Abstract
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. GBM is very aggressive due to its poor cellular differentiation and invasiveness, which makes complete surgical resection virtually impossible. Therefore, GBMs invasive nature as well as its intrinsic resistance to current treatment modalities makes it a unique therapeutic challenge. Extensive examination of human GBM specimens has uncovered that these tumors overexpress a variety of receptors that are virtually absent in the surrounding non-neoplastic brain. Human GBMs overexpress receptors for cytokines, growth factors, ephrins, urokinase-type plasminogen activator (uPA), and transferrin, which can be targeted with high specificity by linking their ligands with highly cytotoxic molecules, such as Diptheria toxin and Pseudomonas exotoxin A. We review the preclinical development and clinical translation of targeted toxins for GBM. In view of the clinical experience, we conclude that although these are very promising therapeutic modalities for GBM patients, efforts should be focused on improving the delivery systems utilized in order to achieve better distribution of the immuno-toxins in the tumor/resection cavity. Delivery of targeted toxins using viral vectors would also benefit enormously from improved strategies for local delivery.
Keywords: IL-13, IL-13Rα2, TGF-α, EGFR, EGFRvIII, pseudomonas exotoxin, diphtheria toxin, gene therapy, targeted toxins
Anti-Cancer Agents in Medicinal Chemistry
Title: Targeted Toxins for Glioblastoma Multiforme: Pre-Clinical Studies and Clinical Implementation
Volume: 11 Issue: 8
Author(s): Marianela Candolfi, Kurt M. Kroeger, Weidong Xiong, Chunyan Liu, Mariana Puntel, Kader Yagiz, AKM Ghulam Muhammad, Yohei Mineharu, David Foulad, Mia Wibowo, Hikmat Assi, Gregory J. Baker, Pedro R. Lowenstein and Maria G. Castro
Affiliation:
Keywords: IL-13, IL-13Rα2, TGF-α, EGFR, EGFRvIII, pseudomonas exotoxin, diphtheria toxin, gene therapy, targeted toxins
Abstract: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. GBM is very aggressive due to its poor cellular differentiation and invasiveness, which makes complete surgical resection virtually impossible. Therefore, GBMs invasive nature as well as its intrinsic resistance to current treatment modalities makes it a unique therapeutic challenge. Extensive examination of human GBM specimens has uncovered that these tumors overexpress a variety of receptors that are virtually absent in the surrounding non-neoplastic brain. Human GBMs overexpress receptors for cytokines, growth factors, ephrins, urokinase-type plasminogen activator (uPA), and transferrin, which can be targeted with high specificity by linking their ligands with highly cytotoxic molecules, such as Diptheria toxin and Pseudomonas exotoxin A. We review the preclinical development and clinical translation of targeted toxins for GBM. In view of the clinical experience, we conclude that although these are very promising therapeutic modalities for GBM patients, efforts should be focused on improving the delivery systems utilized in order to achieve better distribution of the immuno-toxins in the tumor/resection cavity. Delivery of targeted toxins using viral vectors would also benefit enormously from improved strategies for local delivery.
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Candolfi Marianela, M. Kroeger Kurt, Xiong Weidong, Liu Chunyan, Puntel Mariana, Yagiz Kader, Ghulam Muhammad AKM, Mineharu Yohei, Foulad David, Wibowo Mia, Assi Hikmat, J. Baker Gregory, R. Lowenstein Pedro and G. Castro Maria, Targeted Toxins for Glioblastoma Multiforme: Pre-Clinical Studies and Clinical Implementation, Anti-Cancer Agents in Medicinal Chemistry 2011; 11 (8) . https://dx.doi.org/10.2174/187152011797378689
DOI https://dx.doi.org/10.2174/187152011797378689 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
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