American Association for Cancer Research
00085472can152138-sup-153044_1_supp_0_nyqpql.docx (2.64 MB)

Supplementary Figures 1-6 from Peptide–Drug Conjugate GnRH–Sunitinib Targets Angiogenesis Selectively at the Site of Action to Inhibit Tumor Growth

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journal contribution
posted on 2023-03-30, 23:51 authored by Orestis Argyros, Theodoros Karampelas, Xenophon Asvos, Aimilia Varela, Nisar Sayyad, Athanasios Papakyriakou, Constantinos H. Davos, Andreas G. Tzakos, Demosthenes Fokas, Constantin Tamvakopoulos

Supplementary Figures 1-6. Figure S.I.1 - 1HNMR spectra of the six sunitinib analogues Figure S.I.2 - LC-MS/MS characterization of SAN1 Figure S.I.3 - Molecular models of VEGFR-2 kinase domain complexed with SAN1,2,3 Figure S.I.4 - Synthesis and characterization of SAN1GSC by NMR and LC-MS/MS Figure S.I.5 - Body weights of xenografted mice during the course of treatment Figure S.I.6 - Evaluation of the hematological toxicities following treatment


Greek Ministry of Education, National Strategic Reference Framework (NSRF) 2007-2013



The potential to heighten the efficacy of antiangiogenic agents was explored in this study based on active targeting of tumor cells overexpressing the gonadotropin-releasing hormone receptor (GnRH-R). The rational design pursued focused on five analogues of a clinically established antiangiogenic compound (sunitinib), from which a lead candidate (SAN1) was conjugated to the targeting peptide [d-Lys6]-GnRH, generating SAN1GSC. Conjugation of SAN1 did not disrupt any of its antiangiogenic or cytotoxic properties in GnRH-R–expressing prostate and breast tumor cells. Daily SAN1GSC treatments in mouse xenograft models of castration-resistant prostate cancer resulted in significant tumor growth delay compared with equimolar SAN1 or sunitinib alone. This efficacy correlated with inhibited phosphorylation of AKT and S6, together with reduced Ki-67 and CD31 expression. The superior efficacy of the peptide–drug conjugate was also attributed to the finding that higher amounts of SAN1 were delivered to the tumor site (∼4-fold) following dosing of SAN1GSC compared with equimolar amounts of nonconjugated SAN1. Importantly, treatment with SAN1GSC was associated with minimal hematotoxicity and cardiotoxicity based on measurements of the left ventricular systolic function in treated mice. Our results offer preclinical proof-of-concept for SAN1GSC as a novel molecule that selectively reaches the tumor site and downregulates angiogenesis with negligible cardiotoxicity, thus encouraging its further clinical development and evaluation. Cancer Res; 76(5); 1181–92. ©2015 AACR.