DNA repair and cancer stem-like cells--potential partners in glioma drug resistance?
ABSTRACT Glioblastoma is the most malignant and frequent primary brain tumour in adults. Current treatment remains insufficient as these tumours display a diffuse infiltrative growth pattern and tend to recur despite extensive debulking surgery followed by radio- and chemotherapy. The alkylating agents carmustine (1,3-bis-(2-chloroethyl)-1-nitrosourea, or BCNU) and temozolomide (TMZ) are the drugs of choice for adjuvant glioma chemotherapy. However, several independent DNA repair mechanisms can restore the integrity of alkylated DNA bases, and thus contribute to drug resistance and subsequent therapy failure. Recent work suggests that glioblastomas develop as cellular and functional hierarchies through small subpopulations of stem cell-like cancer cells that are responsible for tumour initiation and maintenance. Such cells also appear to possess enhanced DNA repair capacity compared to other cells within the tumours. Challenges in glioblastoma therapy are to determine (1) whether the cancer stem-like cell subpopulations represent a clinically novel target for therapy, and (2) which additional treatment strategies should be applied to improve quality of life and prolong survival of glioblastoma patients. This review addresses clinically relevant mechanisms which contribute to glioma resistance towards current alkylating agent-based chemotherapy, and discusses related mechanisms and treatment strategies in the light of the cancer stem cell hypothesis.
[show abstract] [hide abstract]
ABSTRACT: Molecularly targeted therapies are transforming the care of patients with malignant gliomas, including glioblastoma, the most common malignant primary brain tumor of adults. With an arsenal of small molecule inhibitors and antibodies that target key components of the signal transduction machinery that are commonly activated in gliomas, neuro-oncologists and neurosurgeons are poised to transform the care of these patients. Nonetheless, successful application of targeted therapies remains a challenge. Strategies are lacking for directing kinase inhibitor or other pathway-specific therapies to individual patients most likely to benefit. In addition, response to targeted agents is determined not only by the presence of the key mutant kinases, but also by other critical changes in the molecular circuitry of cancer cells, such as loss of key tumor suppressor proteins, the selection for kinase-resistant mutants, and the deregulation of feedback loops. Understanding these signaling networks, and studying them in patients, will be critical for developing rational combination therapies to suppress resistance for malignant glioma patients. Here we review the current status of molecular targeted therapies for malignant gliomas. We focus initially on identifying some of the insights gained to date from targeting the EGFR/PI3K/Akt/mTOR signaling pathway in patients and on how this has led toward a reconceptualization of some of the challenges and directions for targeted treatment. We describe how advances from the world of genomics have the potential to transform our approaches toward targeted therapy, and describe how a deeper understanding of the complex nature of cancer, and its adeptness at rewiring molecular circuitry to evade targeted agents, has raised new challenges and identified new leads.Neurotherapeutics 08/2009; 6(3):500-12. · 6.01 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: At this time, brain tumor stem cells remain a controversial hypothesis while malignant brain tumors continue to present a dire prognosis of severe morbidity and mortality. Yet, brain tumor stem cells may represent an essential cellular target for glioma therapy as they are postulated to be the tumorigenic cells responsible for recurrence. Targeting oncogenic pathways that are essential to the survival and growth of brain tumor stem cells represents a promising area for developing therapeutics. However, due to the multiple oncogenic pathways involved in glioma, it is necessary to determine which pathways are the essential targets for therapy. Furthermore, research still needs to comprehend the morphogenic processes of cell populations involved in tumor formation. Here, we review research and discuss perspectives on models of glioma in order to delineate the current issues in defining brain tumor stem cells as therapeutic targets in models of glioma.Yonsei medical journal 09/2010; 51(5):633-40. · 0.77 Impact Factor