Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma

Abstract

Malignant gliomas are the most common and deadly brain tumors. Nevertheless, survival for patients with glioblastoma, the most aggressive glioma, although individually variable, has improved from an average of 10 months to 14 months after diagnosis in the last 5 years due to improvements in the standard of care. Radiotherapy has been of key importance to the treatment of these lesions for decades, and the ability to focus the beam and tailor it to the irregular contours of brain tumors and minimize the dose to nearby critical structures with intensity-modulated or image-guided techniques has improved greatly. Temozolomide, an alkylating agent with simple oral administration and a favorable toxicity profile, is used in conjunction with and after radiotherapy. Newer surgical techniques, such as fluorescence-guided resection and neuroendoscopic approaches, have become important in the management of malignant gliomas. Furthermore, new discoveries are being made in basic and translational research, which are likely to improve this situation further in the next 10 years. These include agents that block 1 or more of the disordered tumor proliferation signaling pathways, and that overcome resistance to already existing treatments. Targeted therapies such as antiangiogenic therapy with antivascular endothelial growth factor antibodies (bevacizumab) are finding their way into clinical practice. Large-scale research efforts are ongoing to provide a comprehensive understanding of all the genetic alterations and gene expression changes underlying glioma formation. These have already refined the classification of glioblastoma into 4 distinct molecular entities that may lead to different treatment regimens. The role of cancer stem-like cells is another area of active investigation. There is definite hope that by 2020, new cocktails of drugs will be available to target the key molecular pathways involved in gliomas and reduce their mortality and morbidity, a positive development for patients, their families, and medical professionals alike.

FIGURE 1

Sequential Genetic Changes Observed in the Pathogenesis of Different Subtypes of Glioblastoma. Some cells in the normal brain undergo genetic alterations, which leads to a population of tumor–initiating cells (TICs), which can then further accumulate genetic and epigenetic changes and become brain cancer–propagating cells (BCPC). The latter cells are responsible for the formation of glioblastoma. GBM indicates glioblastoma multiforme; EGFR, epidermal growth factor receptor; PTEN, phosphatase and tensin homolog; TNF, tumor necrosis factor; PDGFRA, platelet-derived growth factor receptor–A; IDH, isocitrate dehydrogenase; PI3K, phosphoinositol 3–kinase; HIF, hypoxia-inducible factor.

FIGURE 2

Genetic Alterations in Glioblastoma Occur Frequently in 3 Cellular Signaling Pathways. DNA alterations and copy number changes in the following signaling pathways are indicated in (a) receptor tyrosine kinase (RTK), RAS, and phosphoinositol–3–kinase (PI3K); (b) p53 tumor suppressor; and (c) retinoblastoma (Rb) tumor suppressor. Activating genetic alterations are shown in red. Genetic alterations that lead to a loss of function are indicated in blue. In each pathway, the altered components, the type of alteration, and the percentage of tumors carrying each alteration are shown. Blue boxes contain the total percentages of glioblastomas with alterations in at least 1 known component gene of the designated pathway. EGFR indicates epidermal growth factor receptor; MET, mesenchymal- epithelial transition factor; PDGFRA, platelet-derived growth factor receptor–A; PTEN, phosphatase and tensin homolog; . Reprinted with permission from The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061–1068.

FIGURE 3

Possible Lineage Relations for the Ontogeny and Production of Brain Cancer–Propagating Cells (BCPCs) and Generation of Glioblastoma Multiforme (GBM) Tumors. During normal central nervous system differentiation, neural stem cells undergo an amplification step to produce transit–amplifying progenitor cells (type C cells), which then differentiate into neural/glial progenitor cells. These progenitor cells retain the capacity to produce progeny along either neural or glial lineages (oligodendrocytes and/or astrocytes), but not both. Mutations generating GBM tumors can occur at all levels within this lineage and produce tumor–initiating cells (TICs). TICs are believed to be stem-like in behavior based on their ability to self-renew, proliferate, and generate BCPCs, differentiated tumor or cancer-like progenitor cells within the tumor mass. Dedifferentiation events may also take place to generate self-propagating cancer cells from astrocytes and oligodendrocytes. SVZ indicates subventricular zone. Adapted with kind permission of Springer Science+Business Media from figure 2 in Hadjipanayis CG, et al., Initiating cells in malignant gliomas: biology and implications for therapy. J Mol Med. 2009;87:363–374. © Springer

FIGURE 4

Generation of Neurosphere Cultures and Propagation in Rodent Brains. EGF indicates epidermal growth factor; bFGF, basic fibroblast growth factor.

