| Abstract |
Cancer cells in solid tumors form a mass with augmented metabolic needs due to constant vigorous changes. As the solid tumor develops, it must generate its own blood supply due to insufficient diffusion of nutrients and oxygen from pre-existing vasculature. Intra-tumoral hypoxia is considered to be the main driving force of induced angiogenesis within the tumor in agreement with Folkman’s assertion. Hypoxia-inducible factor (HIF-1α) is a transcription factor that promotes ischemia-driven angiogenesis through the induction of differential expression of the vascular endothelial growth factor (VEGF). VEGF appears to be a key-molecule for both the pro-angiogenic events and the survival of newly formed vessels [1]. In general, aspects such as cell proliferation and invasion, angiogenic net rates, oxygen consumption and vasculature have been approved to be fundamental for shaping the cancer in a heterogeneous and compartmentalized tumor mass.
High grade (astrocytic) gliomas and particularly glioblastoma multiforme (GBM), are known to have a prominence of vasculature and appear to be among the most common brain cancers. In addition, as an extreme malignant form of cancer in conjunction with its special features, the importance of early diagnosis and effective treatment options make evident the need for exploitation and improvement of the imaging techniques. Imaging techniques such as dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) with the administration of a Gd-based contrast agent (GBCA) are used for diagnosis and characterization of GBM. Studies correlating imaging biomarkers with clinical outcome are of great interest.
The work is comprised of two parts:
First, a feasibility study is performed using DCE-MRI in order to provide patient-specific input to a proliferation- invasion- hypoxia- necrosis- angiogenesis (PIHNA) model. This work focuses on correlating pharmacokinetic (PK)-based imaging biomarkers to underlying biological phenomena regarding vasculature composition of the tumor. The assumptions made represent novel work in this direction. Feasibility results of applying the tumor growth model to real clinical cases are presented, accompanied by a study of the effect of changing certain model parameters on the pattern of the simulated tumor.
Second, an examination of the tracer’s kinetics in DCE-MRI has been made in order to assess the vessel leakage through the estimation of the transfer and disposition of GBCAs in a putative lesion. In this case, a physiologically-based pharmacokinetic (PBPK) model was used through the application of Simcyp® simulator platform to assess in silico the disposition of pharmacologic agents in the body. A whole-body PBPK approach is presented evaluating the impact of vasculature in the extravascular-extracellular disposition of Gd-DTPA (Gadopentetic acid, Magnevist®) in a brain tumor lesion.
The aim of this work in overall is to shed light in the interconnections between imaging biomarkers and related mechanisms and molecules, focusing mainly on the effect of vasculature. In other words, to find a way of translating MRI biomarkers to biologically significant phenotype and brain tumor physiology.
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Magnetic resonance imaging in human brain cancer : the physiology underneath and perspectives
