The Challenges and the Promise of Molecular Targeted Therapy in Malignant Gliomas

Abstract

Malignant gliomas are the most common malignant primary brain tumors and one of the most challenging forms of cancers to treat. Despite advances in conventional treatment, the outcome for patients remains almost universally fatal. This poor prognosis is due to therapeutic resistance and tumor recurrence after surgical removal. However, over the past decade, molecular targeted therapy has held the promise of transforming the care of malignant glioma patients. Significant progress in understanding the molecular pathology of gliomagenesis and maintenance of the malignant phenotypes will open opportunities to rationally develop new molecular targeted therapy options. Recently, therapeutic strategies have focused on targeting pro-growth signaling mediated by receptor tyrosine kinase/RAS/phosphatidylinositol 3-kinase pathway, proangiogenic pathways, and several other vital intracellular signaling networks, such as proteasome and histone deacetylase. However, several factors such as cross-talk between the altered pathways, intratumoral molecular heterogeneity, and therapeutic resistance of glioma stem cells (GSCs) have limited the activity of single agents. Efforts are ongoing to study in depth the complex molecular biology of glioma, develop novel regimens targeting GSCs, and identify biomarkers to stratify patients with the individualized molecular targeted therapy. Here, we review the molecular alterations relevant to the pathology of malignant glioma, review current advances in clinical targeted trials, and discuss the challenges, controversies, and future directions of molecular targeted therapy.

Novel Targeting of Transcription and Metabolism in Glioblastoma

“…Despite the statistical improvement of current standard treatment with radiotherapy and temozolomide (TMZ) compared with radiotherapy alone, less than one third of patients survive beyond 2 years and cure is exceedingly rare (2). Therapies targeting particular altered gene products or signal transduction pathways have not provided durable responses in GBM likely due to multiple dynamic and interactive, compensatory, dysregulated pathways (3,4). Targeting multiple survival mechanisms in tumor can potentially avoid the development of adaptive resistance.…”

The correlation of microRNA-181a and target genes with poor prognosis of glioblastoma patients

“…Glioma is the most common malignant tumor in the central nervous system, with incidence rate of 5-7 per 100,000 and 5-year survival rate of approximately 20-30% (1). Gliomas originate from astrocytes, oligodendrocytes and neural stem cells or their precursors.…”

Emerging Proteomic Technologies Provide Enormous and Underutilized Potential for Brain Cancer Research

“…Deep Biological Insight-Single cell proteomics technologies provide an important capability to study the high degree of cellular heterogeneity found in tumors (3,4) at a higher level of resolution, which is critical to understanding their resilience to therapy and to designing strategies for treatments that deal with the problem of recurrence (5). A microfluidics-based single-cell proteomic chip-the single-cell barcode chip-has demonstrated its usefulness in studying brain tumor cell models (6).…”