Hypoxia-activated probiotic agents for breast cancer

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ABSTRACT Hypoxia is one of the main features of solid tumors including breast cancer and has been shown to correlate with a poor prognosis. Although many chemotherapeutic agents such as paclitaxel and doxorubicin are significantly effective in a normoxia environment, they are less effective in hypoxic tumor regions due to poor infusion, hypoxia, and acidity. Given its significant impact on treatment and tumor progression, the development of a new approach to specifically target the hypoxic regions of tumors is clinically needed. To address the challenges (unmet medical needs), our objective for this proposal is to develop a new probiotic-assisted approach as bacteria preferentially migrate and accumulate in the hypoxic region of the tumor. We developed our original hypoxia-inducible expression system and have optimized its use in E. coli G3/10 cells, which have been used as a probiotic in humans. We demonstrated that the G3/10 cells preferentially localized the hypoxic regions of xenografted breast tumors in mice. With the new tools of the hypoxia-inducible expression system in G3/10 cells, we will deliver cancer-killing cupredoxin proteins, azurin or rusticyanin, in the hypoxic region of triple-negative breast cancer as they have limited treatment options and a worse prognosis. We hypothesize that the development of a new bacteria-assisted approach to express cancer-killing proteins under the hypoxia-inducible promoter will provide functional tools for specifically targeting hypoxic tumors. To test our hypothesis and improve current therapy, we designed experiments based on our “bi-directional” strategy; a combination of the G3/10-based therapy with standard chemotherapeutic agents (paclitaxel and doxorubicin), so that the chemotherapy suppresses tumors in the outer periphery regions, perfused tumor regions, and our bacterial approach kills tumor in the hypoxic inner regions. Our preliminary data strongly support this concept. Considering the NIH/NCI’s focusing areas in FOA PAR-22-085 (Microbial-based Cancer Imaging and Therapy - Bugs as Drugs), we specifically formed a multidisciplinary team that integrates expertise in basic, translational, and clinical breast cancer biology, microbiology, molecular biology, immunology, pathology, and biostatistics. With the five years of preclinical research proposed in this application, we will discern the value of engineered G3/10 cells as effective bacteria-assisted functional tools. Results from the proposed studies will potentially provide new and effective treatment strategies that specifically target the hypoxic tumor microenvironment.