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Bahreyni, Amirhossein

University of British Columbia

Breast cancer poses a significant global challenge, impacting millions worldwide. Despite significant progress in understanding and treating it, there is still a critical need for more effective approaches due to the heterogeneity of breast cancer. Our lab previously developed a safe variant of Coxsackievirus B3 (CVB3), namely microRNA-modified CVB3 (miR-CVB3), with remarkable antitumor activity against lung cancer. In this thesis, I aimed to assess the safety and efficacy of miR-CVB3 in breast cancer therapy. Additionally, I sought to develop a safe platform capable of delivering multiple therapeutic agents, including miR-CVB3, to breast cancer cells. My hypothesis is that miR-CVB3, encapsulated into modified extracellular vesicles, is an excellent candidate for development into a novel oncolytic virotherapy for breast cancer. When applied, miR-CVB3 utilized miR sequences to selectively target cancerous cells while sparing healthy tissue. In vivo experiments revealed promising outcomes, with miR-CVB3 effectively reducing tumor size in mice bearing 4T1 breast tumors. Moreover, miR-CVB3 treatment led to increased immune cell infiltration within the tumor microenvironment, all while maintaining superior safety compared to its parent virus, CVB3. Furthermore, combining miR-CVB3 with additional therapeutic elements such as melittin and CpG sequences significantly enhanced immunogenic cell death in tumor cells. This combination therapy not only enhanced immune cell infiltration but also exhibited efficacy against both primary and distant tumors. Additionally, I showed that miR-CVB3 was able to modify proteins within cancer cells and exosomes, transforming them into immunostimulatory molecules and generating a pro-immune environment within the tumor. To optimize delivery, I harnessed exosomes as carriers for miR-CVB3. These exosomes, released from miR-CVB3-infected cancer cells, contained miR-CVB3 and efficiently transported it to other breast cancer cells. Further modification of miR-CVB3-encapsulating exosomes with the AS1411 aptamer and doxorubicin significantly improved treatment safety and efficacy in 4T1-tumor bearing mice. In summary, my thesis suggests that combining miR-CVB3 with immune enhancers and advanced delivery methods could reduce breast tumor growth and improve survival in 4T1 tumor-bearing mice. This approach represents a significant step forward in breast cancer treatment, potentially leading to more effective therapies.

Text

2024-08-01

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/88845

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/