Disease Progression and Treatment-induced Alterations in Glioblastoma

• Conditions: Brain Tumor
• Interventions: Genetic: analyze systematically morphological and molecular changes associated with glioblastoma progression and therapy-resistance

• Registration Number: NCT02152748
• Lead Sponsor: Medical University of Vienna

Brief Summary

Summary of scientific evidence and rationale of this project:

Integrative molecular-genetic approaches have provided important insights in the biology of glioblastoma. It has meanwhile become clear, that glioblastoma is not a single tumor entity but comprises different molecular subtypes, which are associated with a distinct genetic/epigenetic signature and prognosis. Multimodal treatment approaches combining radio- and chemotherapy as well as the recent introduction of novel antiangiogenic agents have resulted in increasing survival times and improved quality-of-life of glioblastoma patients. Yet, despite these intense treatment efforts the therapeutic efficacy in glioblastoma patients is limited, leading in virtually all cases to tumor recurrence and death of the patients.

As only a limited fraction of glioblastoma patients undergo second neurosurgery at tumor recurrence (\< 10%), post-therapeutic samples are rare and no systematic, large-scale studies exist, which address post-therapeutic morphological and molecular alterations in glioblastoma tumor tissue. Yet, these data would help to improve the understanding of mechanisms involved in therapy-resistance and tumor progression, to develop new therapeutic approaches and could pave the way for personalized treatment strategies.

Detailed Description

Objectives of the project:

The aim of this study is to analyze systematically morphological and molecular changes associated with glioblastoma progression and therapy-resistance in matched pre- and post-therapeutic glioblastoma samples.

The following primary aims will be addressed:

1. Morphological characterisation of changes in a large series of matched glioblastoma tissues pertaining to i. Vascularization and hypoxia-mediated factors ii. Tumor necrosis and chemoradiation-induced necrosis iii. Inflammatory response iv. Tumor cellularity and proliferation v. Tumor cell phenotype after treatment e.g. glial-mesenchymal transition

2. Molecular analyses

i. Transcriptomic, DNA methylation and genomic profiling will be performed to detect changes in gene expression, methylation and copy number aberrations in post-therapeutic as compared to pre-therapeutic tumor tissue. ii. The relationship between the transcriptomic, DNA methylation and genomic profiles will be analyzed.

3. Exploratory analysis of associations between morphological and molecular changes in a screening set of 30 glioblastoma cases (with available fresh frozen tissues at first and second surgery) and subsequent validation of relevant findings in a larger glioblastoma cohort (150 cases with matched formalin-fixed paraffin-embedded tissues) by appropriate methods including immunohistochemistry, fluorescence-in-situ-hybridization, and sequencing.

4. Special attention will be paid to gender-specific patterns of therapy-related changes and tumor progression.

Study Timeline

• Study Start: 2014-04
• Study First Submitted: 2014-05-22
• Study First Submitted QC: 2014-05-28
• Study First Posted: 2014-06-02
• Status Verified: 2017-03
• Last Update Submitted: 2017-03-21
• Last Update Posted: 2017-03-22
• Primary Completion: 2017-12
• Study Completion: 2017-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: Not specified
• Target Recruitment: 60

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Glioblastoma	analyze systematically morphological and molecular changes associated with glioblastoma progression and therapy-resistance	The aim of this study is to analyze systematically morphological and molecular changes associated with glioblastoma progression and therapy-resistance in matched pre- and post-therapeutic glioblastoma samples.

Primary Outcome Measures

Name	Time	Method
Molecular analysis	24 months	Assessment of genomic alterations at DNA-, RNA- and methylation level
Morphology- based analysis	24 months	Histopathological workup and evaluation

Trial Locations

Locations (1)

Medical University of Vienna, Institute of Neurology; 🇦🇹 Vienna, Austria