Expression of interleukin-13 receptor α2 in glioblastoma multiforme: Implications for targeted therapies
ABSTRACT Glioblastoma multiforme is the most common primary malignant brain tumor and despite treatment with surgery, radiation, and chemotherapy, the median survival of patients with glioblastoma multiforme is approximately 1 year. Glioblastoma multiforme explants and cell lines have been reported to overexpress the interleukin-13 receptor alpha2 subunit (IL13Ralpha2) relative to nonneoplastic brain. Based on this finding, a recombinant cytotoxin composed of IL13 ligand and a truncated form of Pseudomonas aeruginosa exotoxin A (IL13-PE38QQR) was developed for the targeted treatment of glioblastoma multiforme tumors. In a recently completed phase III clinical trial, however, IL13-PE38QQR was found to be no more effective than an existing therapy in prolonging survival. To determine possible explanations for this result, we analyzed the relative expression levels of IL13Ralpha2 in glioblastoma multiforme and nonneoplastic brain specimens using publicly available oligonucleotide microarray databases, quantitative real-time reverse transcription PCR, and immunohistochemical staining. Increased expression of the IL13Ralpha2 gene relative to nonneoplastic brain was observed in 36 of 81 (44%) and 8 of 17 (47%) tumor specimens by microarray and quantitative real-time reverse transcription PCR analyses, respectively. Immunohistochemical staining of tumor specimens showed highly variable expression of IL13Ralpha2 protein both within and across specimens. These data indicate that prescreening of subjects may be of benefit in future trials of IL13Ralpha2 targeting therapies.
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ABSTRACT: Finding widely overexpressed proteins specific to glioblastoma multiforme (GBM) was considered unlikely. Contrary to expectations, a number of such factors have been identified to be expressed in a majority of GBM but not in normal brain. These tumor-specific proteins are very attractive targets for novel, specific, rationally designed molecular therapies. Here we discuss the opportunities presented by two such factors, IL-13Rα2 and EphA2 receptor. IL-13Rα2 is a nonsignaling form of interleukin-13 receptor, which, in contrast to its physiological counterpart, is not bound by interleukin-4. IL-13Rα2 is overexpressed in 75% of GBM, and its presence in normal organs is very low or nonexistent, with the exception of the testes. EphA2 receptor belongs to the largest family of receptor tyrosine kinases. EphA2 is present in nearly all GBM, is highly overexpressed in 66% of them, is absent in normal brain, and is strongly associated with poor patient survival. Molecularly targeted cytotoxins that contain derivatives of bacterial toxins that specifically and potently kill GBM cells overexpressing either IL-13Rα2 or EphA2 receptor were produced. The first generation of an IL-13-based cytotoxin reached Phase III clinical trial, demonstrated safety of the approach in humans, improved progression-free survival of GBM patients in some centers, but did not modify mean survival of the whole cohort. The first EphA2-targeted cytotoxin has already demonstrated attractive features in recent preclinical examination. The overexpression of either IL-13Rα2 or EphA2 is seen in 95% of GBM, which means that by cotargeting these two receptors almost all patients will be eligible, making the need for pretherapy screening for marker expression unnecessary. The future efforts in exploiting potent cytotoxins for the treatment of GBM should focus on combinatorial targeted therapy that involves either a multivalent approach or combination cocktails of the cytotoxins. In this way, multiple compartments of GBM tumors will be targeted benefiting all the patients.
Article: Immunotherapy for Glioblastoma[Show abstract] [Hide abstract]
ABSTRACT: The most common and deadliest brain tumor is glioblastoma, which escapes immune recognition and kills the patients with a year of diagnosis. Glioblastomas, like other malignancies, are highly capable of overcoming host immune defenses through a variety of mechanisms some of which are quite clear. Currently, there is a growing interest in developing immunotherapeutics for treatment of glioblastomas; however, very little is known about glioblastoma-specific immune responses. A better understanding of the molecular interactions between the tumor and the host immune system may allow the development of novel integrated approaches based on the simultaneous control of tumor escape pathways and the activation of anti-tumor immune responses. An appropriate combination therapy that may induce long-lasting immune responses against glioblastoma should be attempted. The primary goal of immunotherapy for glioblastoma should be to overcome tolerance and to re-educate the immune system, when the tumor burden is reduced following surgery, radiotherapy and chemotherapy. This article describes the latest developments in the glioblastoma immunology and immunotherapy.
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ABSTRACT: Gliomas are the most common primary brain tumours. In keeping with the degree of aggressiveness, gliomas are divided into four grades, with different biological behaviour. Furthermore, as different gliomas share a predominant histological appearance, the final classification includes both, histological features and degree of malignancy. For example, gliomas of astrocytic origin (astrocytomas) are classified into pilocytic astrocytoma (grade I), astrocytoma (grade II), anaplastic astrocytoma (grade III) and glioblastoma multiforme (GMB) (grade IV). Tumors derived from oligodendrocytes include grade II (oliogodendrogliomas) and grade III neoplasms (oligoastrocytoma). Each subtype has a specific prognosis that dictates the clinical management. In this regard, a patient diagnosed with an oligodendroglioma totally removed has 10-15 years of potential survival. On the opposite site, patients carrying a glioblastoma multiforme usually die within the first year after the diagnosis is made. Therefore, different approaches are needed in each case. Obviously, prognosis and biological behaviour of malignant gliomas are closely related and supported by the different molecular background that possesses each type of glioma. Furthermore, the ability that allows several low-grade gliomas to progress into more aggressive tumors has allowed cancer researchers to elucidate several pathways implicated in molecular biology of these devastating tumors. In this review, we describe classical pathways involved in human malignant gliomas with special focus with recent advances, such as glioma stem-like cells and expression patterns from microarray studies.Clinical and Translational Oncology 10/2006; 8(9):635-41. DOI:10.1007/s12094-006-0033-9 · 2.08 Impact Factor