Anti‐tumor activity and tumor vessel normalization by the vascular endothelial growth factor receptor tyrosine kinase inhibitor KRN951 in a rat peritoneal disseminated tumor model

Abstract

We assessed the antitumor efficacy of KRN951, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptors, using a rat colon cancer RCN-9 syngeneic model in which the tumor cells are transplanted into the peritoneal cavity of F344 rats. KRN951 treatments that commenced 4 days after tumor transplantation (day 4) significantly inhibited tumor-induced angiogenesis, the formation of tumor nodules in the mesenteric windows, and the accumulation of malignant ascites. Moreover, KRN951 treatments initiated on day 14, by which time angiogenesis and malignant ascites have already been well established, resulted in the regression of newly formed tumor vasculatures with aberrant structures and also in the apparent loss of malignant ascites by the end of the study period. Quantitative analysis of the vessel architecture on mesenteric windows revealed that KRN951 not only regressed, but also normalized the tumor-induced neovasculature. Continuous daily treatments with KRN951 significantly prolonged the survival of rats bearing both early stage and more advanced-stage tumors, compared with the vehicle-treated animals. The results of our current study thus show that KRN951 inhibits colon carcinoma progression in the peritoneal cavity by blocking tumor angiogenesis, ascites formation, and tumor spread, thereby prolonging survival. Moreover, these studies clearly demonstrate the therapeutic effects of KRN951 against established tumors in the peritoneal cavity, including the regression and normalization of the tumor neovasculature. Our findings therefore suggest that KRN951 has significant potential as a future therapeutic agent in the treatment of peritoneal cancers with ascites. (Cancer Sci 2008; 99: 623-630) V ascular endothelial growth factor and VEGFR are promising targets for antitumor therapies as they play major roles during tumor angiogenesis, which is an essential process for tumor growth and metastasis. A number of studies have now demonstrated a clear correlation between VEGF expression, microvessel density, and a poorer prognosis.(1-4) VEGF mediates angiogenic signaling to the endothelium via two receptor tyrosine kinases, VEGFR-1 and VEGFR-2. In particular, VEGFR-2 in vascular endothelial cells is the main transmitter of the activation signals that induce the proliferation and migration of endothelial cells upon their binding of VEGF.(5) In addition, it seems that the signaling pathways mediated via VEGFR-1 and -2 are also involved in the VEGF-induced hyperpermeability of tumor vasculatures. (6) As a result of these previous findings, there is now great interest in developing blocking antibodies and small molecules that target the VEGF and VEGFR pathway as such agents are good candidate anticancer therapeutics. In this regard, several agents that target angiogenesis through VEGF function, including those targeting VEGF itself or the VEGFR, are now in advanced stages of development.(7-13) Bevacizumab, a VEGF-neutralizing monoclonal antibody, is the first antiangiogenic agent to be approved by the...

Normalization of the Vasculature for Treatment of Cancer and Other Diseases

“…In mice bearing orthotopic GBM xenografts, cediranib produces structural changes similar to those observed after DC101 treatment of GBM, namely, reduced vessel diameter, basement membrane thinning, and a tightening of association between PVCs and ECs, first observed after 2 days of therapy (160). Finally, normalization of tumor vasculature has been reported within 4 days of commencing treatment of rats bearing a syngeneic colorectal cancer with KRN 951, a pan-VEGFR TKI (270), and increased vessel coverage by PVCs has been noted after treatment with TSU68 (an inhibitor of VEGFR2, PDGFRs, and the fibroblast growth factor receptor, FGFR) (216). …”

Small-Molecule Inhibitors of the Receptor Tyrosine Kinases: Promising Tools for Targeted Cancer Therapies

“…Treatment of RCN-9 transplanted mice decreased angiogenesis, the formation of tumor nodules and the accumulation of malignant ascites. Furthermore, this TKI displayed regression of vascularization in newly formed tumor and increased the survival of rats even with more advanced-stage tumors [79]. …”

Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease

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“…Preclinical studies have used a number of approaches including (1) specific VEGF blockade with agents that interfere with VEGF binding to its receptors (including antihuman VEGF antibodies such as A4.6.1 and bevacizumab), antimurine VEGF antibodies, and the "VEGF-Trap" aflibercept; (2) inhibition of VEGFR2 function (using anti-VEGFR2 antibodies such as DC101 or receptor tyrosine kinase inhibitors [TKIs] which inhibit the kinase domain of VEGFRs). In addition, elegant preclinical work examining the role of Yuan et al 1996;Tong et al 2004;Dickson et al 2007b;Taguchi et al 2008;Falcon et al 2009;Juan et al 2009;Kamoun et al 2009;Chae et al 2010;Koh et al 2010;Primo et al 2010. b Jain et al 1998;Izumi et al 2002;Delmas et al 2003;Qayum et al 2009. d Inai et al 2004;Tong et al 2004;Nakahara et al 2006;Dickson et al 2007b;Dings et al 2007;Fischer et al 2007;Zhou et al 2008;Falcon et al 2009;Juan et al 2009;Kamoun et al 2009;Ohta et al 2009;Zhou and Gallo 2009;Chae et al 2010;Primo et al 2010.…”