Enhancement of radiation response with bevacizumab

Journal of Experimental & Clinical Cancer Research (Impact Factor: 4.43). 04/2012; 31(1):37. DOI: 10.1186/1756-9966-31-37
Source: PubMed


Vascular endothelial growth factor (VEGF) plays a critical role in tumor angiogenesis. Bevacizumab is a humanized monoclonal antibody that neutralizes VEGF. We examined the impact on radiation response by blocking VEGF signaling with bevacizumab.
Human umbilical vein endothelial cell (HUVEC) growth inhibition and apoptosis were examined by crystal violet assay and flow cytometry, respectively. In vitro HUVEC tube formation and in vivo Matrigel assays were performed to assess the anti-angiogenic effect. Finally, a series of experiments of growth inhibition on head and neck (H&N) SCC1 and lung H226 tumor xenograft models were conducted to evaluate the impact of bevacizumab on radiation response in concurrent as well as sequential therapy.
The anti-angiogenic effect of bevacizumab appeared to derive not only from inhibition of endothelial cell growth (40%) but also by interfering with endothelial cell function including mobility, cell-to-cell interaction and the ability to form capillaries as reflected by tube formation. In cell culture, bevacizumab induced a 2 ~ 3 fold increase in endothelial cell apoptosis following radiation. In both SCC1 and H226 xenograft models, the concurrent administration of bevacizumab and radiation reduced tumor blood vessel formation and inhibited tumor growth compared to either modality alone. We observed a siginificant tumor reduction in mice receiving the combination of bevacizumab and radiation in comparison to mice treated with bevacizumab or radiation alone. We investigated the impact of bevacizumab and radiation treatment sequence on tumor response. In the SCC1 model, tumor response was strongest with radiation followed by bevacizumab with less sequence impact observed in the H226 model.
Overall, these data demonstrate enhanced tumor response when bevacizumab is combined with radiation, supporting the emerging clinical investigations that are combining anti-angiogenic therapies with radiation.


Available from: Shyhmin Huang, Apr 15, 2014
  • Source
    • "Moreover, few clinical studies assessed the role of rechallenge in the era of targeted therapy and no studies evaluated the activity of bevacizumab as a rechallenge therapy (both as a monotherapy or in combination with standard chemotherapy) so far. However, it has been demonstrated that targeted therapy could enhance sensitivity to both chemotherapy and radiotherapy [46]. Brite and TML study showed a benefit in the use of bevacizumab beyond disease progression. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Fluoropyrimidines, oxaliplatin, irinotecan and biologic therapies (Bevacizumab, Panitumumab, and Cetuximab) represent the backbone of metastatic colorectal cancer (CRC) treatment. The improvement in survival for mCRC patient led to two main outstanding issues: 1) there is a significant number of patients progressing beyond the third or fourth line of treatment still suitable for further therapy when enrollment into clinical trial is not possible. In this situation, the role of any therapy rechallenge (either chemotherapy alone, chemotherapy and biologic therapy or biologic therapy alone) is still not clear, particularly in patients who had previously responded, and if treatment choice is based on traditional dogma of primary and secondary resistance, rechallenge does not seem to be justified. 2) Prolonged intensive treatment is burdened from the high risk of cumulative toxicity, worsening in quality of life and a not well defined possibility of early acquired resistance. Different hypothesis could justify the research of different strategy in treatment of mCRC: 1) Epigenetic changes might drive resistance and treatment could induce these changes. Re-expression of silenced tumor suppressive genes might resensitize tumors to therapy. It is therefore possible that a drug holiday (intermittent treatment) could allow reversion to a previous epigenetic profile. Moreover an intermittent treatment could delay acquired resistance. 2) It is plausible that tumor grows as a polyclonal mass. If it responds but then becomes resistant to one or more treatments, retreatment might be successful if changing therapies allows to that clone of cells to re-emerge. On these basis, we focused this review on the actual evidences in management of mCRC patients in terms of chemotherapy or biological therapies rechallenge and intermittent treatment. Moreover, we will discuss the potential biological mechanisms of the observed results of early clinical trials.
    Journal of Experimental & Clinical Cancer Research 11/2013; 32(1):92. DOI:10.1186/1756-9966-32-92 · 4.43 Impact Factor
  • Source
    • "Preclinical studies have demonstrated that blocking the VEGF pathway with bevacizumab can enhance the sensitivity of both tumor and endothelial cells to the cytotoxic effects of radiation.35,36 In tumor xenograft models, the administration of bevacizumab in combination with RT induces inhibition of tumor growth with an additive effect compared to treatment with bevacizumab or radiation alone.36,37 "
    [Show abstract] [Hide abstract]
    ABSTRACT: The expansion in understanding the molecular biology that characterizes cancer cells has led to the rapid development of new agents to target important molecular pathways associated with aberrant activation or suppression of cellular signal transduction pathways involved in gliomagenesis, including epidermal growth factor receptor, vascular endothelial growth factor receptor, mammalian target of rapamycin, and integrins signaling pathways. The use of antiangiogenic agent bevacizumab, epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib, mammalian target of rapamycin inhibitors temsirolimus and everolimus, and integrin inhibitor cilengitide, in combination with radiation therapy, has been supported by encouraging preclinical data, resulting in a rapid translation into clinical trials. Currently, the majority of published clinical studies on the use of these agents in combination with radiation and cytotoxic therapies have shown only modest survival benefits at best. Tumor heterogeneity and genetic instability may, at least in part, explain the poor results observed with a single-target approach. Much remains to be learned regarding the optimal combination of targeted agents with conventional chemoradiation, including the use of multipathways-targeted therapies, the selection of patients who may benefit from combined treatments based on molecular biomarkers, and the verification of effective blockade of signaling pathways.
    OncoTargets and Therapy 08/2013; 6:1079-95. DOI:10.2147/OTT.S48224 · 2.31 Impact Factor
  • Source
    • "The pro-angiogenic factor VEGF is a crucial gene involved in angiogenesis that is strongly induced by hypoxia. Anti-angiogenic therapy, for example by using anti- VEGF monoclonal antibodies such as bevacizumab, can result in a reduction of tumour vascularisation, but counter-intuitively also in normalisation of the aberrant tumour vasculature, thereby improving oxygenation and blood flow that could enhance the efficacy of radiation [7] [8]. However, VEGF can also be upregulated in an oxygen-independent manner. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Treatment failure through radioresistance of tumours is associated with activation of the epidermal growth factor receptor (EGFR). Tumour cell proliferation, DNA-repair, hypoxia and metastases-formation are four mechanisms in which EGFR signalling has an important role. In clinical trials, a correlation has been demonstrated between high EGFR expression in tumours and poor outcome after radiotherapy. Inhibition of EGFR signalling pathways improves the effectiveness of radiotherapy of head and neck cancers by overcoming these main mechanisms of radioresistance. The fact that only a minority of the patients respond to EGFR inhibitors reflects the complexity of interactions between EGFR-dependent signalling pathways and the tumour microenvironment. Furthermore, many components of the microenvironment are potential targets for therapeutic interventions. Characterisation of the interaction of EGFR signalling and the tumour microenvironment is therefore necessary to improve the effectiveness of combined modality treatment with radiotherapy and targeted agents. Here, the current status of knowledge is reviewed and directions for future research are discussed.
    Radiotherapy and Oncology 06/2013; 108(1). DOI:10.1016/j.radonc.2013.05.006 · 4.36 Impact Factor
Show more