The aim of this study was to investigate the effects of cediranib and understand mechanisms of resistance in syngeneic mouse models of high grade serious ovarian cancer (HGSOC). Cediranib, a VEGFR targeting agent, improves progression free survival in ovarian cancer patients but the benefits can be short lived. We recently conducted an extensive analysis of the tumor microenvironment, TME, of orthotopic syngeneic HGSOC models, including two cell lines, 30200 and 60577, which were P53 -/-, Brca1 -/- and had Rb inactivation (Maniati et al, Cell Reports 2020). In spite of the same genetic mutations, the transcriptional profile of peritoneal tumors from these two models had some distinct differences including regulation of genes in the IL-6 signaling pathway, with higher levels in 30200 compared to 60577.
Four- 5 weeks cediranib treatment of mice bearing 30200 or 60577 intraperitoneal tumors significantly reduced tumor burden with inhibition of vessel density and modulation of immune cell profiles in the TME. However, there was little impact on overall survival of mice even with continued treatment, but mechanisms of resistance appeared to be different. In 30200-bearing mice treated with cediranib, there was an increase in peritoneal metastasis and pSTAT3 signaling in the TME. In 60577-bearing mice, there was still a decrease in vessel density and pSTAT3 signaling at survival endpoint with distinct changes to immune infiltrate, including a decrease in CD8 T cells, an increase in alternatively activated macrophages and upregulation of checkpoint molecules PD-1/PDL-1.
In view of these results we combined cediranib treatment with anti-IL-6 antibodies in the 30200 model and with anti-PD-1 antibodies in the 60577 model to see if this would overcome resistance. These combination treatments significantly increased mouse survival compared to the monotherapies with no increase in peritoneal metastases.
To further understand the relevance of the pre-treatment transcriptional profile in dictating response to cediranib treatment, we studied the effects of cediranib treatment in another HGSOC mouse model, HGS2. This model shared similar levels of IL-6 pathway expression to 30200 tumors and showed no survival benefit to cediranib treatment and, again, increased peritoneal metastasis. The combination of anti-IL-6 and cediranib significantly improved HGS2 mouse survival.
As the transcriptomes of these mouse model had significant correlations with human HGSOC tumors, we looked for these pathway correlations with angiogenic signatures in human patient dataset. Analysis of the ICGC dataset revealed strong correlations of angiogenesis signature with IL-6 and PD-1 pathways suggesting biomarkers for treatments to combine with VEGF inhibitors in ovarian cancer.
Citation Format: Ganga Gopinathan, Eleni Maniati, Chiara Berlato, Anissa Lakhani, Colin Pergum, Florian Laforets, Ludmila Szabova, Frances Balkwill. Differential responses and mechanisms of resistance to cediranib in high grade serous ovarian cancer mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1094.