Evolvement of Molecular Biomarkers in Targeted Therapy of Malignant Gliomas

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Abstract

Gliomas account for almost half of all diagnosed adult brain tumors Glioblastoma multiforme (GBM), the most aggressive type of glioma, is also the most common primary malignant brain tumor. Even though tremendous effort has been made to treat high grade gliomas, the prognosis for patients with malignant gliomas remains poor. The dismal prognosis of patients with glioblastoma is in part caused by the resistance of these tumors to both chemotherapy and radiation. Furthermore, high grade gliomas often diffusely infiltrate into neighboring brain tissue, thus complicating treatment and commonly preventing a cure for the disease. Treatment modalities containing chemotherapy often have high levels of toxicity and depending on the drug have to be locally injected as crossing the blood-brain barrier is an impediment for certain drug therapies. The addition of temozolomide (TMZ) to the standard of care treatment for GBM in 2005 circumvented the aforementioned problems as it is taken orally, crosses the blood-brain barrier, and has a relatively low toxicity profile. However, the average life expectancy of patients treated with the addition of temozolomide increased by only a couple of months. Therefore, more effective treatment strategies are critically needed for the treatment of gliomas. In recent years, the research efforts in identifying molecular biomarkers for tumor subtypes have exponentially increased. These biomarkers can help serve a diagnostic role by helping classify grade or subtype, as well as a predictive role in determining the expected response to a specific treatment, and/or a prognostic role in estimating the natural course of the disease. Furthermore, gaining a better understanding of the molecular mechanisms involved in gliomagenesis, migration, and tumor resistance is essential for identifying novel tumor targets to overcome the poor prognosis of patients harboring gliomas. Additionally, characterizing the best treatment(s) for each grade and molecular subtype of gliomas will enable clinicians to increase efficacy of therapies for patients. The ability to categorize tumors based on molecular biomarkers for each glioma grade will further enhance the effectiveness of treatments by broadening the therapeutic window between normal and malignant tissues. In this chapter, molecular mechanisms (see Figure

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