Abstract
BackgroundVEGF is one of the key drivers of physiological or pathological angiogenesis hence several VEGF inhibitors are in different stages of clinical development. To further dissect the role of VEGF in different stages of tumor progression in lung tumors, we utilized KrasG12D-LSL GEMMs (genetically engineered mouse models).MethodsIntranasal delivery of adenoviruses expressing cre recombinase in KrasG12D-LSL mice results in the expression of mutant Kras that leads to development of tumor lesions ranging from adenomatous hyperplasia to large adenoma and adenocarcinoma over time in lung. In the current study, we treated KrasG12D-LSL mice at 14 weeks post inhalation with three different angiogenic inhibitors including axitinib and PF-00337210 both of which are selective inhibitors of VEGFR and sunitinib which targets VEGFR, C-SF1-R, PDGFR and KIT.ResultsPathology findings showed no significant difference in percentage of adenomatous hyperplastic lesions between the vehicle vs. any of the treatments suggesting that angiogenesis may not play a major role at early stages of tumorigenesis. However, each inhibitor suppressed percentage of benign adenoma lesions and almost fully inhibited growth of adenocarcinoma lesions in the recipients which was consistent with a reduction in tumor vasculature. Treatment with sunitinib which is a multi-targeted RTKI did not provide any advantage compared to selective VEGFR inhibitor further emphasizing role of VEGF in tumor angiogenesis in this model.ConclusionOverall, our studies indicate significance of VEGF and angiogenesis in a spontaneous model of lung tumorigenesis and provide a proof of mechanism for anti-cancer activity of VEGF inhibitors in this model.
Highlights
VEGF is one of the key drivers of physiological or pathological angiogenesis several VEGF inhibitors are in different stages of clinical development
Sunitinib which is a multi-targeted kinase inhibitor targets VEGFRs, C-SF1R, KIT and platelet-derived growth factor (PDGFR) which plays an important role in blood vessel maturation [4]
In the present study we investigated anti-tumor efficacy of three receptor tyrosine kinase inhibitors (RTKIs) including sunitinib, axitinib and PF-210 in KrasG12D-LSL lung tumor model
Summary
VEGF is one of the key drivers of physiological or pathological angiogenesis several VEGF inhibitors are in different stages of clinical development. To further dissect the role of VEGF in different stages of tumor progression in lung tumors, we utilized KrasG12D-LSL GEMMs (genetically engineered mouse models). We treated KrasG12D-LSL mice at 14 weeks post inhalation with three different angiogenic inhibitors including axitinib and PF-00337210 both of which are selective inhibitors of VEGFR and sunitinib which targets VEGFR, C-SF1-R, PDGFR and KIT. Bevacizumab (an anti-VEGF monoclonal antibody) was the first angiogenic inhibitor (hereafter AI) initially approved for use in patients with NSCLC (non-small cell lung cancer) or mCRC (metastatic colorectal cancer) [2,3]. Axitinib (AG-013736; Pfizer) is another oral potent tyrosine kinase inhibitor which mainly targets VEGFR and was approved by FDA for use in patients with advanced RCC [7]. PF-210 has been shown to inhibit HUVEC cell survival in vitro and suppresses tumor angiogenesis in xenograft models [10]
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