Mechanisms of Disease: genetic predictors of response to treatment in brain tumors

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Abstract

Brain tumors are currently diagnosed on the basis of their histology. The most common types in adults are astrocytomas, oligodendrogliomas and oligoastrocytomas or mixed tumors, which almost invariably lead to death. Improvements in outcome have been elusive despite intensive research. Recent findings indicate that response to conventional therapy, at least in some cases, correlates better with genetic characteristics than histopathology. An understanding of the molecular mechanisms that underlie the malignant phenotype of gliomas also provides the possibility of rational design of molecularly targeted therapies. This approach has proved successful in other areas of oncology. As many tumors have the same types of molecular abnormalities, molecular targeted therapies developed for nonbrain tumor types might be adapted for the treatment of brain tumors. There are a number of unique problems involved in treating tumors in the brain that must be overcome. The genetic predictors of response to conventional therapies, the genes and cellular mechanisms involved in glioma development, and potential therapeutic targets are reviewed. The possibility of designing tailored molecular therapy based on the molecular characteristics of the tumors is also explored.

Key Points

  • Patients with tumors that have hemizygous loss of 1p and 19q chromosomal arms have a survival advantage, which might be a predictor of response to conventional treatment with irradiation and alkylating agents

  • Methylation of MGMT in glioblastomas seems to predict a good response to alkylating agents, particularly temozolomide

  • Genetic and transcriptome studies indicate that technologies assessing global genetic changes and gene expression in brain tumors may provide information relevant for prognostication (prognostic indicators) and choice of therapy (therapy response indicators)

  • The introduction of molecularly targeted therapies will obligate a molecular (i.e. genetic and/or expression) analysis of tumor tissue to help determine the appropriate therapy in an individual case

  • Combinations of molecularly targeted therapies with or without conventional therapies are likely to be required for success

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Figure 1: Adult diffuse astrocytic tumors
Figure 2: The proteins involved in the RB1 and p53 pathways with some interactions with the P13K/PKB pathway
Figure 3: Schematic diagram of the receptor tyrosine kinase and signaling pathways implicated in glioblastoma development
Figure 4: Histology of oligodendroglioma WHO grade II and anaplastic oligodendroglioma WHO grade III tumors

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