Dr. Sinha on the Antitumor Effects of Onvansertib in a Preclinical Endometroid Endometrial Cancer Model

Nikita Sinha, MD, fellow, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of North Carolina (UNC), UNC Chapel Hill School of Medicine, discusses the potential effects of the oral Plk1 inhibitor onvansertib on endometroid endometrial cancer pathogenesis in a preclinical model of disease.

In this preclinical study, the human endometrioid endometrial cancer cell lines KLE and EC-023 were exposed to onvansertib at varying concentration, and its impact on Plk1 cell proliferation, apoptosis, cellular stress, adhesion, and invasion was assessed.

2024 Society of Gynecologic Oncology Winter Meeting

, demonstrated that onvansertib had both anti-tumorigenic and anti-proliferative effects in an endometrioid endometrial cancer model, Sinha begins.

Onvansertib exhibited dose-dependent inhibition of cellular proliferation in both KLE and EC-023 cell lines, along with a reduction in colony count, she reports. Moreover, treatment with onvansertib led to a significant increase in cleaved Caspase-3 activity, indicating enhanced apoptosis in both cell types, Sinha explains. Mechanistically, onvansertib downregulated anti-apoptotic proteins like Mcl-1 and Bcl-2 while upregulating the pro-apoptotic BCL-2 protein Bax, she adds.

Additionally, onvansertib induced cellular stress by increasing the production of reactive oxygen species and decreasing mitochondrial membrane potential, Sinha continues. This was corroborated by the upregulation of cellular stress proteins such as BIP, Calnexin, and ATF-4, Sinha explains. Onvansertib also effectively reduced the adhesive ability and migratory capacity of the endometrial cancer cell lines, which is evident from the downregulation of proteins associated with cellular adhesion and migration such as N-cadherin and B-catenin, and upregulation of E-cadherin, Sinha expands.

In an exploration of the agent's mechanism of action, onvansertib was determined to increase cell arrest in the G2 phase, thereby decreasing the production of cell cycle proteins such as CDK4, c-myk, and CDK2, Sinha notes.

Notably, the addition of onvansertib to paclitaxel resulted in synergistic enhancement of cellular stress, underscoring the potential utility of this combination regimen, she says.

These findings collectively highlight the potential anti-tumorigenic and anti-proliferative effects of onvansertib in endometrioid endometrial cancer cell lines, suggesting its potential for therapeutic application in clinical settings, Sinha emphasizes. Further evaluation of onvansertib's efficacy as a therapeutic approach in endometrial cancer is needed to determine the clinical translatability of these findings, Sinha concludes.

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Nikita Sinha, MD, discusses the potential effects of onvansertib on endometroid endometrial cancer pathogenesis in a preclinical model.

Nikita Sinha, MD

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Dr. Sinha on the Antitumor Effects of Onvansertib in a Preclinical Endometroid Endometrial Cancer Model