The Role Of DCE-MRI In Drug Discovery Support

By Olga Kubassova, PhD, CEO and founder, Image Analysis ltd.

Medical imaging has become an integral part of clinical trials as a mean of diagnosing and assessing disease progression. Traditional imaging methods provide detailed structural information, but lack the ability to provide functional information. Novel functional imaging techniques quantify real-time physiologic and metabolic processes at the cellular or molecular level that supplies valuable information to detect and assess stage of the disease, select and monitor treatment, gauge prognosis, and measure outcomes. Such imaging endpoints have become one of the primary biomarkers for all phases of new drug discovery.

Dynamic contrast-enhanced MRI (DCE-MRI) is a sequence of MRI designed to show the functional information about highly perfused, e.g. vascular tissues such as a tumour or local inflammation. In DCE-MRI, images are taken sequentially over time after an intravenous injection of the contrast agent. The concentration of the contrast agent is measured when it passes from the blood vessels to the extra-cellular space of the tissue (it cannot enter the cells) and returns to the blood vessels.

In clinical oncology trials, the ability of DCE-MRI to assess blood flow in terms of degree and rate of early tumour contrast enhancement is increasingly used as an indication of tumor vascularity. Since tumors need to be near a blood supply to metastasize, vascular disrupting agents are a new class of anti-cancer drugs designed to prevent nutrient supply to the tumor, thereby leading to the necrosis of solid tumors such as breast cancer, prostate tumour, carcinomas, cervix cancer or colorectal tumors. These anti-angiogenic agents can be effective anti-tumor therapies, particularly in combination with other drugs. Vascular changes can be observed and quantified with DCE-MRI, which allows earlier assessment of drug efficacy and saves time and money in the drug development process.

Another attractive role of DCE-MRI in drug discovery is to assess the early response of autoimmune inflammatory diseases such as Rheumatoid Arthritis. Despite MRI-based biomarkers are not approved by FDA or EU’s equivalent EMEA as the end-points in clinical trials, there is an obvious need for this since the use of X-ray does not allow early detection of treatment effect and requires more patients (who receive radiation) to participate in the trial to get statistically significant results. Since the cost of a clinical development for a single compound can amount to hundreds of millions of dollars , it is crucial to know if the treatment is working as early as possible.

In inflammatory joint diseases, such as Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis and often Osteoarthritis, MRI provides more than twice the sensitivity in measuring bone erosion compared with X-radiography. A complete MRI protocol with a DCE-MRI sequence permits visualise the earliest inflammatory changes. The latest research confirms that the use of DCE-MRI in studies increases the study’s discriminative power and helps reduce the number of patients and study sites. Furthermore, use of DCE-MRI helps shorten drug development time, as the efficacy can be accurately demonstrated within much shorter time than with conventional radiography.

Many studies have evaluated DCE-MRI results as predictors of clinical outcomes, including treatment response to chemotherapy in tumours and Disease-modifying anti-rheumatic drugs (DMARDs) and biological treatments for Rheumatoid Arthritis. DCE-MRI results have also been compared to conventional diagnostics as predictive biomarkers. Some studies have shown vascular changes on serial DCE-MRI to be predictive of disease progression and/or malignant transformation of tumors.

Successful integration of functional imaging techniques such as DCE-MRI in a clinical trial requires thoughtful orchestration and rigorous standardization to reduce variability. Functional acquisition techniques that might be employed in trials, variability in technology across sites, and the nature of image-derived information require a different approach to quality assurance than is generally employed in therapeutic trials. For example, most DCE-MRI protocols include test-retest procedures to ensure similar levels of contrast accumulation and exam reproducibility. Adequate site training, patient selection, MRI scanner set up, imaging protocols, definition of region of interest, quality control of images and image analysis are key in making strategic go / no go decisions on the future development of the drug, via early phase clinical trials.

Despite challenges to employing DCE-MRI, this imaging method has a promising future in drug development trials. As the number of imaging endpoints involved in various phases of clinical trials is rapidly growing, DCE-MRI will be increasingly employed and its role will become better established over time. Ultimately, DCE-MRI will prove to be a widely recognized and reliable predictive biomarker for clinical outcomes.

Dr. Olga Kubassova is founder and CEO of Image Analysis Ltd (www.ImageAnalysis.org.uk), which performs quantification of MRI and supports clinical studies and trials in oncology and inflammatory conditions where MRI is used as a marker for treatment effect assessment.