Abstract
BackgroundEpidermal growth factor receptor (EGFR) inhibitors have shown only modest clinical activity when used as single agents to treat cancers. They decrease tumor cell expression of hypoxia-inducible factor 1-α (HIF-1α) and vascular endothelial growth factor (VEGF). Hypothesizing that this might normalize tumor vasculature, we examined the effects of the EGFR inhibitor erlotinib on tumor vascular function, tumor microenvironment (TME) and chemotherapy and radiotherapy sensitivity.Methodology/Principal FindingsErlotinib treatment of human tumor cells in vitro and mice bearing xenografts in vivo led to decreased HIF-1α and VEGF expression. Treatment altered xenograft vessel morphology assessed by confocal microscopy (following tomato lectin injection) and decreased vessel permeability (measured by Evan's blue extravasation), suggesting vascular normalization. Erlotinib increased tumor blood flow measured by Power Doppler ultrasound and decreased hypoxia measured by EF5 immunohistochemistry and tumor O2 saturation measured by optical spectroscopy. Predicting that these changes would improve drug delivery and increase response to chemotherapy and radiation, we performed tumor regrowth studies in nude mice with xenografts treated with erlotinib and either radiotherapy or the chemotherapeutic agent cisplatin. Erlotinib therapy followed by cisplatin led to synergistic inhibition of tumor growth compared with either treatment by itself (p<0.001). Treatment with erlotinib before cisplatin led to greater tumor growth inhibition than did treatment with cisplatin before erlotinib (p = 0.006). Erlotinib followed by radiation inhibited tumor regrowth to a greater degree than did radiation alone, although the interaction between erlotinib and radiation was not synergistic.Conclusions/SignificanceEGFR inhibitors have shown clinical benefit when used in combination with conventional cytotoxic therapy. Our studies show that targeting tumor cells with EGFR inhibitors may modulate the TME via vascular normalization to increase response to chemotherapy and radiotherapy. These studies suggest ways to assess the response of tumors to EGFR inhibition using non-invasive imaging of the TME.
Highlights
The idea of manipulating the tumor microenvironment (TME) to improve cancer therapy has been around for decades; finding ways in which to do this in the clinic has proven difficult
Our previous work demonstrated that small molecule Epidermal growth factor receptor (EGFR) inhibitors including erlotinib decreased vascular endothelial growth factor (VEGF) mRNA expression, decreased secretion of VEGF protein, and blunted hypoxia-inducible factor 1-a (HIF-1a) induction in response to hypoxia in SQ20B head and neck squamous cell carcinoma cells [20]
We confirmed that erlotinib inhibited HIF-1a and VEGF both in vitro and in vivo in SQ20B squamous cell carcinoma cells
Summary
The idea of manipulating the tumor microenvironment (TME) to improve cancer therapy has been around for decades; finding ways in which to do this in the clinic has proven difficult. More recently Jain and colleagues showed that anti-angiogenic therapy can result in a ‘‘normalization’’ of aberrant tumor vasculature in such as way as to improve oxygenation and blood flow that could enhance the efficacy of subsequent radiation and chemotherapy [7,8]. Their approach relied on using agents that directly target vascular endothelial growth factor (VEGF) or its receptor (VEGFR) on endothelial cells. Epidermal growth factor receptor (EGFR) inhibitors have shown only modest clinical activity when used as single agents to treat cancers They decrease tumor cell expression of hypoxia-inducible factor 1-a (HIF-1a) and vascular endothelial growth factor (VEGF). Hypothesizing that this might normalize tumor vasculature, we examined the effects of the EGFR inhibitor erlotinib on tumor vascular function, tumor microenvironment (TME) and chemotherapy and radiotherapy sensitivity
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