Abstract
Ovarian cancer has the highest mortality of all of the gynecological malignancies. There are several distinct histotypes of this malignancy characterized by specific molecular events and clinical behavior. These histotypes have differing responses to platinum-based drugs that have been the mainstay of therapy for ovarian cancer for decades. For histotypes that initially respond to a chemotherapeutic regime of carboplatin and paclitaxel such as high-grade serous ovarian cancer, the development of chemoresistance is common and underpins incurable disease. Recent discoveries have led to the clinical use of PARP (poly ADP ribose polymerase) inhibitors for ovarian cancers defective in homologous recombination repair, as well as the anti-angiogenic bevacizumab. While predictive molecular testing involving identification of a genomic scar and/or the presence of germline or somatic BRCA1 or BRCA2 mutation are in clinical use to inform the likely success of a PARP inhibitor, no similar tests are available to identify women likely to respond to bevacizumab. Functional tests to predict patient response to any drug are, in fact, essentially absent from clinical care. New drugs are needed to treat ovarian cancer. In this review, we discuss applications to address the currently unmet need of developing physiologically relevant in vitro and ex vivo models of ovarian cancer for fundamental discovery science, and personalized medicine approaches. Traditional two-dimensional (2D) in vitro cell culture of ovarian cancer lacks critical cell-to-cell interactions afforded by culture in three-dimensions. Additionally, modelling interactions with the tumor microenvironment, including the surface of organs in the peritoneal cavity that support metastatic growth of ovarian cancer, will improve the power of these models. Being able to reliably grow primary tumoroid cultures of ovarian cancer will improve the ability to recapitulate tumor heterogeneity. Three-dimensional (3D) modelling systems, from cell lines to organoid or tumoroid cultures, represent enhanced starting points from which improved translational outcomes for women with ovarian cancer will emerge.
Highlights
Ovarian cancer is the eighth most frequently diagnosed malignancy and cause of cancer-related death in women (Sung et al, 2021)
The majority of in vitro studies in ovarian cancer have relied on the use of 2D cell culture of immortalized cell lines derived from primary ovarian cancers, pleural effusion, ascitic fluid from the peritoneal cavity or a distant metastatic site
genetically engineered mouse (GEM) models have enabled specific gene knockout to be modelled in a whole-body system, contributing to the understanding of individual and combinations of genes commonly mutated in ovarian cancer
Summary
Ovarian cancer is the eighth most frequently diagnosed malignancy and cause of cancer-related death in women (Sung et al, 2021). The classification of ovarian cancer includes distinct histological subtypes with varied sites of origin underpinned by defining molecular events affecting tumor suppressors and oncogenes These events drive specific patterns of clinical behavior characteristic of histotypes, including response to chemotherapeutic agents and molecular target drugs. The mutations and genomic variations described above offer opportunities to develop new molecular-based therapeutic strategies to treat ovarian cancer subtypes Some molecular events, such as those described in the HRR pathway, are already being targeted clinically by FDA-approved PARPis. Some molecular events, such as those described in the HRR pathway, are already being targeted clinically by FDA-approved PARPis For both discovery science and translational approaches to predicting which women are likely to benefit from which therapies, robust models are needed that expand upon traditional 2D cell culture and pre-clinical models, and include both molecular profiling and functional analyses. We discuss methods of 3D modelling that are either currently being employed in ovarian cancer cell lines, primary or metastatic tumor tissue and ascites, or have the potential to be used into the future for these purposes
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