Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT02904525 |
| Other study ID # |
268/14 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
June 2015 |
| Est. completion date |
April 30, 2021 |
Study information
| Verified date |
January 2021 |
| Source |
Centre Hospitalier Universitaire Vaudois |
| Contact |
Andreas F Hottinger, MD-PhD |
| Phone |
+41 21 314 0168 |
| Email |
andreas.hottinger[@]chuv.ch |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Despite maximal safe surgery followed by combined chemo-radiation therapy, the outcome of
patients suffering from glioblastoma (GBM) remains extremely poor with a median survival of
15 months. Hence, new avenues have to be taken to improve outcome in this devastating
disease. Given their intracerebral localization and their highly invasive features, GBM pose
some specific challenges for the development of adequate tumor models. Orthotopic xenograft
models directly derived from the tumor of a patient might represent an attractive perspective
to develop patient-specific targeted therapies. This approach remains however to be validated
for GBM as it offers specific challenges, including the demonstration that the properties of
xenograft models validly represent treatment relevant features of the respective human
tumors.
In this innovative project the investigators aim to compare and validate an approach of
paired human GBM and respective derived orthotopic xenografts in the mouse brain on the
levels of radiological behavior and metabolism of the tumors, as determined by high
resolution MRI of the patients (7T MRI) and the respective orthotopic mouse xenografts (14.1T
MRI), as well as on the level of the transcriptome, genome, and methylome of the original GBM
tissue and respective derived xenografts/glioma sphere lines. The data will be integrated in
multidimensional analyses and interrogated for similarities and associations with molecular
GBM subtype.
This pilot project will provide the basis for the crucial next steps, which will include drug
intervention studies. New promising drugs, tested pre-clinically in the mouse orthotopic
xenograft models established here using the radiologic/metabolic/molecular procedures
described for this project, will be taken into patients in phase 0 studies. GBM patients will
receive radiologic/metabolic follow-up using high resolution MRI under drug treatment,
followed by resection of the tumor and subsequent acquisition of molecular data.
Description:
The presented project will focus on the evaluation of a multimodal approach comparing human
GBM to paired samples of orthotopic xenografts using high resolution MRI and MRS and
multidimensional molecular profiling.
20 patients with a high probability for newly diagnosed GBM based on MRI-scan ( 3 Tesla (3T)
MRI, T1, T2, T1 gadolinium, DWI & MRI Spectroscopy) will be identified in the CHUV prior to
undergoing neurosurgical resection. Patients will undergo extensive experimental radiological
examination using specific MRI sequences on the 7 Tesla (7T) MRI to identify specific
metabolic pathways (see below, section on imaging). Thereafter patients will undergo maximal
safe neurosurgical resection of their tumors. The portion of the tumor that is not used for
diagnostic purposes will be collected immediately for further use (see below, section on
molecular evaluations). Following resection, patients will undergo standard of care treatment
[usually combined radio-chemotherapy, or will be offered participation in a clinical trial.
The clinical parameters will be collected, including histopathological features and the
evolution and growth pattern of the residual tumor (if present), or the development of
recurrences will thereafter be compared to the parameters and evolution of the xenograft
models.
At high magnet field strength (7T), high signal-to-noise ratio and increased spectral
dispersion allow more reliable measurement of a large number of metabolites using Magnetic
Resonance Spectroscopy in comparison to clinical available field strengths (3T and below). In
addition, the authors have developed a full sensitivity short-echo-time single voxel
spectroscopy (SVS) sequence "semi-adiabatic SPECIAL"(2) which was implemented, validated at
7T and allows the quantification of 15 metabolites with high precision including
N-acetylaspartate(NAA), glutamine(Gln), glutamate(Glu), myo-inositol(Ins),
phosphorylethanolamine(PE), total choline(tCho), creatine, phosphocreatine,
N-acetylaspartylglutamate(NAAG), lactate(Lac), glutathione(GSH), aspartate (Asp),
taurine(Tau), scyllo-inositol and γ-aminobutyric acid(GABA). This localization technique was
further extended to a MR Spectroscopic Imaging (MRSI) technique at 7T, which allows mapping
of the spatial distributions of cerebral metabolites. Furthermore, glycine is a possible
marker for tumor malignancy and its detection in vivo has been established in our previous
study using TE=30ms with SPECIAL sequence at 7T. Therefore, in this study the aforementioned
techniques will be used to obtain the neurochemical information and its spatial distribution
in the glioblastoma of the patients. These data will be further compared with the
neurochemical information obtained in the orthotopic xenografts in the mouse brain derived
from the respective glioblastoma patient.
All MRS measurements of glioblastoma patients will be performed on a 7T MR scanner with a CP
Transmit / 32 channel receive array head coil. Based on the high resolution T1-weighted
images obtained using the MP2RAGE sequence, Volume of Interest (VOI) for spectroscopy will be
placed according to the location of the glioblastoma. Total acquisition time of MRS will be
within 30 min. In vivo MRS spectra will be post-processed and metabolite concentrations will
be quantified to create metabolite maps.
Molecular and functional investigations of paired samples of primary glioblastoma and
respective orthotopic xenografts in the mouse
The aim of the present study is to determine the molecular, histopathological, and functional
properties, including growth patterns such as invasiveness, of the original GBM and the
respective derived orthotopic xenografts in the mouse, and link them to imaging/ metabolism
parameters obtained by high resolution MRI.
GBM samples from patients collected at surgery will be divided into 2 parts, (i) snap frozen
for molecular analyses, and (ii) cultivated under stem cell conditions for subsequent
stereotactic transplantation into male immune-compromised mice and establishment of sphere
lines.
