Investigating the Blockade of Transforming Growth Factor-beta Signaling in Preclinical Models of Epithelial Ovarian Cancer
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Ovarian cancer is the most the lethal gynecologic malignancy and most commonly develops as epithelial ovarian cancer (EOC). Most EOC tumours are genetically unstable high-grade serous carcinomas that initiate and grow rapidly leading patients to present with late stage metastatic disease. Patients undergo debulking surgery followed by rounds of platinum-based chemotherapy and, although initial response rates are favorable, over 70% of patients experience recurrence of treatment-resistant tumours resulting in dismal 5-year survival rates (~30%). The need to develop therapeutic strategies for metastatic EOC has spurred investigation into signaling networks in the tumour microenvironment that support malignant progression. Transforming growth factor-β (TGF-β) is a pleiotropic growth factor that contextually impacts cell behaviour and is frequently employed by advanced tumours to exacerbate growth and metastasis. Current inhibitors of this pathway are limited by poor specificity, toxicity, or insufficient efficacy as single agents. In EOC, TGF-β signaling networks induce epithelial-mesenchymal transition (EMT)-mediated metastasis and promote resistance to platinum chemotherapy. In this thesis, novel synthetic antibody fragments targeting TGF-β receptor II (TGFBR2) were characterized in EOC cell lines and in mouse models as single agents and in combination with carboplatin. Targeting TGFBR2 successfully improved sensitivity to chemotherapy by limiting EMT and immune exclusion, leading to infiltration of cytotoxic immune cells and fewer suppressive cells in EOC tumours. M7824, the bifunctional inhibitor of PD-L1 and TGF-β, was also deployed in a syngeneic EOC mouse model. M7824 treatment hindered EOC metastasis and impaired immune exclusion by eliciting anti-tumour responses in macrophages and T cells. Prolonged treatment with M7824 elevated T cell exhaustion and costimulatory signatures characteristic of T cell dysfunction following persistent stimulation. Taken together, this thesis highlights the potential therapeutic benefits of TGF-β signaling blockade in EOC and provides rationale for investigating new combination therapies that impair EOC metastasis and improve survival.