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REST, not REST4, is a risk factor associated with radiotherapy plus chemotherapy efficacy in glioma.

ABSTRACT: Background/aim:Repressor element silencing transcription factor (REST) is a transcription repressor, expressed in several malignancies. This study aims to evaluate the prognostic values of REST and its splicing variant REST4 in glioma, and investigate the potential correlation between REST and REST4. Methods:REST and REST4 expression values were evaluated by qRT-PCR in 89 patients with gliomas and 10 with normal brain tissues. Results:Upregulation of REST was related to higher World Health Organization (WHO) grade, larger tumor size, higher ki67, and higher p53 positive rate. After radiotherapy+temozolomide (RT+TMZ) treatment, low REST expression patients could get better therapeutic efficacy (P=0.031). The positive rate of REST4 expression was only 13.5% in glioma tissues, and REST4 expression was not associated with clinical characteristics and REST expression in this study. Conclusions:REST was a prognostic factor in glioma, while REST4 was not. REST expression can be a predictor in evaluating the survival outcome of gliomas patients treated with RT+TMZ after surgery.

SUBMITTER: Li C

PROVIDER: S-EPMC5968789 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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<i>REST</i>, not <i>REST4</i>, is a risk factor associated with radiotherapy plus chemotherapy efficacy in glioma.

Li Cuilin C Zou Hecun H Wang Zhifei Z Tang Xinyue X Fan Xitang X Zhang Ke K Liu Jianqiu J Li Zhi Z

Drug design, development and therapy 20180522

<h4>Background/aim</h4>Repressor element silencing transcription factor (<i>REST</i>) is a transcription repressor, expressed in several malignancies. This study aims to evaluate the prognostic values of <i>REST</i> and its splicing variant <i>REST4</i> in glioma, and investigate the potential correlation between <i>REST</i> and <i>REST4</i>.<h4>Methods</h4><i>REST</i> and <i>REST4</i> expression values were evaluated by qRT-PCR in 89 patients with gliomas and 10 with normal brain tissues.<h4>Re ...[more]

PMID: 29861627

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Project description:BackgroundEpidermal growth factor receptor (EGFR) inhibitors have shown only modest clinical activity when used as single agents to treat cancers. They decrease tumor cell expression of hypoxia-inducible factor 1-alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF). Hypothesizing that this might normalize tumor vasculature, we examined the effects of the EGFR inhibitor erlotinib on tumor vascular function, tumor microenvironment (TME) and chemotherapy and radiotherapy sensitivity.Methodology/principal findingsErlotinib treatment of human tumor cells in vitro and mice bearing xenografts in vivo led to decreased HIF-1alpha and VEGF expression. Treatment altered xenograft vessel morphology assessed by confocal microscopy (following tomato lectin injection) and decreased vessel permeability (measured by Evan's blue extravasation), suggesting vascular normalization. Erlotinib increased tumor blood flow measured by Power Doppler ultrasound and decreased hypoxia measured by EF5 immunohistochemistry and tumor O(2) saturation measured by optical spectroscopy. Predicting that these changes would improve drug delivery and increase response to chemotherapy and radiation, we performed tumor regrowth studies in nude mice with xenografts treated with erlotinib and either radiotherapy or the chemotherapeutic agent cisplatin. Erlotinib therapy followed by cisplatin led to synergistic inhibition of tumor growth compared with either treatment by itself (p<0.001). Treatment with erlotinib before cisplatin led to greater tumor growth inhibition than did treatment with cisplatin before erlotinib (p = 0.006). Erlotinib followed by radiation inhibited tumor regrowth to a greater degree than did radiation alone, although the interaction between erlotinib and radiation was not synergistic.Conclusions/significanceEGFR inhibitors have shown clinical benefit when used in combination with conventional cytotoxic therapy. Our studies show that targeting tumor cells with EGFR inhibitors may modulate the TME via vascular normalization to increase response to chemotherapy and radiotherapy. These studies suggest ways to assess the response of tumors to EGFR inhibition using non-invasive imaging of the TME.

Project description:BackgroundNon-small cell lung cancer is the most common cause of cancer death worldwide, highlighting the need for novel therapeutic concepts. In particular, there is still a lack of treatment strategies for the group of elderly and frail patients, who are frequently not capable of receiving standard therapy regimens. Despite comprising the majority of lung cancer patients, this group is underrepresented in clinical trials. This applies also to elderly and frail patients suffering from unresectable stage III NSCLC, who are unfit for chemotherapy, and, therefore, cannot receive the standard therapy comprising of radiochemotherapy and the recently approved subsequent durvalumab consolidation therapy. These patients often receive radiotherapy only, which raises the concern of undertreatment. The TRADE-hypo trial aims at optimizing treatment of this patient group by combining radiotherapy with concomitant durvalumab administration, thereby employing the immune-promoting effects of radiotherapy, and determining safety, feasibility, and efficacy of this treatment.Methods/ designIn this prospective phase II clinical trial, durvalumab therapy will be combined with either conventionally fractionated (CON-group) or hypofractionated (HYPO-group) thoracic radiotherapy. A safety stop-and-go lead-in phase will assess safety of hypofractionated radiotherapy with respect to severe pneumonitis in small patient cohorts before opening full enrollment. Tumor tissue, blood and stool samples will be collected before and during the study period to investigate the immunological mechanisms responsible for checkpoint inhibitor efficacy and immune-promoting effects of radiotherapy.DiscussionPreclinical data suggests that irradiation-induced immunogenicity can be further increased if applied in a hypofractionated setting, potentially boosting the expected synergistic effect with immune checkpoint inhibition in restoring the immune anti-tumor response. If proven safe and efficient, a hypofractionated radiation schedule can provide a considerably more practicable option for the patient. Taking into consideration the intend to develop a combination treatment strategy that can be made available to patients soon after proving to be efficient and the potentially elevated toxicity of a hypofractionated radiotherapy approach, this trial was designed as a two-trials-in-one design. An accompanying translational research program is planned striving to gain insights into the tumor-host biology and to identify suitable biomarkers to predict therapy response.Trial registrationClinicaltrials.gov , NCT04351256 . Registered 17 April 2020, Eudra-CT, 2019-002192-33 . Registered 24 October 2019.

Dataset Information

REST, not REST4, is a risk factor associated with radiotherapy plus chemotherapy efficacy in glioma.

Publications

<i>REST</i>, not <i>REST4</i>, is a risk factor associated with radiotherapy plus chemotherapy efficacy in glioma.

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