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European Biopharmaceutical Review
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Developments in magnetic resonance imaging, bringing higher magnet
strengths and more sophisticated analysis methods, are establishing the
technology as a desirable alternative for the discovery of biomarkers
and early proof of concept studies.
One of the most important unmet needs in drug discovery, as well as the
delivery and monitoring of new medicinal entities, is the development of
new biomarkers that can be used as surrogate endpoints to assess a
therapeutic effect. Beside genetic and invasive methods, imaging
techniques are recognised to be essential tools for drug discovery,
development and evaluation. Most prominently, positron-emission
tomography (PET) is utilised in this context to radioactively label and
study drugs and targeted molecules in the organism in question. However,
magnetic resonance imaging (MRI) presents an alternative, as it is
non-invasive and can be used for longitudinal studies without being
limited by radiation exposure.
MRI techniques to assess tissue states are continuously evolving and so
is the potential impact of MRI on pharmacology. MRI is of most value at
three distinct stages in the process of drug discovery: understanding
disease; investigation of mechanisms of drug action; and providing
quantitative markers of drug action, or endpoints, in candidate
compounds for the clinic.
Understanding the Disease and Target Identification
Since its inception in the 1980s, MRI has quickly become indispensable
for clinical imaging. MRI is a versatile tool to assess tissue
composition and function, and by manipulating magnetisation allows
different tissue features to be probed. Due to this flexibility, MRI is
increasingly used to diagnose diseases and to monitor disease
progressions and the success of interventions.
In neurology (for example stroke, multiple sclerosis, epilepsy,
Parkinson and Alzheimer’s diseases), MRI plays a crucial role in
detecting diseases before clinical symptoms appear, allowing more
effective treatment. In addition, it allows differentiating of diseases
with similar symptoms (differential diagnosis) and monitoring disease
progression. In musculoskeletal imaging, the goal of MRI is to detect
damages to joints at the interface of general tissue and bones (muscle,
menisci, bone, tendon, ligaments, spine and so on). MRI is particularly
important in these disorders because of the various image contrasts
available to shed light on the type and origin of the damages. Cardiac
magnetic resonance imaging has become a routinely used imaging modality
for the diagnosis of ischaemic heart disease and non-ischaemic
cardiomyopathies, and can provide non-invasive evaluation of reperfusion
therapy through comprehensive evaluation of wall motion, global
function, perfusion and viability due to its excellent spatial
resolution, reproducibility and safety.
MRI also plays an important role in the diagnosis and management of
cancer. MRI is used non-invasively to obtain information on the location
and extent of cancer, as well as assessments of tissue characteristics
(such as hypoxia, apoptosis, necrosis and tumour vasculature) that can
monitor and predict treatment response.
Target identification and elucidation of mechanisms of action can also
be tackled using MRI. The development of molecular imaging methods, such
as MR spectroscopy (MRS), has allowed the further elucidation of
multiple mutations and dysregulatory effects of pathways leading to
oncogenises. It is of crucial importance to develop imaging methods to
optimise the design, dosage and schedule of novel therapeutic and
pharmacological approaches. For example, an aberrant choline
phospholipid metabolism and enhanced flux of glucose derivatives through
glycolysis, which sustain the redirection of mitochondrial ATP to
glucose phosphorylation, are two major hallmarks of cancer cells. MRS
provides an excellent tool to monitor these processes and the effect of
anticancer drugs as choline, phosphor, ATP and other metabolites are
measured with this technique, both in vivo and in vitro (1).
Another emerging field of pharmacological MRI is functional MRI (fMRI)
in neurology. Functional neuroimaging has the potential to improve the
decision-making process in the development of new drugs. It probes the
neuronal activity following a behavioural task and the alteration of
neuronal activity following a drug administration. With the high cost of
failure of compounds in later stages of development, there is a need to
establish, early in humans, reliable measures of drug activity and
efficacy in the brain. fMRI is helping us to understand therapeutic
mechanisms and can provide clinically relevant markers of disease
responses to drugs. Thus, for the field of diseases in the central
nervous system (CNS), fMRI can add additional information to evaluate
drug effects on cognitive and sensory brain functions.
In addition, measuring blood flow not only in the brain, but also in
other body parts (for example heart, kidney), using contrast agent
techniques or arterial spin labelling, provides information about the
level of metabolism and blood vessel integrity. These methods provide
valuable information for the effect and efficacy of drug actions.
Functional Biomarkers: from Preclinical Models to Patient Stratification
The biomarker concept is an important one in drug discovery because of
the need to measure the relevant responses of drug intervention. For
imaging biomarkers to be useful, they need to identify patterns that can
be correlated with biological events with the aim of validating novel
drug targets and predicting drug responses. Specifically, clinically
relevant biomarkers are needed to inform the therapeutic development of
candidate drugs and in demonstrating significant drug effects for the
purposes of regulatory approval (2). For example, MRI could become a
powerful tool in patient stratification. By differentiating diverse
patient populations based on clinical imaging, and then carrying out
clinical trials within those stratified patient populations, the
significance of results could be greatly enhanced – with the added
benefit of shorter, smaller, more focused trials.
