Disease Progression and Treatment-induced Alterations in Glioblastoma

Analysis of Disease Progression and Treatment-Induced Alterations in Glioblastoma - an Integrative Morphological and Molecular Approach

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.

Study Overview

• Status: Unknown
• Conditions: Brain Tumor
• Intervention / Treatment: Genetic: analyze systematically morphological and molecular changes associated with glioblastoma progression and therapy-resistance

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 Type: Observational
• Enrollment (Anticipated): 60

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medical University of Vienna, Institute of Neurology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

All newly diagnosed GB patients will be identified in the Austrian population since 2007 - after the current firstline therapy has become standard, in order to warrant a homogenously treated patient cohort. GB patients with multiple resections will be identified.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Glioblastoma; 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.	Genetic: analyze systematically morphological and molecular changes associated with glioblastoma progression and therapy-resistance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Morphology- based analysis	Histopathological workup and evaluation	24 months
Molecular analysis	Assessment of genomic alterations at DNA-, RNA- and methylation level	24 months

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Investigators: Principal Investigator: Adelheid Wöhrer, MD PhD, Medical University Vienna

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (Anticipated): December 1, 2017
• Study Completion (Anticipated): December 1, 2017

Study Registration Dates

• First Submitted: May 22, 2014
• First Submitted That Met QC Criteria: May 28, 2014
• First Posted (Estimate): June 2, 2014

Study Record Updates

• Last Update Posted (Actual): March 22, 2017
• Last Update Submitted That Met QC Criteria: March 21, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: glioblastoma; progression; morphological and molecular changes; therapy-resistance
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Disease Progression; Glioblastoma
• Other Study ID Numbers: KLI 394