Authors: Paula M. Manan-Mejias, Nicha Boonpattrawong, Manish Patankar, Maria Virumbrales Munoz
Published: 2025-04-22
DOI: 10.1158/1538-7445.am2025-1221
Source: Full article
Ovarian cancers are the 8th most common cause of cancer related deaths in women, which outcomes have not meaningfully improved since the 1980s. High-grade serous ovarian carcinoma (HGSOC), is the most common subtype of ovarian cancer and the deadliest, responsible for 70-80% of ovarian cancer deaths. HGSOC is typically diagnosed at advanced stages, due to lack of reliable tests and vague external symptoms. When detected, treatment options are limited and result in a 60% recurrence rate. Consequently, there is an urgent need for new therapeutic agents for HGSOC. Atovaquone is an FDA-approved drug for malaria that has been effective against HGSOC in 2D models. Atovaquone (ATO) is an OXPHOS inhibitor that induces reactive oxygen species (ROS) by binding to complex III, leading to apoptosis. However, the mechanism of action of Atovaquone is not well understood, arguably limited to using traditional HGSOC models in mechanistic studies. For example, 2D in-vitro models fail to include oxygen and nutrient gradients, as well as relevant mitochondrial organization for 3D migration processes, whereas in-vivo models make real-time cell inspection challenging. To bridge this gap, we have designed a microphysiological system (MPS) to investigate the role of the 3D tumor microenvironment (TME) in the HGSOC response to therapeutics. Our MPS includes an HGSOC cell spheroid that models intra-tumor metabolic heterogeneity, by recapitulating a necrotic core, quiescent area, and proliferative edge. Adjacent to the tumor spheroid, we can include 3D tubular vessels to study the delivery and effects of atovaquone in lymphatic drainage. Migration and invasion of HGSOC spheroids decrease with ATO treatment. We also showed that atovaquone alters mitochondrial dynamics within 48-72 h of treatment. In addition, a non-destructive imaging technique capable of assessing real-time metabolic profiles in spheroids, revealed that ATO is capable of shifting cancer cell metabolism in spheroids, impeding ATP production. Using this HGSOC MPS, we aim to better understand the mechanism of action of atovaquone and accelerate its translation into the clinic as a sole or combination therapy agent.