Nimotuzumab as a radiosensitizing agent in the treatment of high grade glioma: challenges and opportunities

OncoTargets and Therapy Dovepress open access to scientific and medical research R e v ie w OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 2.58.12.218 on 24-Jun-2020 For personal use only. Open Access Full Text Article Nimotuzumab as a radiosensitizing agent in the treatment of high grade glioma: challenges and opportunities This article was published in the following Dove Press journal: OncoTargets and Therapy 23 July 2013 Number of times this article has been viewed Arlhee Diaz-Miqueli 1,* Giselle Saurez Martinez 2,* Department of System Biology, Center of Molecular Immunology, Havana, Cuba; 2Medical Division, Center of Molecular Immunology, Havana, Cuba 1 *Both authors contributed equally to this manuscript Introduction Correspondence: Arlhee Diaz-Miqueli Center of Molecular Immunology, 216 St, PO Box 16040, Havana 11600, Cuba Tel +53 7 271 5057 Fax +53 7 273 3509 Email submit your manuscript | www.dovepress.com Dovepress http://dx.doi.org/10.2147/OTT.S33532 Powered by TCPDF (www.tcpdf.org) Abstract: Nimotuzumab is a humanized monoclonal antibody that binds specifically to human epidermal growth factor receptor, blocking receptor activation. Evidence of its radiosensitizing capacity has been widely evaluated. This article integrates published research findings regarding the role of nimotuzumab in the treatment of high grade glioma in combination with radiotherapy or radiochemotherapy in adult and pediatric populations. First, the mechanisms of action of nimotuzumab and its current applications in clinical trials containing both radiation and chemoradiation therapies are reviewed. Second, a comprehensive explanation of potential mechanisms driving radiosensitization by nimotuzumab in experimental settings is given. Finally, future directions of epidermal growth factor receptor targeting with nimotuzumab in combination with radiation containing regimens, based on its favorable toxicity profile, are proposed. It is hoped that this review may provide further insight into the rational design of new approaches employing nimotuzumab as a useful alternative for the therapeutic management of high grade glioma. Keywords: nimotuzumab, radiation, high grade gliomas Gliomas are the most frequently occurring primary tumor of the central nervous system, classified as grade 1 to 4 on the basis of histopathological features and clinical criteria established by the World Health Organization. This classification includes pilocytic astrocytoma (grade 1), diffuse astrocytoma (grade 2), anaplastic astrocytoma ([AA] grade 3), and glioblastoma multiform ([GBM] grade 4).1 Grade 3 and 4 tumors are considered malignant or high grade gliomas (HGG). HGG are the most aggressive form of primary brain tumor without an effective therapy. Despite its relatively low incidence, which is approximately 5 cases per 100,000 people,2 the highly aggressive nature of this tumor remains a challenge for oncologists. HGG usually proliferate and invade extensively into surrounding areas in the brain yielding short life expectancies despite new aggressive modalities of treatment. Therefore, a need for further therapy options, as well as new approaches that evaluate potential combinations of existing modality treatments, is urgently needed. The aim of this review is to integrate published research findings regarding the role of nimotuzumab, a monoclonal antibody against the epidermal growth factor receptor (EGFR) in combination with radiotherapy and chemoradiation in the treatment of HGG, focusing on its additional value for enhancing the efficacy of radiotherapy through accumulated nonclinical and clinical evidence. OncoTargets and Therapy 2013:6 931–942 931 © 2013 Diaz-Miqueli and Suarez Martinez, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Diaz-Miqueli and Suarez Martinez OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 2.58.12.218 on 24-Jun-2020 For personal use only. Current standard therapies in HGG The current standard treatment in HGG consists of a combined approach of surgery and radiation, or combined radiation and chemotherapy, depending on the site of the disease as well as a patient´s health condition.3,4 Surgery is the first treatment choice and a maximal surgical resection is indicated whenever possible. However, because of their highly infiltrative nature, HGG cannot be completely eliminated surgically. Indeed, the value of surgery in prolonging patient survival is still controversial.5–8 Subsequent to an optimal surgical resection or biopsy, ionizing radiation is the dominant form of therapy administered postoperatively, prolonging median survival for a maximum of 6 to 8 months.2 Indeed, ionizing radiation is prescribed in the majority of patients with HGG. However, despite the fact that new methods have increased the therapeutic potential of radiation in oncology, a curative treatment remains dismal. The local failure of radiotherapy has been previously outlined by others with respect to the application of sublethal doses of irradiation that may promote the migration and invasiveness of glioma cells.9 Tumor recurrences at the original site invariably occur after radiation therapy impairing its efficacy.10 Migrating tumor cells may reach the edges of the target volume of postoperative radiotherapy, escape delivery of a cumulatively lethal dose, and form the basis for locoregional relapse during or after a few months of radiotherapy.10 Radiotherapy is also frequently indicated in glioblastoma patients with palliative intention, however, with significant limitations. Such limitations include intrinsic resistance of glioma cells to damage induced by ionizing radiation.11 Furthermore, an important proportion of glioma cells can survive irradiation, inducing their proliferation to accelerate tumor cell repopulation during radiation challenge.12,13 More recently, chemotherapy has gained prominence in the management of malignant gliomas. The 1-year patient survival rate increased from 6% to 10% after adjuvant chemotherapy.14 However, despite the moderate success of several agents such as temozolomide, an oral alkylating agent with encouraging results, current conventional protocols still demonstrate a high incidence of locoregional failure and poor overall survival (OS) rates. The introduction of temozolomide has significantly prolonged patient survival, but its efficacy strongly depends on the presence of the DNA repair enzyme, O6-methyl-guanine-DNA methyltransferase (MGMT). DNA promoter methylation status of MGMT is emblematic of repair enzyme activity in the tumor,15 particularly in GBM.14,16 Patients with unmethylated MGMT 932 Powered by TCPDF (www.tcpdf.org) submit your manuscript | www.dovepress.com Dovepress Dovepress promoters, which accounts for approximately half of GBM patients,17 who receive concurre (...truncated)