The devastating consequence of a brain tumor on a patient’s quality of life and survival has sparked a widespread search for novel therapeutic approaches (e.g. antiangiogenic therapies) to arrest cancer progression. This in turn has galvanized the development of new biomarkers capable of assessing the efficacy of such drugs in vivo. This lecture will provide an overview of how, why and which MRI-derived biomarkers are ideally suited for assessing the angiogenic status of brain tumors, noninvasively and safely in patients. Specifically, this lecture will introduce core concepts about the blood vessels of brain tumors, their role in disease progression, and how one can image them with certain MRI contrast mechanisms, in the preclinical and clinical setting.
Angiogenesis or the de novo formation of blood vessels is one of the ‘hallmarks’ of cancer and a key prerequisite for tumor progression and metastasis (Hanahan et al. 2011). The healthy body controls angiogenesis through a balance of ‘on’ and ‘off’ switches known as angiogenesis stimulating growth factors (e.g. vascular endothelial growth factor or VEGF) and angiogenesis inhibitors (e.g. thrombospondin-1), respectively (Bergers et al. 2003). However in cancer, the body loses control of this homeostatic balance, resulting in excessive growth of tumor blood vessels that are structurally and functionally distinct from the vasculature of healthy tissue (Carmeliet et al. 2000, Jain et al. 2001).
Tumor-induced blood vessels are typically sinusoidal, exhibit discontinuous basement membranes, and lack tight endothelial cell junctions making them highly permeable to macromolecules (Konerding et al. 1995, Nagy et al. 2010). Other characteristics include spatial heterogeneity, loss of branching hierarchy, arterio-venous shunts, acutely and transiently collapsing vessels, a dearth of smooth muscle cell lining, and an inability to match the elevated metabolic demand of cancer cells, resulting in areas of hypoxia and necrosis (Semenza 2003). Pioneering work by Jain, Vaupel and others has demonstrated that these morphological anomalies profoundly alter tumor hemodynamics, blood rheology, and perfusion (Jain 1988, Vaupel et al. 2007).
These observations led Folkman to hypothesize that inhibiting tumor growth with specialized ‘antiangiogenesis’ drugs could profoundly affect the quality of life of cancer patients (Folkman 1971). Over the past several years, a large number of angiogenesis inhibitors have been identified and are currently in clinical trials (Folkman 2007). Most of these inhibitors achieve their effects by inhibiting VEGF (Ferrara 2002). Recently, it was shown that antiangiogenic therapies can transiently ‘normalize’ the chaotic brain tumor vasculature (Jain 2001, Jain 2005), improve brain tumor blood flow and enhance delivery and efficacy of anti-cancer drugs (Batchelor et al. 2007, Batchelor et al. 2013). Preclinical studies have demonstrated that tumors respond to VEGF inhibition with a loss of blood vessels (i.e. vascular pruning), which decreases perfusion and elevates hypoxia, inducing mechanisms of evasive resistance to antiangiogenic therapy that include revascularization via alternative proangiogenic pathways (Bergers et al. 2008), increased invasiveness and enhanced metastasis (Ebos et al. 2011).
With these developments in the field of brain tumor angiogenesis has come a crucial need for reliable biomarkers to (Pathak et al. 2008): (i) test novel antiangiogenic drugs; (ii) assess their therapeutic efficacy in vivo; (iii) provide early measurable signs of tumor relapse/recurrence; (iv) stratify patients according to their angiogenic/tumor phenotype; (v) identify the best combinatory drug regime (i.e. antiangiogenic drug plus chemo- or radio-therapy); and (vi) repeatedly monitor patients with maximal safety.
A wide array of non-invasive imaging modalities have been used to image the tumor vasculature. These include x-ray computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), ultrasound, and different types of optical imaging, each with its own distinct advantages as a tool in the non-invasive, in vivo assessment of tumor angiogenesis (McDonald et al. 2003). However, the assortment of available ‘functional’ contrast mechanisms in conjunction with the development of novel imaging probes, has made MRI invaluable for the functional and molecular imaging of the brain tumor vasculature (Pathak et al. 2010). This includes probing tumor vasculature using the endogenous contrast produced by paramagnetic deoxyhemoglobin in tumor microvessels or the blood oxygenation level dependent (BOLD) contrast mechanism (Ben Bashat et al. 2012, Boult et al. 2013), and imaging tumor perfusion with arterial spin labeling (ASL), in which the intrinsic magnetization of arterial blood water serves as the endogenous tracer (Silva et al. 2000). Exogenous low and high molecular weight gadolinium (Gd)-based complexes, as well as para- and superparamagnetic contrast agents have been used in pre-clinical and clinical studies of tumor angiogenesis (Pathak et al. 2004) and the efficacy of novel antiangiogenic therapeutics (Kim et al. 2015). The MR pulse sequences used to characterize tumor vascularization depend on the physical properties and pharmacokinetics of the contrast agent used, following which a range of tumor vascular parameters (e.g. blood volume, blood flow, vascular permeability, microvessel density and radius etc.) can be calculated from tracer kinetic principles and MR biophysical principles (Zaharchuk 2007, Pathak 2009, Kim et al. 2013).
This lecture will cover the following topics:
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