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Published on: February 16, 2015
Genotoxic therapy and resistance mechanism in gliomas
Fengchao Lang1, Yang Liu1, Fu-Ju Chou1
1Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Abstract:
Glioma is one of the most common and lethal brain tumors. Surgical resection followed by radiotherapy plus chemotherapy is the current standard of care for patients with glioma. The existence of resistance to genotoxic therapy, as well as the nature of tumor heterogeneity greatly limits the efficacy of glioma therapy. DNA damage repair pathways play essential roles in many aspects of glioma biology such as cancer progression, therapy resistance, and tumor relapse. O6-methylguanine-DNA methyltransferase (MGMT) repairs the cytotoxic DNA lesion generated by temozolomide (TMZ), considered as the main mechanism of drug resistance. In addition, mismatch repair, base excision repair, and homologous recombination DNA repair also play pivotal roles in treatment resistance as well. Furthermore, cellular mechanisms, such as cancer stem cells, evasion from apoptosis, and metabolic reprogramming, also contribute to TMZ resistance in gliomas. Investigations over the past two decades have revealed comprehensive mechanisms of glioma therapy resistance, which has led to the development of novel therapeutic strategies and targeting molecules.
Insights
Glioma treatment resistance is a major challenge, driven by DNA repair pathways and cellular mechanisms. Understanding these resistance pathways is key to developing new glioma therapies.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Molecular Oncology
Background:
- Glioma is a common and deadly brain tumor, with standard treatment including surgery, radiotherapy, and chemotherapy.
- Therapy resistance and tumor heterogeneity significantly limit treatment efficacy in glioma patients.
- DNA damage repair (DDR) pathways are crucial in glioma progression, resistance, and relapse.
Purpose of the Study:
- To comprehensively review the mechanisms of therapeutic resistance in glioma.
- To highlight the role of DNA damage repair pathways in glioma treatment failure.
- To discuss cellular mechanisms contributing to temozolomide resistance in gliomas.
Main Methods:
- Literature review of studies investigating glioma therapy resistance mechanisms.
- Analysis of the roles of specific DNA repair pathways (MGMT, MMR, BER, HRR) in resistance.
- Examination of cellular processes like cancer stem cells, apoptosis evasion, and metabolic reprogramming.
Main Results:
- O6-methylguanine-DNA methyltransferase (MGMT) is a primary driver of temozolomide resistance.
- Other DNA repair pathways, including mismatch repair, base excision repair, and homologous recombination repair, also contribute significantly to resistance.
- Cellular mechanisms such as cancer stem cells, apoptosis evasion, and metabolic reprogramming are implicated in temozolomide resistance.
Conclusions:
- Understanding the multifaceted mechanisms of glioma therapy resistance is essential for improving patient outcomes.
- Targeting DNA damage repair pathways and cellular resistance mechanisms offers potential for novel therapeutic strategies.
- Continued research into glioma biology is vital for developing more effective treatments against these lethal brain tumors.
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