Hypoxia modulation and radiosensitization by the novel dual EGFR and VEGFR inhibitor AEE788 in spontaneous and related allograft tumor models

Abstract

Concomitant inhibition of ErbB1/2-and VEGF receptorsignaling synergizes when used in combination with DNAdamaging agents. Here, we investigated for the first time the combined treatment modality of the novel dual specific receptor tyrosine kinase inhibitor AEE788 with ionizing radiation and analyzed treatment-induced end points in situ as indicators for a potential sensitizing mechanism. Furthermore, we assessed tumor hypoxia in response to different antiangiogenic and antiproliferative treatment modalities. The combined treatment effect was investigated in a spontaneously growing mammary carcinoma model and against Her-2/neu-overexpressing mammary carcinoma allografts. In tumor allografts derived from murine mammary carcinoma cells of mouse mammary tumor virus/c-neu transgenic mice, a minimal treatment regimen with AEE788 and fractionated irradiation resulted in an at least additive tumor response. Treatment response in the corresponding spontaneous tumor model strongly exceeded the response induced in the isogenic allografts. Treatment-induced changes of tumor proliferation, apoptosis, and microvessel density were similar in the two tumor models. Treatment with AEE788 alone or in combination with IR strongly improved tumor oxygenation in both tumor models as determined by the detection of endogenous and exogenous markers of tumor hypoxia. Specific inhibition of the VEGF-receptor tyrosine kinase versus Erb1/2-receptor tyrosine kinase indicated that it is the antiproliferative and not the antiangiogenic potency of AEE788 that mediates the hypoxia-reducing effect of this dual kinase-specific inhibitor. Overall, we show that concomitant inhibition of ErbB-and VEGF-receptor signaling by AEE788, in combination with ionizing radiation, is a promising treatment approach, especially in hypoxic, oncogenic ErbB-driven tumors. [Mol Cancer Ther 2007;6(9):2496 -504]

Role of the Microenvironment for Radiosensitization by Patupilone

“…Patupilone also induces vascular disruption leading to reduced tumor blood volume (8). We showed previously an at least additive antitumor effect by the combined treatment of IR with different inhibitors of angiogenesis, such as the VEGF receptor tyrosine kinase inhibitor PTK787 or the dual receptor tyrosine kinase inhibitor AEE788 (21,22). Based on the putative direct antiangiogenic property of patupilone, a partial tumor growth delay effect was expected on treatment with patupilone alone or in combination with IR even in tumors derived from the patupilone-resistant tumor cells (A549.Epo40).…”

“…Here, we observed an increase of tumor hypoxia induced by patupilone alone presumably through this antiangiogenic, indirect MVD-reducing effect. We investigated previously the dynamics of tumor hypoxia in response to inhibitors of angiogenesis alone and in combination with IR and observed that irradiation counteracts the risk of treatment-induced hypoxia by the inhibition of angiogenesis (21,22). Although treatment with the VEGF receptor/tyrosine kinase inhibitor PTK787/ZK222584 also increased overall and local tumor hypoxia, combined treatment with IR resulted in extended tumor growth delay and tumor cell apoptosis but no increase in tumor hypoxia (22).…”

Ionizing radiation and inhibition of angiogenesis in a spontaneous mammary carcinoma and in a syngenic heterotopic allograft tumor model: a comparative study

“…Immunohistochemical stainings of tumor sections were performed after tumor excision at day 4 of treatment. Detailed descriptions of the experimental procedures are given elsewhere [11]. The Student's t-test was used to statistically analyse the differences between the treatment groups.…”

HER2/neu: an increasingly important therapeutic target. Part 1: basic biology & therapeutic armamentarium

“…AEE788 is a pan-HER inhibitor with capacity to inhibit the three VEGF receptors, which has roughly equivalent activity inhibiting HER1 and HER2 [181]. Preclinical work with AEE788 suggests antiangiogenesis activity, radiosensitizing capacity, and potential synergy with aromatase inhibition in breast cancer models [182,183]. The initial Phase I study demonstrated the expected dose-limiting toxicities rash and diarrhea with the maximum-tolerated dose of 450 mg/day, but based on biomarker data suggested that in humans there was limited antiangiogenic activity [184].…”