Abstract 1178: Gene and protein expression profiling identifies molecular signature of resistance to anti-VEGF therapy in ovarian cancer
Authors: Devapatla Bharat Kumar , Jaiprasart Pharavee , Woo Sukyung 
Published: May 2015

Purpose: Angiogenesis plays an important role in ovarian cancer progression, and the addition of anti-angiogenic agents targeting the vascular endothelial growth factor (VEGF) signaling pathways to conventional chemotherapy improves progression-free survival in relapsed, platinum-resistant ovarian cancer when bevacizumab is given as concurrent or maintenance therapy. Unfortunately, the long-term clinical benefits of anti-VEGF therapy have been consistently limited by the rapid development of tumor resistance. Understanding of tumor's functional adaptations to anti-VEGF therapy and identifying early indicators of resistance are crucial for better exploiting anti-angiogenic therapies. The objective of this study was to perform gene and protein expression profiling of ovarian cancer to identify tumor and stroma signature of anti-VEGF treatment-resistance using preclinical resistance models.

Methods: We developed phenotypic resistance xenograft models of anti-VEGF therapy that mimic the clinical feature of resistance. SKOV3 xenografted mice were treated with sorafenib or bevacizumab over two months until there were phenotypic differences between tumors that remained responsive to the treatment and that regained growth after initial response. We conducted Illumina next generation sequencing to compare the gene expression in resistant and sensitive tumors. Sequencing analysis was performed using Perkin Elmer's Genesifter software and alignment to the H. sapiens and M. musculus reference genomes. Further, Reverse phase protein array (RPPA) analysis was done to identify differentially expressed proteins between resistant and sensitive tumors.

Results: Our sequencing analysis revealed significant differences in expression of various genes between sensitive and resistant tumors. Based on their role in angiogenesis and angiogenesis resistance, we chose a set of genes for follow-up studies. In sorafenib treatment group amphiregulin and heparanase expression was ≥4 fold higher (P ≤ 0.05) in resistant group compared to sensitive group. In bevacizumab resistant group prostaglandin E receptor 1 and keratin 24 ≥3 fold higher expression ((P ≤ 0.05) was observed. RPPA analysis indicated that proteins such as ER alpha, VEGFR-2, elF4G, E-cadherin, mTOR and beta-catenin expressed ≥ 2.8 fold (P ≤ 0.0001) higher in sorafenib resistant tumors compared to sensitive tumors. Neurofibromin 2 (NF2) protein is expressed 2 fold (P ≤ 0.0001) higher in bevacizumab resistant tumors compared to sensitive tumors.

Conclusion: Using gene and protein profiling, we identified important tumor and stroma biomarkers of resistance to anti-VEGF therapy in ovarian cancer that may provide insight into ovarian tumor's adaption principles to VEGF inhibition.

Citation Format: Bharat Kumar Devapatla, Pharavee Jaiprasart, Sukyung Woo. Gene and protein expression profiling identifies molecular signature of resistance to anti-VEGF therapy in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1178. doi:10.1158/1538-7445.AM2014-1178