mechanisms of pro-apoptotic and drug-resistant activity. This bacterial carrier opens a versatile avenue to overcome diffusion barriers in glioblastoma by virtue of its active motility in extracellular space and can lead to tailored therapies via tumor-specific expression of tumoricidal proteins.
Highlights
The diffuse and infiltrative nature of glioblastoma (GBM) tumors presents unique challenges for effective treatment
This indicates that bacterial carriers could migrate throughout the tumor and preferentially colonize it compared to the surrounding tissue
The particular novelty of this study is the use of S. typhimurium to deliver a tumoricidal combination therapy of p53 and Azurin that synergistically induce apoptosis in an intracranial rat model of aggressive GBM tumor in the absence of an adjuvant therapy
Summary
The diffuse and infiltrative nature of glioblastoma (GBM) tumors presents unique challenges for effective treatment. The dominant strategy to overcome diffusion barriers is convection enhanced delivery (CED) whereby a pressure gradient enhances interstitial infusion of drugs.[4] is it challenging to accurately model drug dosing with this method given brain tissue heterogeneity,[5,6] and the increased pressure within the brain caused by CED could lead to cerebral edema, hemiparesis, and other neurological damage.[7] there is a critical need to explore alternate approaches to overcome diffusion barriers that impede adequate drug dosing into solid tumors
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