Molecular neuro-oncology and the development of targeted therapeutic strategies for brain tumors Part 5: apoptosis and cell cycle

Abstract

Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches. Molecular neuro-oncology has now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that might be amenable to targeted therapy. Abnormalities of the apoptotic and cell cycle signaling pathways are key molecular features of many brain tumors and are currently under evaluation for potential therapeutic intervention. The apoptosis pathway has numerous targets for molecular therapeutic development, including p53, Bax, Bcl-2, cFLIP, effector caspases, growth factor receptors, phosphatidylinositol-3-kinase, Akt and apoptosis inhibitors. Current molecular treatment approaches include antisense techniques, gene therapy and small-molecule modulators and inhibitors. Potential targets of the cell cycle pathway include the cyclins, cyclin-dependent kinases, p53, retinoblastoma, E2F and the cyclin-dependent kinase inhibitors. Developmental molecular therapeutics for this pathway include adenoviral and gene therapy, small-peptide cyclin-dependent kinase modulators, proteasomal inhibitors and small-molecule cyclin-dependent kinase inhibitors. Several of these recently identified agents have begun evaluation in clinical trials. Further development of targeted therapies designed to modulate apoptosis and the cell cycle, and evaluation of these new agents in clinical trials, will be needed to improve survival and quality of life for patients with brain tumors.

Targeted drug therapy for meningiomas

“…Defects in programmed cell death (apoptosis) mechanisms play an important role in tumor pathogenesis and resistance to therapy. 95,113,115,132 Apoptosis occurs via two main mechanisms. The extrinsic pathway is characterized by activation of death receptors with subsequent activation and cleavage of caspase 8.…”

Epigenetics of Glioblastoma Multiforme

“…The conventional forms of treatment for GBM are not predicated on the biology of the malignant phenotype. Due to the insufficiency of conventional therapeutic approaches for GBM, new treatment modalities must be developed that have a more molecular, "targeted" mechanism of action [9][10][11][12][13][14].…”

Expression of Epidermal Growth Factor Receptor and HER-2 in Pediatric Embryonal Brain Tumors

“…Abnormalities of the cell cycle, apoptosis and signal transduction are molecular features of many brain tumors and are currently under evaluation for potential therapeutic intervention [1]. Despite previous investigations, the role of epidermal growth factor receptor (EGFR) and c-erbB2/HER-2 in the pathogenesis of embryonal brain neoplasms has not been fully elucidated [2,3,4].…”