The evolving roles and controversies of radiotherapy in the treatment of glioblastoma

Hau, Eric; Shen, Han; Clark, Catherine; Graham, Peter; Koh, Eng‐Siew; McDonald, Kerrie L.

doi:10.1002/jmrs.149

Cited by 21 publications

(20 citation statements)

References 74 publications

(95 reference statements)

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“…32 Radiation applied to the brain generally ranges between 50 and 60 Gy; higher doses are more likely to induce necrosis and radiation-induced secondary tumors. 19,28,31 We tested fractionated radiotherapy with single fractions of 2 Gy until a significant effect on ACP cells was detected. To reveal the impact of EGFR activation on radiosensitivity we analyzed primary ACP cultures after EGF treatment and subsequent radiotherapy.…”

Section: Results Egfr Activation and Radioresistance In Primary Acp Tmentioning

confidence: 99%

Drug priming enhances radiosensitivity of adamantinomatous craniopharyngioma via downregulation of survivin

Stache

Bils

Fahlbusch

et al. 2016

FOC

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OBJECTIVE In this study, the authors investigated the underlying mechanisms responsible for high tumor recurrence rates of adamantinomatous craniopharyngioma (ACP) after radiotherapy and developed new targeted treatment protocols to minimize recurrence. ACPs are characterized by the activation of the receptor tyrosine kinase epidermal growth factor receptor (EGFR), known to mediate radioresistance in various tumor entities. The impact of tyrosine kinase inhibitors (TKIs) gefitinib or CUDC-101 on radiation-induced cell death and associated regulation of survivin gene expression was evaluated. METHODS The hypothesis that activated EGFR promotes radioresistance in ACP was investigated in vitro using human primary cell cultures of ACP (n = 10). The effects of radiation (12 Gy) and combined radiochemotherapy on radiosensitivity were assessed via cell death analysis using flow cytometry. Changes in target gene expression were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Survivin, identified in qRT-PCR to be involved in radioresistance of ACP, was manipulated by small interfering RNA (siRNA), followed by proliferation and vitality assays to further clarify its role in ACP biology. Immunohistochemically, survivin expression was assessed in patient tumors used for primary cell cultures. RESULTS In primary human ACP cultures, activation of EGFR resulted in significantly reduced cell death levels after radiotherapy. Treatment with TKIs alone and in combination with radiotherapy increased cell death response remarkably, assessed by flow cytometry. CUDC-101 was significantly more effective than gefitinib. The authors identified regulation of survivin expression after therapeutic intervention as the underlying molecular mechanism of radioresistance in ACP. EGFR activation promoting ACP cell survival and proliferation in vitro is consistent with enhanced survivin gene expression shown by qRT-PCR. TKI treatment, as well as the combination with radiotherapy, reduced survivin levels in vitro. Accordingly, ACP showed reduced cell viability and proliferation after survivin downregulation by siRNA. CONCLUSIONS These results indicate an impact of EGFR signaling on radioresistance in ACP. Inhibition of EGFR activity by means of TKI treatment acts as a radiosensitizer on ACP tumor cells, leading to increased cell death. Additionally, the results emphasize the antiapoptotic and pro-proliferative role of survivin in ACP biology and its regulation by EGFR signaling. The suppression of survivin by treatment with TKI and combined radiotherapy represents a new promising treatment strategy that will be further assessed in in vivo models of ACP.

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Section: Results Egfr Activation and Radioresistance In Primary Acp Tmentioning

confidence: 99%

Drug priming enhances radiosensitivity of adamantinomatous craniopharyngioma via downregulation of survivin

Stache

Bils

Fahlbusch

et al. 2016

FOC

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“…RT using three-dimensional conformal beam or intensity-modulated RT is used now. The typical total dose delivered is 60 Gy in 2 Gy fractions, administered 5 days per week for 6 weeks and there is no evidence that higher doses improve outcome [60,61]. The RT involved fields should include the tumor bed with a 2-3 cm margin, based on the observation that GBM commonly recurs within 2 cm of the original tumor location in 80-90% of cases.…”

Section: Radiation Therapymentioning

confidence: 99%

Current Trends in Glioblastoma Treatment

Tătăranu¹,

Ciubotaru²,

Cazac³

et al. 2018

Brain Tumors - An Update

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Glioblastoma (also called glioblastoma multiforme-GBM) is a primary brain neoplasm, representing about 55% of all gliomas. It is a very aggressive and infiltrative tumor. Glioblastoma is usually highly malignant, with more than 90% 5-year mortality and a median survival of about 14.6 months. Compared to other cancers, the survival rate has not greatly changed over time and no current treatment is curative for this disease. Because the tumor has a heterogeneous cell population containing several types of cells, the treatment for GBM is one of the most challenging in clinical oncology. This chapter will discuss the current approaches in glioblastoma treatment, including resection techniques, chemotherapy and radiation therapy.

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“…RT aims to destroy the residual GBM cells at the resection border and prevent the disease relapse, but it has wide biological effects on different molecular and physiological parameters in the irradiated brain tissue as well ( 6 ). Negative side effects of X-ray radiation include: increased permeability of the blood-brain barrier ( 7 , 8 ); brain necrosis ( 9 ); morphological changes, microvascular injury, and activation of astrocytes after irradiation of mouse brain ( 10 ); metabolic and histopathological changes in the specific rat brain regions ( 11 ); suppressed cell proliferation in the hippocampal subgranular zone ( 12 ) and long-term neurocognitive impairment ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

Radiation Effects on Brain Extracellular Matrix

Grigorieva

2020

Front. Oncol.

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Radiotherapy is an important therapeutic approach to treating malignant tumors of different localization, including brain cancer. Glioblastoma multiforme (GBM) represents the most aggressive brain tumor, which develops relapsed disease during the 1st year after the surgical removal of the primary node, in spite of active adjuvant radiochemotherapy. More and more evidence suggests that the treatment's success might be determined by the balance of expected antitumor effects of the treatment and its non-targeted side effects on the surrounding brain tissue. Radiation-induced damage of the GBM microenvironment might create tumor-susceptible niche facilitating proliferation and invasion of the residual glioma cells and the disease relapse. Understanding of molecular mechanisms of radiation-induced changes in brain ECM might help to reconsider and improve conventional anti-glioblastoma radiotherapy, taking into account the balance between its antitumor and ECM-destructing activities. Although little is currently known about the radiation-induced changes in brain ECM, this review summarizes current knowledge about irradiation effects onto the main components of brain ECM such as proteoglycans, glycosaminoglycans, glycoproteins, and the enzymes responsible for their modification and degradation.

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The evolving roles and controversies of radiotherapy in the treatment of glioblastoma

Cited by 21 publications

References 74 publications

Drug priming enhances radiosensitivity of adamantinomatous craniopharyngioma via downregulation of survivin

Drug priming enhances radiosensitivity of adamantinomatous craniopharyngioma via downregulation of survivin

Current Trends in Glioblastoma Treatment

Radiation Effects on Brain Extracellular Matrix

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