In the near future, fMRI is likely to be of great value to the
pharmaceutical industry in early proof-of-concept studies for novel
therapies. Imaging biomarkers, especially those with clinical relevance,
would be used to prioritise the application of resources in drug
discovery. For example, the correct choice of dose in large, and by
implication costly, late-phase clinical trials can be crucial to their
success. At a given dose, fMRI can be used to demonstrate a drug effect
in the CNS that correlates with behavioral reports such as those
reported in treatment of depression. Robust fMRI imaging biomarkers,
because of their application in humans, could potentially provide much
more relevant data than animal models, and thus better inform the
subsequent design of clinical trials (3).
However, pharmacological fMRI in animals can complement and provide more
extensive physiological data than human investigations. fMRI can
provide comparative measures between animal and human, potentially
validating an animal model or assessing the relevance of an animal model
once the compound is tested on man.
It is important to remember, however, that in addition to interspecies
differences, there will necessarily be methodological differences
between pharmacological studies performed in small animals and man.
Probably the most significant of these, in influencing data
interpretation, is the need for anaesthesia in most animal studies,
which produces its own fMRI-pharmacological interactions (4). This
places limits on the usefulness of preclinical animal models with fMRI
in drug discovery and, therefore, highlights the value of
pharmacological fMRI studies for drug development in man.
Bigger and Better
As already discussed, imaging, combining high-resolution spatial
information with specific functional and molecular information, is
making important inroads in producing new biomarkers. High field
magnetic resonance imaging is capable of detecting subtle morphological,
functional or even metabolic changes based on the detection of
endogenous contrast. To overcome the inherent sensitivity limitation of
magnetic resonance imaging (MRI) and magnetic resonance spectroscopy
(MRS), increasingly stronger magnetic field strengths are being used to
boost signal to noise. MRI systems based on magnetic field strengths of
7T and higher have recently been introduced to further increase the
sensitivity and specificity of clinical magnetic resonance applications.
Currently, more than 50 ultra high field MRI systems have been installed
worldwide in clinical research centres exploring new techniques that
can be used for the noninvasive, in vivo tissue characterisation and opening up a range of possibilities with implications for medical diagnosis and treatment (5).
When looking at brain anatomy, for example, the potential to improve
spatial resolution to a range of 100-200μm will enable visualisation of
different layers of the cerebral cortex, with impact on the diagnosis of
diseases such as early dementia, epilepsy and small-vessel stroke, as
well as understanding of vascularisation, myelin pathology and other
phenomena. Furthermore, microbleeds can be identified, oxygen saturation
quantified and vasculature mapped via techniques such as susceptibility
weighted imaging. In addition, studies have already shown huge benefits
for body imaging, for example in prostate and breast imaging.
In terms of brain function, the enhanced signal-to-noise ratio (SNR)
enables higher resolution (sub-millimetre) functional imaging. This
leads to the possibility of columnar-level imaging, providing insights
about the ‘neuronal code' within specific brain regions. In addition,
the increased contrast optimises the relative impact of physiological
noise, aiding our ability to probe the mechanisms associated with
behaviour, learning and brain development.
Another key advantage of moving to ultra-high field is the improvements
seen in (functional) spectroscopy – brought about by the higher
sensitivity and specificity (spectral dispersion). As a result, it is
possible to reliably identify many metabolites that are invisible with
standard MRI. This opens up many opportunities for oncology,
psychopharmacology and other disciplines.
Conclusion
MRI is already an important weapon in the arsenal of the biotech
community. The ongoing interest from the biotech and pharma communities
in applying MRI to drug discovery indicates that the role of the
technique is likely to continue to expand greatly over the coming years.
Most of the major corporations are embracing this technology via
academic collaborations or by establishing it in-house. The continued
evolution of this technology to higher field strengths, coupled with
more sophisticated analysis methods, enables ever more subtle
understandings to be elucidated.
References
- Glunde K et al, Choline metabolism in malignant transformation, Nature Review Cancer 11: pp835-848, 2011
- Frank R and Hargreaves R, Clinical biomarkers in drug discovery
and development, Nature Review Drug Discovery 2: pp566-580, 2003
- Wise R and Tracey I, The role of fMRI in drug discovery, Journal of Magnetic Resonance Imaging 23: pp862-876, 2006
- Austin V et al, Confounding effects of anesthesia on functional activiation in rodent brain, Neuroimage 24: pp92-100, 2005
- van der Kolk A et al, Clinical applications of 7T MRI in the brain, European Journal of Radiology, 2011
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