Abstract 5096: Heterogeneous response to antiangiogenic therapy in ovarian cancer xenografts: a tool to investigate biomarkers of resistance.
Authors: Decio Alessandra , Cesca Marta , Bizzaro Francesca , Scarlato Valentina , Ghilardi Carmen , Bani Maria Rosa , Giavazzi Raffaella 
Published: August 2014

Vascular Endothelial Growth Factor (VEGF), one of the major player of tumor angiogenesis, is over-expressed and secreted in large amount in epithelial ovarian cancer (EOC) patients, thus the VEGF/VEGFR pathway represents an important therapeutic target for this malignancy. The VEGF neutralizing monoclonal antibody bevacizumab has shown activity in Phase III clinical trials when added to standard chemotherapy in first line treatment and on recurrent ovarian cancers. Also, small molecules, multiple-receptor tyrosine kinase inhibitors (TKRI) are progressing into clinical development in ovarian cancer. Unfortunately, the benefit associated with this class of treatments is often limited and not durable. After an initial response, patients manifest disease progression and resistance; in other cases patients are inherently resistant to therapy.

With the aim to find biomarkers of resistance to antiangiogenic therapy, useful to stratify eligible patients for best response, here we investigated the antiangiogenic activity and the influence on tumor progression and survival of bevacizumab and a TKRI (anti-VEGFR1,2,3) in a panel (n=12) of patient derived EOC-xenografts, established in our laboratory. These xenografts show the different histopathological features observed in EOC patients and maintain the gene mutation profile of the tumor of origin. Transplanted orthotopically in nude mice they produce ascites, invade and metastasize the organ of the peritoneal cavity, thus reproducing the biology of the disease.

The response to bevacizumab and TKRI varied among the EOC-xenografts and allowed their classification in distinct groups: responsive to bevacizumab and TKRI, resistant to both, or responsive to one of the two. All the xenografts were tested for response to cisplatin and taxol, the standard-of-care treatment for EOC; their sensibility to the angiogenesis inhibitors was independent from the response to chemotherapy.

The expression and the release of soluble factors associated to tumor angiogenesis (e.g. VEGFA, VEGFC, VEGFRs) were analyzed as baseline and along the antiangiogenic treatments. The EOC-xenografts released VEGF in plasma and ascites, though a correlation with the response to treatments was not evident. At variance, the modulation of soluble VEGFR1,2 was associated to tumor progression and response to therapy.

Patient derived EOC-xenografts that retain the individual biological-pharmacological differences and genetic heterogeneity of the original tumor are an unique source for the preclinical analysis of new therapeutic strategies and for the discovery of associated biomarkers.

* A.D. fellow of the Italian Foundation for Cancer Research (FIRC)

Citation Format: Alessandra Decio, Marta Cesca, Francesca Bizzaro, Valentina Scarlato, Carmen Ghilardi, Maria Rosa Bani, Raffaella Giavazzi. Heterogeneous response to antiangiogenic therapy in ovarian cancer xenografts: a tool to investigate biomarkers of resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5096. doi:10.1158/1538-7445.AM2013-5096