Inhibition of Multiple Vascular Endothelial Growth Factor Receptors (VEGFR) Blocks Lymph Node Metastases but Inhibition of VEGFR-2 Is Sufficient to Sensitize Tumor Cells to Platinum-Based Chemotherapeutics

Sini, Patrizia; Samaržija, Ivana; Baffert, Fabienne; Littlewood‐Evans, Amanda; Schnell, Christian; Theuer, Andreas; Christian, Sven; Boos, Anja M.; Hess‐Stumpp, Holger; Foekens, John A.; Setyono-Han, Buddy; Wood, Jeanette M.; Hynes, Nancy E.

doi:10.1158/0008-5472.can-06-4685

Cited by 40 publications

(33 citation statements)

References 48 publications

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“…Synergistic anticancer effects are potentially interesting for the clinical application of drugs, following the dual aim of reducing side effects (by reducing the concentration of the agents used for anticancer therapy) and improving therapeutic efficacy (by obtaining systemic lethal effects on tumor cells). It has been shown in the past that inhibition of HER1 can induce cell death in HER1-dependent cancer cells (Helfrich et al, 2006), and it has also been shown that inhibition of VEGFR can exert direct (cell-autonomous) effects on VEGFR-expressing tumor cells, beyond the angiostatic (non-cell-autonomous) effects of VEGFR inhibitors on endothelial cells (Fan et al, 2005;Bianco et al, 2008;Simiantonaki et al, 2008;Sini et al, 2008). Here, we show that pazopanib and lapatinib together are much more potent in their …”

Section: Discussionmentioning

confidence: 58%

Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines

et al. 2009

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Pazopanib and lapatinib are two tyrosine kinase inhibitors that have been designed to inhibit the VEGF tyrosine kinase receptors 1, 2 and 3 (pazopanib), and the HER1 and HER2 receptors in a dual manner (lapatinib). Pazopanib has also been reported to mediate inhibitory effect on a selected panel of additional tyrosine kinases such as PDGFR and c-kit. Here, we report that pazopanib and lapatinib act synergistically to induce apoptosis of A549 non-small-cell lung cancer cells. Systematic assessment of the kinome revealed that both pazopanib and lapatinib inhibited dozens of different tyrosine kinases and that their combination could suppress the activity of some tyrosine kinases (such as c-Met) that were not or only partially affected by either of the two agents alone. We also found that pazopanib and lapatinib induced selective changes in the transcriptome of A549 cells, some of which were specific for the combination of both agents. Analysis of a panel of unrelated human carcinoma cell lines revealed a signature of 52 genes whose up-or downregulation reflected the combined action of pazopanib and lapatinib. Indeed, pazopanib and lapatinib exerted synergistic cytotoxic effects on several distinct non-smallcell lung cancer cells as well as on unrelated carcinomas. Altogether, these results support the contention that combinations of tyrosine kinase inhibitors should be evaluated for synergistic antitumor effects. Such combinations may lead to a 'collapse' of pro-survival signal transduction pathways that leads to apoptotic cell death.

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Section: Discussionmentioning

confidence: 58%

Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines

et al. 2009

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“…The results are poor and controversial. In some studies, antiangiogenic therapy was extremely effective on the primary tumor and metastasis, improving survival (13)(14)(15). However, surprisingly, recent studies reported that treatment of tumor-bearing mice, mainly with anti-VEGF/VEGFR-related compounds, increased tumor invasiveness and metastasis (16)(17)(18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Chemotherapy Counteracts Metastatic Dissemination Induced by Antiangiogenic Treatment in Mice

