Ovarian cancer is the deadliest gynecological malignancy causing over 14,000 deaths per year in America with a 5-year survival below 50%. A combinational chemotherapy of a DNA damaging platinum-based drug (Ex. Cisplatin or Carboplatin) and an anti-mitotic (Ex. Paclitaxel) is the standard of care treatment. Although these treatments typically result in an initial response, ovarian cancer traditionally acquire resistance to DNA damaging therapies, ultimately resulting in death of the patient, signifying the need for novel DNA damaging independent therapeutic strategies. OSW-1 is a natural product saponin with a high cytotoxic potency in vitro through binding to its cellular targets Oxysterol-Binding Protein (OSBP) and OSBP-Related Protein 4 (ORP4). OSW-1 induces apoptosis, mitochondrial dysfunction, and intracellular calcium release, consistent with ORP4 dysfunction, suggesting that OSW-1 exhibits its neoplastic activity through ORP4 inhibition rather than OSBP targeting. ORP4 is expressed in the brain, retina, and testes, but is virtually absent from every other tissue in the body. Interestingly, ORP4 is putatively expressed in most cancers with a specifically strong expression in ovarian, colorectal, and leukemia cancers, providing an ideal precision target for the OSW-1 compound in these cancers. Herein, we describe the potent activity of the OSW-1 compound relative to the clinically used compounds, cisplatin and paclitaxel in both a monolayer (2D) and spheroid (3D) ovarian model system. Furthermore, we provide extensive characterization of spheroid development in multiple mammalian ovarian cancer cell lines, producing an ideal in vitro model for investigating small molecule pharmacology on in vivo tumors. Lastly, OSW-1 compound’s cellular biological regulation was identified through an untargeted mass-spectrometry metabolomic investigation.

Development of OSW-1 as a precision therapeutic targeting OSBP-related protein 4 (ORP4) using monolayer (2D) and spheroid (3D) ovarian cancer cell models

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.