| TECHNOLOGIES
OVERVIEW |
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| A
PARADIGM SHIFT IN CANCER THERAPY |
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Most
current cancer drug evaluation strategies
have shifted from conventional cytotoxic approaches
toward specific oncogene and suppressor gene-related
targets directly involved in neoplastic transformation
and the enhanced survival of cancer cells.
The study of these processes in a living organism
has created a similar evolution in imaging
technologies. Recent advances in imaging technologies
support the preclinical use of imaging to
track a tumor’s response to therapy
at both the anatomical and the molecular (mechanism
of action) levels.
An
expanding body of data indicates that the
response of tumor cells to targeted therapies
often depends on the type of proliferative
and survival signals the cells receive from
the local environment (context matters). This
has increased interest in both orthotopic
and transgenic animal models of human cancer
for drug evaluation. The deep tissue locations
of tumors in these model systems makes the
assessment of anticancer activity difficult
without the use of anatomical imaging techniques.
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Fortunately,
advances in imaging technologies such as MRI, µCT
and µPET not only enable measurement of anticancer
activity by determination of tumor burden, but also
provide mechanistic information at the level of the
molecular target.
In
addition, the ability to optimize compounds in vivo
with imaging-derived pharmacodynamic profiles, prior
to the determination of efficacy, can dramatically speed
the cancer drug evaluation and drug discovery process
by shortening turnaround times and reducing the amount
of drug required. Finally, many of the imaging technologies
proposed to evaluate drug function preclinically can
be translated into a clinical benchmark with appropriate
validation. |
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| TUMOR
MODELS |
Heterogeneity
is a hallmark of cancer in the clinic. Similarly,
cancer models vary widely in genotype and phenotype
making no one model predictive of clinical outcome.
MIR Preclinical Services has collected over
150 syngeneic and human tumor xenograft models,
validated by its research staff and available
for client studies. Many of these models (our
core tumor models) are maintained in continual
early passage in vivo. These models encompass
tumors of essentially all major tumor types.
Click
here for list of tumor models in current passage
(core models) and endpoints offered
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| IMAGING |
Non-invasive
imaging capabilities allow MIR Preclinical Services
to detect cancers and follow treatment response,
even at the molecular level, in subcutaneous,
orthotopic, autochthonous and transgenic tumor
models. These non-invasive imaging capabilities
allow data procurement without sacrificing the
animal. This reduces the number of animals needed
for a study and allows the assessment of the
time course of drug effect. MIR Preclinical
Services can also validate the use of clinical
imaging modalities, ensuring that treatment
with the client’s compound does not alter
the interpretation of the imaging signal. Imaging
technologies available at MIR Preclinical Services
include MRI, µCT, µPET, bioluminescence
and fluorescence |
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PRECLINICAL MRI |
Studies
using preclinical MRI imaging can provide detailed information
on tumor size and heterogeneity (T1 and T2 weighted images),
an early indication of therapeutic response (Diffusion
MRI), tumor blood flow, blood volume, and vascular permeability
(Arterial Spin Labeling and Dynamic Contrast Enhanced
MRI) and other relevant parameters. MRI provides quantitative
assessments of these and other parameters with high spatial
resolution. |
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| Click
here for more information |
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PRECLINICAL CT |
MIR
Preclinical Services utilizes a first of its
kind µCT scanner for in vivo imaging.
In vivo resolution at 50 microns is routinely
achieved. Respiratory and cardiac gating can
be used for enhanced contrast and resolution
in the thoracic cavity. Soft tissue imaging,
with a suitable contrast agent, can be used
to quantify normal tissue, tumor perfusion,
and metastases. µCT is also ideally suited
for skeletal phenotyping. |
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| Click
here for more information |
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PRECLINICAL PET |
High
resolution preclinical PET (µPET) imaging
is useful in measuring the metabolic activity
of tumors. The high metabolic rate of tumor
cells cause them to uptake and store large amounts
of glucose. Using isotopically labeled compounds
like 2-deoxy-2-[18F] fluoro-D-glucose (FDG),
which becomes phosphorylated and trapped within
the cell preventing its escape, can indicate
the size, location, and metabolic rate of tumors
and metastases. Isotope labeling of other molecules
can be used to measure DNA replication and cellular
proliferation, detect drug or receptor distributions,
tissue perfusion and blood volume. Preclinical
µPET studies can be used to validate clinical
PET imaging methods. |
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| Click
here for more information |
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Bioluminescence
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Cells
or animals can be genetically altered to express
genes for activating a luminescent substrate. These
genes can be constitutively expressed to indicate
tumor burden or conditionally expressed and used
as a reporter for a specific gene or function of
interest. MIR has a number of proprietary preclinical
assays to non-invasively assess drug function usin
bioluminescence. MIR can utilize bioluminescence
to measure tumor diagnosis, cellular proliferation,
physiological changes, apoptosis, p53 activation,
Akt activation and gene expression. |
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Click
here for more information |
Fluorescence |
By tagging of cells or injectable molecules with fluorescent
probes, or by use of transgenic animals that express genes
for fluorescent proteins, tumor burden or cellular and
molecular level interactions can be quantified. By simultaneous
use of fluorescent labels in different regions of the light
excitation or emission spectrum, multiple readouts can
be obtained in a single experiment. |
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| Inflammation Services |
MIR has recently started offering inflammation services as part of its service offerings. These include preclinical models of rheumatoid arthritis and inflammation. |
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| Click
here for more information |
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| CHOOSING
A TECHNOLOGY |
MIR Preclinical Services has developed general guidelines
to assist in choosing an imaging technology
that best suits the needs of clients. Frequently
needed applications include:
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| IN
VITRO SERVICES |
MIR
is now offering basic in vivo services to broaden
the company’s offerings and provide A
greater range of services to clients. Clients
can now go directly from in vitro to in vivo
using the same model cell lines |
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| Click
here for more information |
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