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• W13794966 abstract "Human gliomagenesis appears to complex network of signaling alterations, rather than the expression particular dominant oncogene, as is observed certain leukemias or breast cancers Glioblastomas (GBMs) can be grouped into least two major categories, primary or “de novo” GBM and secondary GBMs, those tumors that arise and transform from precursor, lower-grade lesions. Primary GBMs tend to be observed in older patients and exhibit alterations of the Epidermal Growth Factor Receptor (EGFR) gene as well as cycle regulatory genes. Secondary GBMs observed in younger patients and typically lower-grade neoplasms. These tumors contain molecular alterations, but also in cell cycle components, in this case the p53 gene, and growth factor receptors, such as the platelet-derived growth factor receptor (PDGF-R), and/or its ligand(s). A common theme is that there appears to be cooperativity between activation of oncogenic growth factors and perturbation of cell cycle regulatory components. The observed clinicopathologic observations have generally been supported to date by mouse models of gliomagenesis. In this era of targeted molecular therapeutics, specific classification schemes will be of great use in clinical trial design and future treatment selection and will be continually refined as the use of genomics and proteomics is more widely applied to glioblastoma diagnosis. Recent reports in Clinical Cancer Research illustrate many of the issues involved in translational application of molecular therapeutics to solid tumors, including glial tumors. Since many of the molecular targets, including the EGFR, are shared between gliomas and other cancers, neurooncologists have an opportunity to learn from preclinical studies and clinical trials conducted in other tumors. EGFR belongs to the ErbB family of receptor tyrosine kinases (RTKs), a family that also includes ErbB2, the target of the Herceptin monoclonal antibody (mAb) expressed in subtypes of breast cancer. Nyati and colleagues (Clin Cancer Res 10: 691–700, 2004) from the University of Michigan and Pfizer demonstrate that an irreversible pan-ErbB tyrosine kinase inhibitor, CI-1033, radiosensitized colon cancer cells in vitro and in vivo, a finding that has been observed for other EGFR inhibitors in multiple preclinical studies. Many basic and translational issues are raised by this observation. First, will ErbB inhibitors be more effective when used in combination with cytotoxic agents, such as chemotherapy and radiation? The preclinical data support combination treatment, but the available clinical trial data are less certain, as outlined by Harari and Huang (Clin Cancer Res 10: 428–432, 2004) in their commentary re: Nyati et al. Will irreversible blockade of ErbB receptors result in greater efficacy than reversible kinase inhibition resulting from treatment with Iressa (ZD1839) or Tarceva (OSI-774), two agents in clinical trial for adult gliomas in the North American Brain Tumor Consortium (NABTC). FIGUREFIGURE: Potential molecular targets for glioma therapy. Inhibitors of molecules shaded in blue (FIGURE ) are currently in clinical trials for various cancers, including malignant gliomas. Inhibitors of molecules shaded in green (FIGURE ) are in preclinical laboratory testing and development.FIGUREFIGUREMany practical issues come to mind regarding the clinical use of these newer agents in treatment of glial tumors. Particular inhibitors should be chosen only if the target is present in the tumor tissue. Stratification of cases has not yet been done in the majority of trials, including glioma trials conducted by the National Brain Tumor Consortia funded by the National Cancer Institute, NABTC and NABTT (New Approaches to Brain Tumor Therapy). But the early proteomic data sugeest the activation (e.g phosphorylation status) of a particular receptor or cellular kinase(s) may be more important than levels of expression. Moreover, there is preclinical evidence that tumor cells harboring mutations downstream of EGFR and PDGF-R will be resistant to receptor inhibitors. These issues will impact on trial design and require broader molecular analysis as part of the patient selection criteria. Timing and duration of administration of the newer agents will also be an issue since the preclinical data suggest that many of these drugs do not directly kill tumor cells. Clinical end-points will have to be reconsidered, since many of the agents are without any appreciable toxicity and could in theory be administered indefinitely. Integration with conventional anticancer therapies and other biologic approaches will be an important issue. Moreover, the brain will, as always, provide a challenge for delivery of many of these agents, although the data seem to suggest that small molecule kinase inhibitors are able to penetrate the blood-brain barrier. Lastly, advances in neuro-imaging will likely have and impact in clinical trial design. For example, MR spectroscopy and perfusion imaging may be valuable complements to anatomic imaging in determining extent of residual disease (a criterion for patient enrollment in the majority of trials conducted by NABTT and NABTC) and treatment response. There has clearly been a paradigm shift in the treatment of cancer that will impact on our management of glial tumors. The challenge for neurosurgical oncologists and neurooncologists will be to learn from these observations so that we can harness the power of genomics to improve the natural history of this formidable disease. DONALD M. O'ROURKE, M.D." @default.
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• W13794966 date "2004-05-01" @default.
• W13794966 modified "2023-10-13" @default.
• W13794966 title "Targeted Molecular Therapy In Glial Tumors" @default.
• W13794966 doi "https://doi.org/10.1227/01.neu.0000309633.00854.fd" @default.
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