Abstract 1184: The effect of dual VEGF/VEGFR inhibition on angiogenic signaling pathways.
Authors: Mittal Kriti , Koon Henry , Elson Paul , Triozzi Pierre , Dowlati Afshin , Borden Ernest , Rini Brian 
Published: August 2014

Background: The vascular endothelial growth factor (VEGF) antibody bevacizumab (Bev) and VEGF receptor (VEGFR) inhibitor sunitinib are efficacious agents in many solid tumors. Non-VEGF angiogenic molecules are postulated as a resistance mechanism against VEGF agents, but these pathways are incompletely understood. Angiogenic proteins were characterized in patients treated with dual VEGF/VEGFR inhibition.

Methods: Patients with metastatic tumors were enrolled on a phase I trial of sunitinib (37.5 mg daily from weeks 1-4) and Bev (5 mg/kg on days 1, 15 and 29) of a 6 week cycle. Angiogenic proteins were quantified in serum samples at baseline, 4 and 6 weeks using ELISA assays (R&D Systems, Antibody On Line and IBL American).

Results: Samples were collected from 13 patients (10 melanoma, 1 angiosarcoma, 1 adrenal and 1 renal cell carcinoma). Dual VEGF/VEGFR inhibition resulted in reduction of soluble (s) VEGFR-2, sVEGFR-3, sTIE-2, Angiopoeitin (Ang)-2 and MMP-9 from baseline to week 4 (See table-1). There was a significant increase in prokineticin-2 at week 4 versus baseline. During the “off-period” of sunitinib from week 4 to 6, sVEGFR-2 and sVEGFR-3 increased. Continued Bev during the off-period resulted in reduction of sVEGF but increase in circulating Ang-2 and sTIE-2.

Discussion: These data support the biological basis of dual VEGF/VEGFR inhibition given the lack of rebound VEGF increase during the sunitinib off-period with continued Bev. Consistent with pre-clinical evidence implicating VEGF signaling in MMP-9 regulation, MMP-9 was down-regulated with VEGF/VEGFR inhibition. Dual VEGF/VEGFR inhibition resulted in decrease in Ang-2 and its receptor TIE-2, which subsequently increased during the sunitinib off period. Up regulation of prokineticin-2, predicted by preclinical studies to mediate Bev resistance, has not previously been identified in patients. Future research will elucidate the mechanistic roles of non VEGF proteins in mediating resistance to antiangiogenic agents.

Table 1: Markers of angiogenesis in patients treated with dual VEGF/VEGFR inhibition Median level Baseline (n = 13) Median level week 4 (n = 13) Median level week 6 (n = 9) p value baseline vs week 4 p value baseline vs week 6 p value week 4 vs week 6 sVEGF (pg/ml) 360.67 217.19 167.66 0.07 0.03 0.004 sVEGFR1 (pg/ml) 109.32 149.33 117.35 1.0 0.30 0.50 sVEGFR2 (pg/ml) 1856.1 1264 1393.1 0.0002 0.004 0.03 sVEGFR3 (ng/ml) 45.04 15.38 23.66 0.0002 0.004 0.004 sTIE-2 (ng/ml) 20.77 15.48 17.42 0.0002 0.004 0.03 Angiopoeitin-2 (pg/ml) 2841.4 1537.2 1843.8 0.0002 0.004 0.04 MMP-9 (ng/ml) 609.3 312.8 363.6 0.01 0.03 0.25 Prokineticin-1 (ng/ml) 0.615 0.646 0.54 0.22 1.0 0.57 Prokineticin-2 (pg/ml) 0.35 3.95 0.83 0.01 0.11 0.43

Citation Format: Kriti Mittal, Henry Koon, Paul Elson, Pierre Triozzi, Afshin Dowlati, Ernest Borden, Brian Rini. The effect of dual VEGF/VEGFR inhibition on angiogenic signaling pathways. [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 1184. doi:10.1158/1538-7445.AM2013-1184