Patient-Derived Ovarian Cancer Models Provide Insight into Cancer Cell-Intrinsic and Immune Cell-Dependent Effects on Therapeutic Response

Ovarian cancer is the most lethal gynecologic malignancy, largely due to late diagnosis and resistance to chemotherapy. This dissertation applies patient-derived organoids (PDOs), xenograft-derived organoids (PDXOs), and humanized xenografts (huPDX) to investigate therapeutic responses and immune interactions. Organoids were shown to retain critical features of the original malignancy. Across platinum-sensitive, -resistant, and -refractory cases, both PDOs and PDXOs exhibited drug sensitivities that aligned with patients’ clinical classifications. Building on this foundation, a drug screen revealed novel strategies. Auranofin restored platinum sensitivity in Notch3-active models, afatinib broadly reduced viability, and adavosertib–gemcitabine and sorafenib–topotecan combinations produced synergy. Extending this work, immune interactions were modeled with M2 macrophages, which enhanced organoid survival and paclitaxel resistance. Targeting macrophages with BMS777607 or CSF-1R inhibitor restored sensitivity in vitro and in huPDX. Altogether, these findings highlight organoid systems as translational platforms capturing tumor-intrinsic and immune-mediated drivers of resistance and support macrophage-targeting as a promising therapeutic strategy for advancing personalized ovarian cancer treatment.