Abstract
1006
Purpose: In males, prostate cancer (PrCa) is the second-leading cancer type causing death in the United States and the top type in all the incident cases of cancer around the world. In the detection and monitoring of PrCa malignancies, to achieve good tissue-specificity in conventional ways with fine patient-compliance and sampling representativeness, or in the onset stage, is challenging. Vascular endothelial growth factor receptor 2 (VEGFR-2) is an over-expressed biomarker of PrCa malignancies and can be delineated by quantitative non-invasive imaging modalities to address such issue. Herein, we report the positron emission tomography (PET) of VEGFR-2 expression in vivo in PrCa using a [89Zr]zirconium-labeled clinical antibody antagonist of VEGFR-2, i.e. Ramucirumab.
Methods: Ramucirumab, an FDA-approved recombinant humanized IgG1 monoclonal antibody, was conjugated with 1-(4-isothiocyanatophenyl)-3-[6,17-dihydroxy-7,10,18,21-tetraoxo-27-(N-acetylhydroxylamino)-6,11,17,22-tetraazaheptaeicosine]thiourea (p-SCN-Df) and chelated with 89Zr. The resulting 89Zr-Df-Ramucirumab was injected into the nude mice bearing the subcutaneous tumors of PC-3, LNCAP and LAPC-4 cell lines for the PET imaging and radioactive bio-distribution study. The expressions of VEGFR-2 in tumor tissue were characterized by ex vivo immuno-fluorescent staining to validate the imaging results.
Results: The data withdrawn from the regions of interest (ROI) in PET images show that the uptake of 89Zr-Df-Ramuciruma in the VEGFR-2-positive PC-3 tumors (9.6±2.3 %ID/g at 96 h, n=3) are obviously higher than that in the VEGFR-2-moderate LNCAP tumors (6.0±1.7 %ID/g at 96 h, n=4) or VEGFR-2-negative LAPC-4 tumors (4.1±0.9 %ID/g at 96 h, n=4), and keep increasing to a plateau over time (4~120 h post-injection); the blockade by cold Ramucirumab can significantly reduce the uptake of 89Zr-Df-Ramucirumab in the PC-3 tumors (4.2±1.2 %ID/g at 96 h, n=3). They coincide with the bio-distribution data and prove the specificity. Additionally, the histopathological results confirm the expression pattern of VEGFR-2 in different PrCa cell lines.
Conclusions: The results of this research demonstrate that the profile of VEGFR-2 expression in PrCa described by in vivo PET with 89Zr-Df-Ramucirumab is feasible and superior to the reported imaging modalities. The potential application of this approach may shed light on the early detection of foci and dynamic monitoring of anti-VEGFR-2 therapy in PrCa.