X Biomarks the Spot: Imaging Biomarker Development and Validation in Preclinical Drug Development

by Patrick McConville, Director for Global Discovery and Imaging at Charles River Laboratories

Imaging biomarkers are seeing unprecedented levels of use. They potentially enable non-invasive means of assessing mechanistically and clinically relevant properties of many diseases including cancer, arthritis, atherosclerosis and other cardiovascular diseases and neurodegenerative conditions. Imaging biomarkers include any anatomical, physiological or molecular parameter detectable by one or more imaging methods, and are used to establish the presence and severity of disease.1 Imaging biomarkers leverage imaging by providing spatial resolution and local tissue concentrations or magnitude for the measured parameter.    

The discovery and development of image-based biomarkers primarily resides in basic research labs in academia and industry. This discovery work can be centered in traditional chemistry, for example, through development of molecular imaging molecules, or probes, that target disease relevant properties. Alternatively, this work could be centered in more mathematically driven endeavors to discover and develop disease-relevant parameters based on modeling of image intensity changes. Discovery of the biomarker in this case relies on proving correlation of the mathematically derived imaging parameter with disease progression. 

While discovery of promising biomarkers is the initial critical step in the process of imaging biomarker introduction, equally important is the development and validation of the biomarker, which can occur only through rigorous testing and broad application in disease models. The aim of this process is to reach the goal of image biomarker qualification and, furthermore, acceptance of the biomarker for use as a surrogate marker--a biomarker that can be used as a substitute for a clinically meaningful disease end point1.

The process of biomarker qualification is not yet well defined, but generally refers to acceptance by the field and regulatory institutions that the marker in question can be used as a standard measure of disease progression or response. This would presumably occur in a specific disease model or indication and possibly in the context of specific treatment classes. Underlying the qualification process is extensive testing in statistically powered studies to validate the biomarker-based endpoints against accepted traditional methods or gold-standard endpoints such as those derived from histopathology. 

There are numerous current examples that illustrate the above concepts. For instance, inflammation is now recognized as playing a major role in a wide variety of diseases including rheumatoid arthritis, atherosclerosis and cancer. Nanoparticles that are actively taken up by specific inflammatory cells (eg, macrophages) and that contain image-based contrast moieties, can be used as biomarkers for acute inflammation. By intravenously injecting inflammatory cell-targeted, contrast-containing nanoparticles into a biological system, researchers can then use imaging methods to generate maps of inflammatory cell accumulation at specific sites. These images can be used to quantify the disease process at the mechanistic level, early in the process of the disease progression. For example, fluorine (19F) magnetic resonance imaging using 19F based nanoparticles has been demonstrated for this purpose2.

A new generation of fluorescent optical imaging reporters, some of which may be clinically translatable, are also seeing increased use.  With the current rapid rates of application and validation of these probes, a suite of drug-research tools will result in the next five years. These include probes targeted to specific receptors and cell surface markers, and probes activated by specific molecules relevant to a disease process. For example, cathepsins and matrix metalloproteinases (MMPs ) are known to play a crucial role in inflammatory diseases such as arthritis, tumor development and atherosclerosis. Optical reporter probes activated by cathepsins3 and MMPs are now available and may provide earlier and more sensitive methods for tracking disease progression, especially in deep tissues that are difficult or impossible to access through non-invasive means. 

Imaged-based biomarkers are also showing rapidly expanded utility in oncology research. For example, abnormal proliferation is a general property of cancer cells and therefore a potentially broad and specific target for assessment of tumor progression and response to therapy.  [18F]-FLT is a developmental positron emission tomography (PET) imaging tracer that is taken up into actively proliferating or multiplying cells4. Following intravenous injection of [18F]-FLT in a patient or research animal, a PET image can be used as a three-dimensional map of cellular proliferation in tumor tissue, providing a method for assessing treatment response for patient care, and assessing efficacy in preclinical and clinical drug development. [18F]-FLT PET can be sensitive enough to image the dynamics of drug action just hours after a single therapeutic dose of a drug that inhibits cell proliferation. As a result, [18F]-FLT PET based biomarkers can help both quantify the effectiveness of the drug as well as provide information on the duration of the drug effect after each dose.

While non-invasive imaging came to prominence initially as a diagnostic tool, the last decade has seen rapid advances in translating traditional diagnostic methods to enable imaging of functional, physiological and molecular processes. Current trends are recognizing the need for standardization of the most promising imaging protocols and biomarkers, to ensure broad acceptance by researchers across academic, industry and regulatory institutions. New consortia are dissecting the process of imaging biomarker validation and protocol standardization, and now recognize the critical importance of validation to drug development, perhaps even more so than the discovery of, and early proof of principle for, the technology itself.  

The above examples demonstrate a few of the promising image-based biomarkers that have been discovered over the last five to ten years. While these examples highlight the unique capabilities of non-invasive imaging, they also highlight the lack of well validated imaging biomarkers, as all of these biomarkers are still developmental. They have not reached the point of qualification or of being considered surrogate markers. 

As increasing numbers of reliable image-based biomarkers are developed and, importantly, validated and qualified, the opportunity for producing effective therapeutics will increase through enabling of more informed decisions at earlier stages in drug development. The future will see a new generation of validated, well understood and accepted imaging biomarkers and introduction of new image-based surrogate markers. In an industry where appropriate early decisions drive efficiency and success, validated, translatable disease-relevant biomarkers are invaluable.

References

1. Biomarkers and Surrogate Markers: An FDA Perspective Russell Katz. NeuroRx, 1(2): 189-195 (2004).

2. Ahrens E. T., Flores R., Xu H., Morel P. A. In vivo imaging platform for tracking immunotherapeutic cells. Nat Biotechnol, 23(8):983-987 (2005).

3. Korideck, H. and Peterson, J. D. Noninvasive quantitative tomography of the therapeutic response to dexamethasone in ovalbumin-induced murine asthma. J Pharmacol Exp Ther, 329(3):882-889 (2009). 

4. Barwick, T., Bencherif, B., Mountz, J. M., Avril, N. Molecular PET and PET/CT imaging of tumour cell proliferation using F-18 fluoro-L-thymidine: a comprehensive evaluation. Nucl Med Commun, 30(12):908-917 (2009). 

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