Malignant gliomas are among the best-vascularized tumors and include glioblastoma multiforme (GBM), for which prognosis remains extremely poor and for which novel therapeutic modalities are required. The mortality surrounding the diagnosis of glioblastoma multiforme (GBM) can be attributed in part to the robust angiogenesis associated with this tumor. Angiogenesis is an essential component of tumor progression, and effective anti-angiogenic compounds, may offer particular promise. By definition, the angiogenic process involves interaction between tumor and host, and hence ultimately must be evaluated in in vivo models.
Specific Aim 1 is to develop and adapt perfusion MRI methodologies for the purpose of noninvasive evaluation of the evolving vasculature changes within mouse intracranial models of malignant glioma. High field micro-imaging technology will be employed to obtain a high resolution, longitudinal, and comprehensive assessment of the critical perfusion parameters relating to blood flow, blood volume and vascular permeability. T2* based dynamic susceptibility contrast MRI (DSC-MRI) will be employed to measure cerebral blood flow and volume. This will employ a novel approach, using a superparamagnetic iron oxide contrast agent, Feridex, to minimize extravascular extravasation. The T1 based dynamic contrast enhanced MRI (DCE-MRI) approach will also be implemented to measure Ktrans, the contrast agent volume transfer constant. Ktrans is an index of vascular permeability, and an important marker of tumor neovasculature, the disruption of the blood brain barrier. This will also utilize novel methodology, via application of the macromolecular contrast agent P792. Strategies for implementing these diagnostic methodologies in the same imaging session are proposed. The perfusion parameters provided by these two approaches will provide critical and complementary vascular information. In combination with anatomical MRI imaging approaches, Specific Aim 2 of the project will then demonstrate the utility of these methodologies in assessing the effect of three (3) biologically distinct anti-vascular strategies on mouse glioma. The experiments will be implemented in conjunction with immunohistologic approaches, and quantification of mean vessel density, for the purpose of comparison to the perfusion MRI results. The project will obtain the first non-invasive documentation of an anti-angiogenic/anti-vascular effect in a mouse glioma model, and importantly, will lay the groundwork for noninvasive, longitudinal and highly diagnostic investigations of anti-vascular strategies in mouse models of malignant glioma. The most common of the tumors which originate in the brain is glioblastoma multiforme (GBM). Prognosis for GBM remains extremely poor, in part because of this tumor's ability to aggressively develop a supportive blood vessel network (vasculature). This proposal will employ novel MRI strategies to obtain a high resolution, noninvasive assessment of tumor vasculature in mouse models of GBM, which can be used to evaluate treatments for GBM which target this vascular network. ? ? ?
