Peering into the aftermath: The inhospitable host?

Sunnybrook Research Institute, Department of Molecular and Cellular Biology, Sunnybrook Health Sciences Centre, Toronto, Canada.
Nature medicine (Impact Factor: 28.05). 10/2010; 16(10):1084-5. DOI: 10.1038/nm1010-1084
Source: PubMed
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    ABSTRACT: We previously reported that the host response to certain chemotherapies can induce primary tumor regrowth, angiogenesis, and even metastases in mice, but the possible impact of anti-vascular endothelial growth factor-A (VEGF-A) therapy in this context has not been fully explored. We therefore used combinations of anti-VEGF-A with chemotherapy on various tumor models in mice including primary tumors, experimental lung metastases, and spontaneous lung metastases of 4T1-breast and CT26-colon murine cancer cell lines. Our results show that a combined treatment with anti-VEGF-A and folinic acid/5-fluorouracil/oxaliplatin (FOLFOX) but not with anti-VEGF-A and gemcitabine/cisplatinum (Gem/CDDP) enhances the treatment outcome partly due to reduced angiogenesis, in both primary tumors and in experimental lung metastases models. However, neither treatment group exhibited an improved treatment outcome in the spontaneous lung metastases model nor were changes in endothelial cell numbers found at metastatic sites. Since chemotherapy has recently been shown to induce tumor cell invasion, we tested the invasion properties of tumor cells when exposed to plasma from FOLFOX-treated mice or cancer patients. While plasma from FOLFOX-treated mice or patients induced invasion properties of tumor cells, the combination of anti-VEGF-A and FOLFOX abrogated these effects, despite the reduced plasma VEGF-A levels detected in FOLFOX-treated mice. These results suggest that the therapeutic impact of antiangiogenic drugs varies in different tumor models, and that anti-VEGF-A therapy can block the invasion properties of tumor cells in response to chemotherapy. These results may implicate an additional therapeutic role for anti-VEGF-A when combined with chemotherapy.
    Molecular Cancer Therapeutics 10/2013; 13(1). DOI:10.1158/1535-7163.MCT-13-0356 · 6.11 Impact Factor
  • Journal of Clinical Oncology 08/2013; 31(28). DOI:10.1200/JCO.2013.49.7941 · 17.88 Impact Factor
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    ABSTRACT: Targeted therapies have become an important therapeutic paradigm for multiple malignancies. The rapid development of resistance to these therapies impedes the successful management of advanced cancer. Due to the redundancy in angiogenic signaling, alternative proangiogenic factors are activated upon treatment with anti-VEGF agents. Higher doses of the agents lead to greater stimulation of compensatory proangiogenic pathways that limit the therapeutic efficacy of VEGF-targeted drugs and produce escape mechanisms for tumor. Evidence suggests that dose intensity and schedules affect the dynamics of the development of this resistance. Thus, an optimal dosing regimen is crucial to maximizing the therapeutic benefit of antiangiogenic agents and limiting treatment resistance. A systems pharmacology approach using multiscale computational modeling can facilitate a mechanistic understanding of these dynamics of angiogenic biomarkers and their impacts on tumor reduction and resistance. Herein, we discuss a systems pharmacology approach integrating the biology of VEGF-targeted therapy resistance, including circulating biomarkers, and pharmacodynamics to enable the optimization of antiangiogenic therapy for therapeutic gains.
    Frontiers in Pharmacology 02/2015; 6:33. DOI:10.3389/fphar.2015.00033

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