TECHNOLOGIES OVERVIEW
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A PARADIGM SHIFT IN CANCER THERAPY

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.

This is a figure showing how preclinical imaging such as positron emission tomography (PET) , magnetic resonance imaging (MRI), computed tomography (CT) and bioluminescence has developed along with new philosophies in approaching drug discovery.  The use of preclinical imaging is becoming more prominent as a tool for drug development.  Biomarkers in translational medicine are also key parts of drug discovery that are increasing the demand for preclinical imaging technology.

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.

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

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

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.

Preclinical magnetic resonance imaging (MRI) is the most dynamic imaging technology that MIR Preclinical Services offers.  MRI is not only capable of anatomical imaging deep in tissues, but also at measuring a number of biological events (angiogenesis, tumor volume, tumor growth, joint integrity, etc.) and generating biological endpoints that are quantitative and clinically translatable.  Many service providers offer preclinical services with equipment that has low resolution and are not capable of generating these endpoints.  MIR uses a 7 Tesla preclinical MRI system that is capable of 50 micron resolution and function imaging.
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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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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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Bioluminescence

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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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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CHOOSING A TECHNOLOGY
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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updated:  4/30/08