Glioblastoma multiforme: a review of therapeutic targets

Kanu, Okezie Obasi; Mehta, Ankit I.; Di, Chunhui; Lin, Ningjing; Bortoff, Kathy; Bigner, Darell D.; Yan, Hai; Adamson, David Cory

doi:10.1517/14728220902942348

Cited by 149 publications

(93 citation statements)

References 153 publications

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“…Even with improved diagnosis and comprehensive therapy, the prognosis of glioma remains dismal (15). Studies of the underlying molecular mechanisms involved in glioma formation and progression provide tremendous opportunities to identify key molecules which may serve as additional targets for drug design in the treatment of brain tumors.…”

Section: Discussionmentioning

confidence: 99%

Effect of 5-Aza-2'-deoxycytidine on SLC22A18 in glioma U251 cells

Chu

Feng

et al. 2011

Mol Med Report

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Abstract. SLC22A18 [solute carrier family 22 (organic cation transporter) member 18] is located within the 11p15.5 cluster, and may be a new tumor suppressor gene; evidence of SLC22A18 hypermethylation is documented in several types of human cancers. In order to determine whether SLC22A18 hypermethylation is involved in glioma, we determined the SLC22A18 gene protein expression, mRNA expression and methylation status in glioma U251 cells before and after treatment with 5-Aza-2'-deoxycytidine (5-Aza-CdR), and observed the change in growth. Glioma U251 cells treated with 5-AzaCdR were analyzed by flow cytometry to identify any change in their cell cycle profiles. Tumors induced via the injection of untreated U251 cells were measured. Immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR) and PCR-based methylation assay were carried out to determine SLC22A18 gene protein expression, mRNA expression and methylation status in glioma U251 cells before and after treatment with 5-Aza-CdR. The treated cells showed an increase in their proportion in G1, from 79.2 to 83.5%, and a decrease in S phase, from 12.4 to 5.8%. The apoptotic rate increased from 6.4 to 15.8%. Tumors induced via the injection of untreated U251 cells were approximately 1.46 cm 3 in size, whereas the tumors induced by U251 cells treated with 5-Aza-CdR averaged 0.88 cm 3 in size. The expression levels of SLC22A18 protein and mRNA in U251 cells were increased following treatment with 5x10 -7 M 5-Aza-CdR. Prior to 5-Aza-CdR treatment, the SLC22A18 gene demonstrated hypermethylation and therefore could not be cleaved by HpaII and MspI. It is known that only the DNA digested with HpaII or MspI can be amplified. Following treatment with 5-Aza-CdR, the SLC22A18 gene became demethylated, and could then be cleaved by both of the enzymes, and this failed to be amplified. 5-Aza-cdR may induce glioma U251 cell division and apoptosis and enhance demethylation and protein and mRNA expression of SLC22A18. The hypermethylation of SLC22A18 may be related to the transcriptional silencing of this gene. The growth inhibitory effects of 5-Aza-CdR treatment in vivo remain recognizable.

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Section: Discussionmentioning

confidence: 99%

Effect of 5-Aza-2'-deoxycytidine on SLC22A18 in glioma U251 cells

Chu

Feng

et al. 2011

Mol Med Report

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“…Thus, more effective initial treatments for this intractable disease are required. Recent therapies under investigation include immunotherapy, chemotherapy, targeted molecular, antiangiogenic and gene therapy, radiation enhancement and drugs for overcoming resistance (2). Statins are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), commonly used as cholesterol-lowering agents (3), that have proven their effectiveness in the treatment of cardiovascular diseases.…”

Section: Introductionmentioning

confidence: 99%

Statins are potential anticancerous agents (Review)

2015

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Abstract. Statins are inhibitors of 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGCR), which is a rate-limiting enzyme in the mevalonate pathway. The pleiotropic effects of statins may be mediated by the inhibition of downstream products such as small GTP-binding proteins, Rho, Ras and Rac whose localization and function are dependent on isoprenylation. Preclinical studies of statins in different cancer cell lines and animal models showed antiproliferative, pro-apoptotic and anti-invasive effects. Notably, statins showed targeted action in cancerous cell lines compared to normal cells. Previous studies have also shown the synergistic effects of statins with chemotherapeutic agents and radiotherapy. This effect of statins was also observed in chemotherapeutic-resistant tumors. Statins were reported to sensitize the cells to radiation by arresting them in the late G1 phase of the cell cycle. Similarly, population-based studies also demonstrated a chemopreventive and survival benefit of statins in various types of cancers. However, this benefit has yet to be proven in clinical trials. The interindividual variation in response to statins may be contributed to many genetic and non-genetic factors, including single-nucleotide polymorphisms in HMGCR gene and the overexpression of heterogeneous nuclear ribonucleoprotein A1, which was reported to reduce HMGCR enzyme activity. However, more studies with large phase III randomized controlled trials in cancer patients should be conducted to establish the effect of statins in cancer prevention and treatment.

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“…This specificity is particularly required when designing therapies for brain tumors, such as glioblastoma multiforme (GBM), in which tumor cells infiltrate the normal brain. GBM is the most common primary brain cancer in adults, and carries a dismal prognosis (14-to 21-mo median survival), in spite of an advanced standard of care, namely surgery, radiotherapy, and chemotherapy with temozolomide (6)(7)(8).…”

mentioning

confidence: 99%

Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics

Candolfi

Xiong

Yagiz

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Restricting the cytotoxicity of anticancer agents by targeting receptors exclusively expressed on tumor cells is critical when treating infiltrative brain tumors such as glioblastoma multiforme (GBM). GBMs express an IL-13 receptor (IL13Rα2) that differs from the physiological IL4R/IL13R receptor. We developed a regulatable adenoviral vector (Ad.mhIL-4.TRE.mhIL-13-PE) encoding a mutated human IL-13 fused to Pseudomonas exotoxin (mhIL-13-PE) that specifically binds to IL13Rα2 to provide sustained expression, effective anti-GBM cytotoxicity, and minimal neurotoxicity. The therapeutic Ad also encodes mutated human IL-4 that binds to the physiological IL4R/IL13R without interacting with IL13Rα2, thus inhibiting potential binding of mhIL-13-PE to normal brain cells. Using intracranial GBM xenografts and syngeneic mouse models, we tested the Ad.mhIL-4.TRE.mhIL-13-PE and two protein formulations, hIL-13-PE used in clinical trials (Cintredekin Besudotox) and a second-generation mhIL-13-PE. Cintredekin Besudotox doubled median survival without eliciting long-term survival and caused severe neurotoxicity; mhIL-13-PE led to ∼40% long-term survival, eliciting severe neurological toxicity at the high dose tested. In contrast, Ad-mediated delivery of mhIL-13-PE led to tumor regression and long-term survival in over 70% of the animals, without causing apparent neurotoxicity. Although Cintredekin Besudotox was originally developed to target GBM, when tested in a phase III trial it failed to achieve clinical endpoints and revealed neurotoxicity. Limitations of Cintredekin Besudotox include its short half-life, which demanded frequent or continued administration, and binding to IL4R/IL13R, present in normal brain cells. These shortcomings were overcome by our therapeutic Ad, thus representing a significant advance in the development of targeted therapeutics for GBM.

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Glioblastoma multiforme: a review of therapeutic targets

Cited by 149 publications

References 153 publications

Effect of 5-Aza-2'-deoxycytidine on SLC22A18 in glioma U251 cells

Effect of 5-Aza-2'-deoxycytidine on SLC22A18 in glioma U251 cells

Statins are potential anticancerous agents (Review)

Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics

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