Onvansertib-Based Second-Line Therapies in Combination with Gemcitabine and Carboplatin in Patient-Derived Platinum-Resistant Ovarian Carcinomas

Abstract

Platinum resistance represents an urgent medical need in the management of ovarian cancer. The activity of the combinations of onvansertib, an inhibitor of polo-like kinase 1, with gemcitabine or carboplatin was tested using patient-derived xenografts of high-grade serous ovarian carcinoma resistant to cisplatin (DDP). Two PDX models were selected from our xenobank: one with acquired resistance to DDP (#266R) and the other (#315) with intrinsic DDP resistance. Tumor-bearing mice were randomized to receive vehicle, single onvansertib, gemcitabine and carboplatin, and their combinations. Onvansertib/gemcitabine and onvansertib/carboplatin combinations were well tolerated. In the #266R model, single drug treatments were completely inactive, while the combinations of onvansertib/gemcitabine and onvansertib/carboplatin resulted in a significant increase in survival compared to controls and single drugs (p < 0.001 versus control, onvansertib, gemcitabine and carboplatin). Similar efficacy was observed in the s.c. #315 PDX model; indeed, onvansertib and carboplatin monotherapies were inactive, gemcitabine monotherapy was marginally active, while both combinations were highly active. The molecular mechanism underlying the efficacy of the combinations suggests a higher induction of DNA damage which seems plausible considering that, in both cases, gemcitabine and carboplatin, respectively, interfere with DNA metabolism and induce alkylation damage. The results suggest that the combinations of onvansertib/gemcitabine and onvansertib/carboplatin are safe and were shown to be of therapeutic value in the platinum-resistant setting of ovarian carcinoma, strongly supporting their clinical translatability.

Keywords: carboplatin; gemcitabine; onvansertib; ovarian carcinoma; platinum resistance; plk1.

Figure 1

Antitumor activity of single agents and combinations in #266R and #315 HGSOC PDXs. Panel (A). Kaplan–Meier survival curves of mice transplanted with #266R. Mice transplanted intraperitoneally with #266R xenograft were randomized to receive vehicle (black), onvansertib (blue), gemcitabine (green), carboplatin (red), onvansertib + gemcitabine (violet) or onvansertib + carboplatin (orange). Log-rank Mantel–Cox test. Panel (B). Upper panels. Tumor growth: #315 xenografts were transplanted subcutaneously and when tumor masses reached 100–150 mg, mice were randomized to receive vehicle (black), onvansertib (blue), gemcitabine (green), carboplatin (red), onvansertib + gemcitabine (violet) or onvansertib + carboplatin (orange). Lower panels. Tumor volumes at the end of the treatment period (4 weeks). Data are the mean ± SD of tumor masses and each group consisted of 8–10 animals.

Figure 2

In vivo pharmacodynamic assessment of mitotic block, DNA damage and apoptosis in PDXs treated with vehicle, single agents or combinations. Western blot analysis showing pSer10 H3 (pH3) and pSer139 H2AX (γH2AX) protein levels in tumor protein extracts from #266R (panel (A)) and #315 (panel (B)) xenografts. Caspase-3 activity in tumor protein extracts from #266R (panel (C)) and #315 (panel (D)) xenografts.