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Invited Abstract (Plenary Session): The Emerging Impact of Novel Preclinical Models

Molecular imaging in preclinical and clinical drug development.

University of Michigan, Ann Arbor, MI

Abstract

PL-08

There is an important need for imaging approaches which can provide accurate and timely quantitation of cancer therapeutic response. Currently, therapeutic response is assessed by monitoring changes in tumor volume using anatomical MRI. Earlier and more sensitive/predictive methods to determine treatment efficacy during treatment would be extremely valuable. Since many therapeutic agents such as chemotherapy are frequently given in fractionated cycles, an early assessment of therapeutic response during the initial phase of administration would provide an opportunity to guage the dosage effectiveness and also provide feedback related to the dosage frequency which would greatly facilitate planning of additional dosage protocols. In this regard, largely untapped potential resides in MRI methods known to be sensitive to tissue structure at the cellular level. Such information may be derived via quantitation of tissue properties that are reflective of dynamics in the microscopic environment. During the course of successful therapeutic intervention, changes in cellular structure and physiology occur which precede macroscopic changes such as decreases in the overall tumor volume. The diffusion of water in tissue is strongly affected by the viscosity of intra- and extra-cellular fluids, membrane permeability, active transport and flow, and directionality of cellular structures that enhance or impede its mobility. As cells are damaged and killed by therapeutic interventions, the integrity of cell membranes are compromised and the fractional volume of the interstitial space may increase due to apoptotic body formation and cell loss. Damage to tissue microvasculature may also lead to vasogenic edema thereby reducing the viscosity of the interstitial fluid and increasing the volume of extracellular water. Thus, the water mobility within a tumor will increase over time following treatment and the magnitude of the change will be related to the effectiveness of the therapy which will result in membrane damage with a subsequent reduction in cell density as shown diagramatically. The diffusibility of tissue water <i>in vivo</i> can be accurately and non-invasively quantified as an apparent diffusion coefficient (ADC) using diffusion MRI. Each voxel within the tumor is described by a single ADC value and all of the voxels can be plotted in a histogram format (right panels) to provide for a quantitative and visual readout of how the tumor diffusion values change over time following therapeutic intervention. The ability to monitor the movement (diffusion) of water using MRI can be accomplished by making the MR signal intensity dependent on water mobility by the application of additional pulsed magnetic field gradients incorporated within the normal MRI sequence. Individual nuclear spins of the tumor water molecules accumulate a phase shift in proportion to their spatial position in these additional gradient fields. After waiting a given evolution time for spins to diffuse, a second gradient pulse is applied to completely refocus stationary spins. The spin of the water molecules which have diffused during the evolution time do not experience an equivalent compensetory pulse and are therefore refocused incompletely. Thus, the paired gradient pulses attenuate signal in proportion to local tissue water mobility. Quantitative measurements of ADC values are obtained by measuring signal attenuation as a function of varying gradient strength and evolution time. This presentation will provide example of using diffusion MRI and other molecular imaging tools for tumor treatment assessment in both the pre-clinical and clinical settings.