FIGURE 5

Diagram Illustrating the Flow of Cerebrospinal Fluid (CSF) in the Brain and the Different Cellular Structures That Create the Blood–CSF Barrier. Incoming arterial blood flow from the heart connects to the choroid plexus, a cauliflower-shaped organ in which blood is “filtered” through a double cellular layer, endothelial cells lining the arterial capillary and the choroid plexus that are connected through tight junctions. This constitutes the first component of the blood–CSF barrier. Note that the endothelial cells in the choroid plexus are not connected by tight junctions. The CSF is produced in the choroid plexus and released into the ventricles, which are lined by ependymal cells in which exchanges between the normal and tumor brain tissue extracellular content and the CSF can occur. The hydrostatic pressure of incoming CSF creates CSF flow through foramens such as the median aperture at the skull base, and the CSF enters a second larger compartment called the subarachnoid space, which surrounds the brain. In this space, the CSF–blood barrier is established by the neurothelium, a layer of meningothelial cells that covers the arachnoid and is connected by tight junctions, constituting the second component of the CSF–blood barrier. The CSF is reabsorbed into the venous circulation through multiple arachnoid granulations, which are small, tufted protrusions that herniate through the dura mater and serve as 1-way, pressure-dependent valves. The positive hydrostatic pressure of the CSF moves fluid into the large superior sagittal sinus back into the venous circulation along with a limited number of proteins and other markers of the central nervous system environment. In addition, for comparison, a blood vessel irrigating the brain is shown on the right. The permeation of blood components into the brain parenchyma is restricted by the blood–brain barrier (BBB), which is constituted by endothelial cells with tight junctions, surrounded by pericytes and astrocytic feet. Drawing by Eric Jablonowski, Department of Radiology, Emory University. Reprinted with permission from Khwaja FW, Van Meir EG. Proteomic discovery of biomarkers in the cerebrospinal fluid of brain tumor patients. In: Van Meir EG, ed. CNS Cancer: Models, Markers, Prognostic Factors, Targets and Therapeutic Approaches. 1st ed. New York: Humana Press (Springer); 2009:577–614.

FIGURE 6

Imaging of a 23–Year–Old Female Who Underwent a Neuroendoscopic Biopsy of a Thalamic Malignant Glioma and an Endoscopic Third Ventriculostomy for Treatment of Her Obstructive Hydrocephalus. (A) Coronal, (B) sagittal, and (C) axial T1-weighted magnetic resonance imaging of the brain after gadolinium administration revealed contrast enhancement of a right thalamic mass (indicated by arrows) extending into the midbrain and causing obstructive hydrocephalus. (D) A postoperative computed tomography scan of the brain demonstrating ventricular decompression and an area of neuroendoscopic sampling of the tumor (indicated by arrow) was obtained for pathologic diagnosis.

FIGURE 7

Fluorescence-Guided Resection of a Glioblastoma Multiforme Tumor. (A) Preoperative axial T1-weighted magnetic resonance imaging (MRI) of the brain after gadolinium administration demonstrated a right frontal contrast–enhancing mass. (B) A postoperative axial T1-weighted MRI of the brain revealed macroscopic total resection of the right frontal mass using intraoperative fluorescence. (C) An intraoperative microscopic view (white light) of the tumor resection cavity is shown. (D) An intraoperative microscopic view of tumor fluorescence (indicated by arrows) using “blue light” is shown. Figures were kindly provided by Dr. David Roberts, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.