Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 1: Growth factor and Ras signaling pathways.
Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches, including radiotherapy and cytotoxic chemotherapy. Molecular neuro-oncology has now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that may be amenable to targeted therapy. Growth factor signaling pathways are often upregulated in brain tumors and may contribute to oncogenesis through autocrine and paracrine mechanisms. Excessive growth factor receptor stimulation can also lead to overactivity of the Ras signaling pathway, which is frequently aberrant in brain tumors. Receptor tyrosine kinase inhibitors, antireceptor monoclonal antibodies and antisense oligonucleotides are targeted approaches under investigation as methods to regulate aberrant growth factor signaling pathways in brain tumors. Several receptor tyrosine kinase inhibitors, including imatinib mesylate (Gleevec), gefitinib (Iressa) and erlotinib (Tarceva), have entered clinical trials for high-grade glioma patients. Farnesyl transferase inhibitors, such as tipifarnib (Zarnestra), which impair processing of proRas and inhibit the Ras signaling pathway, have also entered clinical trials for patients with malignant gliomas. Further development of targeted therapies and evaluation of these new agents in clinical trials will be needed to improve survival and quality of life of patients with brain tumors.
Dardinger Neuro-Oncology Center, Department of Neurology, Ohio State University Hospitals, Columbus 43210, USA. newton.12@osu.edu
Herbert B
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Newton
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy*; D016503:Drug Delivery Systems; D004815:Epidermal Growth Factor / Q000235:genetics / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000502:physiology; D011905:Genes, ras / Q000502:physiology*; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D008967:Molecular Biology / Q000639:trends*; D009462:Neurology / Q000639:trends*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013002:Somatomedins / Q000235:genetics / Q000502:physiology; D015291:Transforming Growth Factors / Q000235:genetics / Q000502:physiology
D006133:Growth Substances; D010982:Platelet-Derived Growth Factor; D013002:Somatomedins; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor; D015291:Transforming Growth Factors