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ASNR 2012
Radiogenogram: MR Imaging as a Screening Tool
for Uncovering Novel Genomic Drug Targets
Rivka R. Colen, M.D.1, Ferenc A. Jolesz, M.D.1, Pascal O. Zinn, M.D.2
1
Department of Radiology, Brigham and Women's Hospital, Boston, MA, USA.
2 M.D. Anderson Cancer Center, Houston, TX, USA.
© NlH National Center for Image Guided Therapy, 2012
Disclosures
No Disclosures.
R25 CA089017(RRC)
P41 RR019703 (FAJ)
© NlH National Center for Image Guided Therapy, 2012
Glioblastoma Multiforme
Glioblastoma Multiforme (GBM) is most common, most aggressive primary brain tumor
Despite current treatment with Surgery, Chemotherapy, and Radiotherapy, the median
survival remains < 2 years.
© NlH National Center for Image Guided Therapy, 2012
Genomic Analysis
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Gene and microRNA microarrays is a method allowing for analysis of thousands
of genomic expression events.
•
This has allowed for greater insight into gliomagenesis, treatment response, and
patient prognosis.
•
As an example, MGMT portends a better patient response to Temozolomide and
increase in pseudoprogression. Another example, IDH-1.
© NlH National Center for Image Guided Therapy, 2012
Genomic Analysis
However, otherwise, the large plethora of genomic information remains largely unused and drug development based on genomics has been limited.
This is largely due to the inability for early identification of genomic targets through
which clinically meaningful and applicable therapeutic targets can be developed.
The current selecting a genetic target to pursue after sifting through myriads of genomic
data will not necessarily result in a clinically applicable or clinical meaningful target for
drug development and this trial and error method is not cost- effective.
© NlH National Center for Image Guided Therapy, 2012
Imaging Genomics
In order to address this, we are developing MRI as a screening method, similar
to mammography, to screen genomic targets.
Given that MRI reflects both underlying biological process and tumor
microenvironment and can do a step further and be correlated with genomic
information, it can be anticipated to yield clinically meaningful and applicable
targets by which therapeutics can be developed.
Furthermore, MRI is non-invasive and cost-effective, as in the latter case done
on a routine basis in the work up of a brain tumor patient.
© NlH National Center for Image Guided Therapy, 2012
Imaging Genomics
MRI (radio) phenotypes( necrosis, edema/tumor infiltration, contrast enhancement,
perfusion, diffusion) correlated with underlying genomic composition (genes,
microRNAs, etc).
This can be correlated in a bidirectional manner as well (from genome to phenome)
© NlH National Center for Image Guided Therapy, 2012
Purpose
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In this study, we seek to validate MRI as a screening tool to screen for glioblastoma
genomic targets for subsequent pharmaceutical development of gene based
therapeutics.
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We seek to develop an efficient, cost-effective system to uncover clinically
meaningful genomic targets from the present overwhelmingly vast genomic data.
© NlH National Center for Image Guided Therapy, 2012
Methods and Materials
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Retrospective study
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Using 78 treatment naïve GBM patients with imaging data obtained
from The Cancer Imaging Archive (http://cancerimagingarchive.net/)
sponsored by the Cancer Imaging Program, DCTD/NCI/NIH,
segmentation were performed.
•
The volumes of these were then correlated with Gene- and
micoRNA- expression profiles obtained from The Cancer Genome
Atlas (TCGA).
© NlH National Center for Image Guided Therapy, 2012
Methods and Materials
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Image Analysis was done in Slicer 3.6 (slicer.org) using the Segmentation module
- T2/FLAIR was registered to the post- contrast T1WI.
- Volumetric segmentation was performed in a simple hierarchical model of
anatomy, proceeding from peripheral to central.
- 3 distinct structures were segmented:
• edema/invasion
• enhancing tumor
• necrosis
© NlH National Center for Image Guided Therapy, 2012
Methods and Materials
Tumor Segmentation. 65 year old male patient with a right temporal GBM. Segmentation of tumor edema (blue),
enhancement (yellow) and necrosis (red) was performed and edema volume was obtained.
© NlH National Center for Image Guided Therapy, 2012
Methods and Materials
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Image Genomic- Biostatistics analysis
- 12,764 genes and 555 microRNAs were analyzed (Affymetrix/Agilent chip
technology) in each patient and correlated to selected imaging radiophehotypes
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Comparative Marker Selection (Broad Institute) identified preferentially upregulated
genomic events in one vs. another predefined patient group (high_low volumes
groups in each radiophenotype)
Low (left) and High (right) FLAIR phenotype (colored in blue) reflecting tumor infiltration/edema
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Results
Screening done using the MRI-FLAIR radiophenotype identified genes and microRNAs
involved in tumor infiltration/edema. These are concordant with the underlying
biological processes evaluated on MRI in the edema/tumor infiltration zone as
depicted by the non-enhancing T2/FLAIR hyperintensity in the surrounding
peritumoral region.
© NlH National Center for Image Guided Therapy, 2012
Results
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Our MRI screen identified top upregulated and down regulated genes and
microRNAs which were novel and not previously described in the literature. These
were concordant with the underlying biologic processes of edema/invasion,
necrosis, and enhancing tumor MRI phenotypes.
• In some cases, the gene expression was a stronger prognostic variable than
either molecular subtype (as defined by Veerkak and colleagues) in the Cox
proportional hazards ratio (P = 0.0001).
•
In vitro and in vivo animal models as well as loss and gain of function models
subsequently confirmed the genomic target’s function which was concordant with
the underlying biologic processes measured by MRI.
© NlH National Center for Image Guided Therapy, 2012
Results
In vitro and in vivo studies in mice confirmed these genomic targets.
© NlH National Center for Image Guided Therapy, 2012
Conclusion
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MR imaging is an effective screening tool to uncover clinically meaningful
genomic targets that can be used in drug development of therapeutic targets for
GBM treatment.
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Effectively, MRI used in this way, we have termed this the Radiogenogram.
© NlH National Center for Image Guided Therapy, 2012
Conclusion
Thank you for your interest!
Acknowledgements: This work was supported by NIH grant R25 CA08901706A2 (RRC).
Any questions please email: [email protected].
© NlH National Center for Image Guided Therapy, 2012