Targeted therapy in the treatment of malignant gliomas

Abstract

Malignant gliomas are invasive tumors with the potential to progress through current available therapies. These tumors are characterized by a number of abnormalities in molecular signaling that play roles in tumorigenesis, spread, and survival. These pathways are being actively investigated in both the pre-clinical and clinical settings as potential targets in the treatment of malignant gliomas. We will review many of the therapies that target the cancer cell, including the epidermal growth factor receptor, mammalian target of rapamycin, histone deacetylase, and farnesyl transferase. In addition, we will discuss strategies that target the extracellular matrix in which these cells reside as well as angiogenesis, a process emerging as central to tumor development and growth. Finally, we will briefly touch on the role of neural stem cells as both potential targets as well as delivery vectors for other therapies. Interdependence between these varied pathways, both in maintaining health and in causing disease, is clear. Thus, attempts to easily classify some targeted therapies are problematic.

Keywords: EGFR; HDAC; Ras; angiogenesis; glioma; mTOR.

Figure 1

Simplified diagram of the two major pathways affected by EGFR-mediated signaling in malignant glioma cells. The PI3 kinase pathway is shown on the right and the Ras/Map kinase pathway on the left. Following EGFR activation, a series of sequential phosphorylation events result in cell proliferation and survival through increased transcription and translation of key proteins while inhibiting pro-apoptotic pathways. Agents that target key points in the pathway that are discussed in the text are shown in parentheses at their respective sites of action. Abbreviation: EGFR, epidermal growth factor receptor; mTOR, mammalian target of rapamycin; mTORI, mTOR inhibitor; TKI, tyrosine kinase inhibitor; FTI, farnesyl transferase inhibitor; HDACI, histone deacetylase inhibitor; PTEN, phosphatase and tensin homologue deleted on chromosome 10; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-triphosphate.

Figure 2

MRI scans showing a typical prolonged response to single-agent erlotinib in a patient with progressive GBM. The image in the left panel is consistent with a partially necrotic enhancing mass and surrounding peri-tumoral edema. The image on the right, obtained 16 months after the initiation of erlotinib, reveals a decrease in the mass and associated edema. The patient was on high-dose dexamethasone treatment (to control cerebral edema) at the time of erlotinib treatment initiation and was off all dexamethasone at the time of the follow-up scan. Abbreviations: GBM, glioblastoma multiforme; MRI, magnetic resonance imaging.

Figure 3

Schematic diagram of the potential sites in the PI3 kinase pathway where resistance to single-agent TKIs directed against the EGFR might occur. 1) The phosphatase activity of the PTEN gene product is lost in the majority of GBM, favoring accumulation of the triphosphate form of phosphatylinositol, PIP₃; 2) Activating mutations in the PIK3CA gene, controlling the catalytic subunit of PI3K are well-documented, also favoring accumulation of PIP₃;3) In addition, increased expression of the phospho-AKT enhancer, PIKE-A, is found. These alterations may occur in isolation or in any combination in GBM. Abbreviations: EGFR, epidermal growth factor receptor; GBM, glioblastoma multiforme; PTEN, phosphatase and tensin homologue deleted on chromosome 10; TKIs, tyrosine kinase inhibitors.

Figure 4

A schematic showing the convergence of the PI3K pathway (through mTOR) and the Ras/MAPK pathway (through ER K) on p70s6K and its effect on translation. Note the inhibitory effect of TSC1 and 2, an area not fully explored in gliomagenesis. Abbreviations: ERK, extracellular signal regulated kinase; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; TSC, tuberous sclerosis complex.

Figure 5

MRI scans showing a typical response of a recurrent GBM to bevacizumab. The image on the right shows the tumor-associated enhancement (large arrow) and accompanying compression of the ventricle by mass effect (small arrow). The image on the right shows the same region following a one month course of bevacizumab. Note the marked reduction in contrast enhancement and mass effect. Abbreviations: GBM, glioblastoma multiforme; MRI, magnetic resonance imaging.