Molecular neuro-oncology and the development of targeted therapeutic strategies for brain tumors. Part 3: brain tumor invasiveness.
Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches. Molecular neuro-oncology has now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that might be amenable to targeted therapy. Cellular invasion of surrounding brain is one of the key features of brain tumor behavior and is currently under evaluation for potential therapeutic targets. Tumor invasion occurs in the context of the extracellular matrix (ECM) of the brain and involves the interaction between cell-surface adhesion molecules, such as integrins and proteins embedded within the ECM. The overexpression of integrins is often associated with invasive behavior and can be inhibited by targeted approaches such as antibodies, antisense constructs and cyclic peptides. Tumor cell-secreted matrix metalloproteinases and serine proteinases degrade ECM proteins and provide space for movement and infiltration. The expression of proteinases positively correlates with tumor grade and infiltrative capacity. Proteinase activity can be reduced by several methods, including antibodies and small-molecule inhibitors such as marimastat. Early clinical trials suggest that marimastat may have activity in combination with traditional chemotherapy regimens. Further development of targeted therapies designed to inhibit tumor infiltration, and evaluation of these new agents in clinical trials, will be needed to improve survival and quality of life for patients with brain tumors.
Newton
Herbert B
HB
Dardinger Neuro-Oncology Center, Department of Neurology, Ohio State University Hospitals, 465 Means Hall, 1654 Upham Drive, Columbus, OH 43210, USA. newton.12@osu.edu
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005109:Extracellular Matrix / Q000502:physiology; D020869:Gene Expression Profiling; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D011788:Quality of Life; D012697:Serine Endopeptidases / Q000378:metabolism; D013534:Survival
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C100342:marimastat; D012697:Serine Endopeptidases; D020782:Matrix Metalloproteinases