Abstract A37: Dual wavelength near-infrared fluorescence imaging of VEGF-A and IGF-1R in ovarian cancer patient-derived xenografts
Authors: Tomar Tushar , Alkema Nicolette G. , Visser Jolanda A.L. , Scheltinga Anton G. Terwisscha van , Meersma Gert Jan , Klip Harry G. , Duiker Evelien W. , Vries Elisabeth G.E. De , Zee Ate G.J. Van der , Jong Steven De 
Published: March 2017

Abstract
Background: Platinum-based chemotherapy in combination with surgery is the cornerstone of treatment for advanced high-grade serous ovarian cancer. Recurrence is common and additional treatments have been developed such as angiogenesis inhibition. Small subgroups of ovarian cancer patients may benefit from upfront selection based on tumor target expression. Here, we focus on near-infrared fluorescence (NIRF) dual imaging of the tumor secreted human vascular endothelial growth factor (VEGF-A) and the membrane-bound insulin-like growth factor 1 receptor (IGF-1R), simultaneously. The aim of our study is to determine tracer uptake and kinetics in relation to target expression in ovarian cancer patient-derived xenograft (PDX) models and the effect of cisplatin treatment on these parameters.
Methods: Monoclonal antibody bevacizumab (anti-human VEGF-A) and MAB391 (anti-human IGF-1R) were coupled to NIRF dyes IRDye-800CW and IRDye-680RD, respectively. Specific tumor uptake was determined in a panel of subcutaneous ovarian cancer PDX models (established from 10 patients) in NOD SCID gamma mice during 1 week after intravenous co-injection of these tracers. In addition, two PDX models were treated weekly with cisplatin (4 mg/kg dose intraperitoneal administration) followed by NIRF dual imaging. Imaging results were compared with ELISA and immunostaining of VEGF-A and IGF1R.
Results: We found large differences in average radiance for bevacizumab-800CW (range 2.53 - 23.3 x 106) and for MAB391-680RD (range 1.5 - 15.5 x 107) between PDX models at 24 hrs. In vivo kinetics of bevacizumab-800CW displayed a rapid tracer decline in PDX tumors 24 hrs after co-injection. MAB391-680RD, however, resided for over 6 days in PDX tumors depending on the IGF-1R positivity of tumors, indicating receptor-mediated tracer trapping. Moreover, IgG labeled with IRDye-800CW or IRDye-680RD showed similar kinetics as the bevacizumab-800CW. Elevated levels of both tracers were found in cisplatin-treated PDX tumors 24 hrs after co-injection. The higher levels of bevacizumab-800CW corresponded with higher intratumoral human VEGF-A levels in PDX tumors after cisplatin treatment. However, tracer decline kinetics in tumors did not change. Enhanced MAB391-680RD accumulation was related to higher IGF-1R tumor levels in the less responsive PDX model. A rapid decline of MAB391-680RD, similar to bevacizumab-800CW, was observed in the cisplatin-sensitive PDX model, which was related to reduced tumor proliferation and viability.
Conclusions: These results indicate that levels and kinetics of targeted NIRF tracers can be used to dissect growth factor receptor-positive from -negative tumors. This encourages further exploration of multi-wavelength NIRF imaging to select targets for personalized medicine in small subgroups of ovarian cancer patients using PDX models.
This work was supported by the Dutch Cancer Society (KWF) grants RUG 2010-4833 and RUG 2011-5231.
Citation Format: Tushar Tomar, Nicolette G. Alkema, Jolanda A.L. Visser, Anton G. Terwisscha van Scheltinga, Gert Jan Meersma, Harry G. Klip, Evelien W. Duiker, Elisabeth G.E. De Vries, Ate G.J. Van der Zee, Steven De Jong. Dual wavelength near-infrared fluorescence imaging of VEGF-A and IGF-1R in ovarian cancer patient-derived xenografts. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A37.