Abstract PO046: Anti-angiogenic tyrosine kinase inhibitor cediranib is superior to bevacizumab in endometrial cancer due to differential effects on cell cycle regulation
Authors: Bi Jianling , Newtson Andreea M. , Devor Eric J. , Zhang Yuping , Thiel Kristina W. , Leslie Kimberly K. 
Published: February 2021

Abstract
Angiogenesis plays a crucial role in tumor development and metastasis, and many cancer cells upregulate vascular endothelial growth factor-A (VEGF-A) expression to promote angiogenesis. Several clinical trials of anti-angiogenic agents have been conducted in advanced and recurrent endometrial cancer, but only bevacizumab and cediranib have demonstrated activity as single agents. Bevacizumab is a monoclonal antibody against VEGF-A, whereas cediranib is a small molecule angiokinase inhibitor.
However, subsequent studies of bevacizumab+chemotherapy failed to improve outcomes compared to chemotherapy alone. We recently demonstrated that chemotherapy plus nintedanib, another angiokinase inhibitor, promotes catastrophic cell death in a xenograft model of endometrial cancer (Ebeid, et al., Nat Nanotech 2019). This effect was specific to cells with loss of function, i.e., null mutations in TP53. Here we compared the efficacy of cediranib vs. bevacizumab in p53-null gynecologic cancer models and determined the mechanism for differential sensitivity. We first performed a phosphoproteomic array of 875 phosphoproteins to define the signaling changes related to bevacizumab vs. cediranib in two p53-null cell gynecologic cancer cell lines. Several signaling events were similar between bevacizumab and cediranib, including phosphorylation of IGF1R, Abl, p70S6K and proteins in the ERK/MAPK and Wnt signaling pathways. We next tested the impact of the anti- angiogenic agents on cell viability using cancer cell lines and over 20 patient-derived organoid cultures of endometrial or ovarian cancer. Neither bevacizumab nor cediranib alone had a notable effect on cell viability, even at 1-10 µM concentrations. By contrast, cediranib but not bevacizumab promoted marked cell death when combined with chemotherapy. This effect was most pronounced in p53-null models.
Cell cycle analysis demonstrated an accumulation in mitosis after treatment with cediranib+chemotherapy, consistent with abrogation of the G2/M checkpoint and subsequent mitotic catastrophe. Molecular analysis of key controllers of the G2/M cell cycle checkpoint confirmed its abrogation. Unexpectedly, the endometrial cancer cell lines were unresponsive to stimulation with VEGF-A, the target of bevacizumab. This was confirmed by the lack of ERK phosphorylation, a downstream signaling event expected after VEGF-A treatment, and was potentially caused low expression of VEGFR1 and 2. Based on these data, we conclude that an anti-angiogenic tyrosine kinase inhibitor such as cediranib has the potential to be superior to bevacizumab in combination with chemotherapy. We hypothesize that the mechanism relates to cediranib inhibition of the tumor vasculature as well as its ability to optimize the impact of chemotherapeutic agents during the cell cycle. Future clinical studies should test this hypothesis by studying the combination of standard chemotherapy with cediranib in advanced and recurrent endometrial cancer.
Citation Format: Jianling Bi, Andreea M. Newtson, Eric J. Devor, Yuping Zhang, Kristina W. Thiel, Kimberly K. Leslie. Anti-angiogenic tyrosine kinase inhibitor cediranib is superior to bevacizumab in endometrial cancer due to differential effects on cell cycle regulation [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO046.