Rovida

Castiglioni

Decio

et al. 2013

Molecular Cancer Therapeutics

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The development of resistance and progressive disease after treatment with angiogenesis inhibitors is becoming a controversial issue. We investigated the experimental conditions that cause multireceptor tyrosine kinase inhibitors (RTKI) to augment metastasis and whether opportune combinations with chemotherapy could counteract this effect. The renal Renca-luc tumor was transplanted orthotopically in the kidney of Balb/c mice, which then were or were not nephrectomized. The Lewis Lung carcinoma (LLC) was transplanted in the tibial muscle of C57/Bl6 mice. Treatment with the RTKI sunitinib started at different stages of tumor progression, mimicking neoadjuvant or adjuvant settings. Combination studies with paclitaxel, doxorubicin, cisplatin, gemcitabine, and topotecan were done on the LLC model, using opportune regimens. In a neoadjuvant setting, sunitinib inhibited Renca-luc tumor growth, prolonging survival despite an increase in lung metastasis; treatment after primary tumor surgery (adjuvant setting) or on established metastasis prolonged survival and decreased metastasis. Sunitinib increased lung metastasis from mice bearing early-stage LLC, but did not affect established metastases (no acceleration) from advanced tumors. Combinations with doxorubicin, topotecan, gemcitabine, but not cisplatin and paclitaxel, counteracted the increase in metastasis from LLC, partly reflecting their antitumor activity. Histology analysis after sunitinib confirmed tumor vascular changes and increased hypoxia. Topotecan at suboptimal daily doses reduced sunitinib-related metastasis, reducing tumor hypoxia. Tyrosine kinase inhibitors, as sunitinib, can have adverse malignant effects mainly in the neoadjuvant setting. The addition of chemotherapy might influence metastasis, depending on each drug mechanism of action and its regimen of administration.

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“…The daily dose was chosen according to previous studies showing a significant inhibitory effect of vatalanib on growth of several human tumor xenografts in nude mice. [25][26][27] Bevacizumab was given intraperitoneally, twice a week, at a dose of 5 mg/kg. Control mice received a treatment with the vehicle only, i.e.…”

Section: Dosing Regimens and Experimental Protocolsmentioning

confidence: 99%

Combination of anti‐angiogenic therapies reduces osteolysis and tumor burden in experimental breast cancer bone metastasis

Bachelier

Confavreux

Peyruchaud

et al. 2014

Intl Journal of Cancer

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The clinical efficacy of anti-angiogenic monotherapies in metastatic breast cancer is less than originally anticipated, and it is not clear what the response of bone metastasis to anti-angiogenic therapies is. Here, we examined the impact of neutralizing tumor-derived vascular endothelial growth factor (VEGF) in animal models of subcutaneous tumor growth and bone metastasis formation. Silencing of VEGF expression (Sh-VEGF) in osteotropic human MDA-MB-231/B02 breast cancer cells led to a substantial growth inhibition of subcutaneous Sh-VEGF B02 tumor xenografts, as a result of reduced angiogenesis, when compared to that observed with animals bearing mock-transfected (Sc-VEGF) B02 tumors. However, there was scant evidence that either the silencing of tumor-derived VEGF or the use of a VEGF-neutralizing antibody (bevacizumab) affected B02 breast cancer bone metastasis progression in animals. We also examined the effect of vatalanib (a VEGF receptor tyrosine kinase inhibitor) in this mouse model of bone metastasis. However, vatalanib failed to inhibit bone metastasis caused by B02 breast cancer cells. In sharp contrast, vatalanib in combination with bevacizumab reduced not only bone destruction but also skeletal tumor growth in animals bearing breast cancer bone metastases, when compared with either agent alone. Thus, our study highlights the importance of targeting both the tumor compartment and the host tissue (i.e., skeleton) to efficiently block the development of bone metastasis. We believe this is a crucially important observation as the clinical benefit of anti-angiogenic monotherapies in metastatic breast cancer is relatively modest.Breast cancer is prone to metastasize to bone: around 70-80% of patients with advanced disease exhibit bone metastases.

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Inhibition of Multiple Vascular Endothelial Growth Factor Receptors (VEGFR) Blocks Lymph Node Metastases but Inhibition of VEGFR-2 Is Sufficient to Sensitize Tumor Cells to Platinum-Based Chemotherapeutics

Abstract: Vascular endothelial growth factor receptors (VEGFR) have important roles in cancer, affecting blood and lymphatic vessel functionality as well as tumor cells themselves. We compared

Cited by 40 publications

References 48 publications

Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines

Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines

Chemotherapy Counteracts Metastatic Dissemination Induced by Antiangiogenic Treatment in Mice

Combination of anti‐angiogenic therapies reduces osteolysis and tumor burden in experimental breast cancer bone metastasis

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