Epidermal Growth Factor Inhibitors Research Articles

Dermatologic adverse events to chemotherapeutic agents, part 1: cytotoxics, epidermal growth factor receptors, multikinase inhibitors, and proteasome inhibitors.

Dermatologic toxicities have profound effects on patients receiving chemotherapy for cancer treatment. Cytotoxic chemotherapies are associated with a number of nonspecific dermatologic adverse events including alopecia, mucositis, and onychodystrophy. Targeted therapies including epidermal growth factor inhibitors, multikinase inhibitors, and proteasome inhibitors are associated with different skin reactions that are class-specific. In Part 1 of this review, we examine the presentations of the most common dermatologic adverse events associated with the above drugs and discuss the strategies used for their prevention and treatment.

Abstract IA10: Molecular testing to personalized EGFR and ALK inhibitor therapies in lung cancer.

Abstract The concept of “oncogene addiction” led to the realization that not all patients respond equally to each targeted therapy, and best therapeutic results are obtained when the therapy is given to patients whose tumor harbors the “driver mutation” that is sensitive to the drug. In lung cancer, two currently approved new therapies require patient selection based on the presence of sensitizing epidermal growth factor (EGFR) tyrosine kinase domain (TKD) mutation or the anaplastic lymphoma kinase (ALK) gene rearrangement. EGFR mutations occur almost always in lung cancer of adenocarcinoma histology, and uncommonly in other histologies except when they also contain adenocarcinoma component. They are more common in East Asian (~45%) compared to Caucasian (~15-25%) patients, in never/light smokers and in female patients. Ninety percent of EGFR sensitizing mutations involve the 3-5 amino acid deletions on exon 19 and the L858R mutation on exon 21. Although ALK rearrangement also occurs mainly in lung adenocarcinoma and never/light smokers, it is not associated with sex or ethnicity. A great majority of the ALK gene rearrangements that occur in lung cancer involve a fusion between the C-terminal of ALK containing the kinase domain and the N-terminal of echinoderm microtubule-associated protein-like 4 (EML4), which results from an inversion on the short arm of chromosome 2. While EGFR mutations are detected by mainly by sequencing or PCR-based techniques, ALK rearrangement is best detected by the fluorescent in situ hybridization (FISH). However, recent data suggest that the oncogenic ALK fusion proteins can be detected with close to 100% sensitivity and specificity in lung cancer by immunohistochemistry using commercially available ALK specific antibodies, while the native ALK protein is not expressed in normal lung cells. Based on a systematic review of the published literatures, experts representing the International Association for the Study of Lung Cancer (IASLC), in collaboration with the College of American Pathologists (CAP) and the Association of Molecular Pathologists (AMP) recently issued a guideline on Molecular Testing of EGFR and ALK in Lung Cancer. The testing algorithm reported in this guideline will be discussed. Citation Format: Ming Sound Tsao. Molecular testing to personalized EGFR and ALK inhibitor therapies in lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr IA10.

Epidermal growth factor receptor inhibitors: a review of cutaneous adverse events and management.

Epidermal growth factor inhibitors (EGFRI), the first targeted cancer therapy, are currently an essential treatment for many advance-stage epithelial cancers. These agents have the superior ability to target cancers cells and better safety profile compared to conventional chemotherapies. However, cutaneous adverse events are common due to the interference of epidermal growth factor receptor (EGFR) signaling in the skin. Cutaneous toxicities lead to poor compliance, drug cessation, and psychosocial discomfort. This paper summarizes the current knowledge concerning the presentation and management of skin toxicity from EGFRI. The common dermatologic adverse events are papulopustules and xerosis. Less common findings are paronychia, regulatory abnormalities of hair growth, maculopapular rash, mucositis, and postinflammatory hyperpigmentation. Radiation enhances EGFRI rash due to synergistic toxicity. There is a positive correlation between the occurrence and severity of cutaneous adverse effects and tumor response. To date, prophylactic systemic tetracycline and tetracycline class antibiotics have proven to be the most effective treatment regime.

Chapter Five - Gefitinib

Gefitinib (Iressa®) is a selective inhibitor of epidermal growth factor, a growth factor that plays a pivotal role in the control of cell growth, apoptosis, and angiogenesis. Gefitinib is clinically used for the treatment of chemoresistant non-small cell lung cancer patients. Gefitinib is freely soluble in dimethylsulphoxide but slightly soluble in methanol and ethanol. Several methods of gefitinib synthesis are included in this review. UV spectroscopy of gefitinib showed a λmax of approximately 331nm, whereas IR spectroscopy principal peaks were observed at 3400cm(-1) (NH), 2956cm(-1) (CH2, CH, alkyl), 1625cm(-1) (CC, CN), 1500cm(-1) (HCCH, aryl), 1110cm(-1) (CO), 1028cm(-1) (CF). In addition, different analytical methods for determination of gefitinib are also described in this review. Pharmacokinetically, after oral administration, gefitinib is slowly absorbed with bioavailability of approximately 60% in human. Gefitinib is metabolized extensively in the liver into five metabolites by cytochrome P450s, primarily by CYP3A4 and to a lesser extent by CYP3A5 and CYP2D6. Gefitinib is eliminated mainly hepatically with total plasma clearance of 595mL/min after intravenous administration. Most of the adverse effects associated with gefitinib therapy are mild to moderate in severity and are usually reversible and manageable with appropriate intervention, such as diarrhea, dry skin, rash, nausea, and vomiting.

Effects of 4-(3-Chloro-Benzyl)-6,7-Dimethoxy-Quinazoline on Kinetics of P120-Catenin and Periplakin in Human Buccal Mucosa Squamous Carcinoma Cell Line

In order to detect molecular markers for the epidermal growth factor inhibitor 4-(3-chloro-benzyl)- 6,7-dimethoxy-quinazoline (tyrphostin), we investigated the kinetics of p120-catenin and periplakin in the human buccal mucosa squamous cancer cell line BICR 10 treated with 3 nM tyrphostin. Growth of BICR 10 cells was inhibited by treatment with tyrphostin. Although changes were not observed in the expression of EGFR and p120-catenin, expression of Akt, Src and periplakin in BICR 10 treated with 3 nM tyrphostin tended to decrease. In addition, phosphorylation of EGFR, Akt and Src was inhibited by treatment with tyrphostin. On immunocytochemical staining, immunoreactions with phosphorylated EGFR, phosphorylated Akt and phosphorylated p120-catenin were weak in BICR 10 treated with tyrphostin. There was a slight immunocy to chemical reaction to periplakin in BICR 10 cells induced by tyrphostin. In conclusion, the decrease in phosphorylation in EGFR and p120-catenin by tyrphostin, following the decrease in Src or Akt phosphorylation, may inhibit expression of several growth factors associated with the proliferation and migration of cancer cells.

Erlotinibe bağlı gelişen akneiform erüpsiyon: Bir olgu sunumu

Erlotinib is an epidermal growth factor inhibitor. It is used for refractory, local invasion or metastasized non-small cell lung cancer. Erlotinib doesn’t cause severe systemic side effects like cytotoxic drugs. But it causes toxic side effects in skin. Acneiform eruption is the most common side effects related to erlotinib using. It is thought that balance is disturbed between differentiation and maturation of keratinocytes, ecrine and sebaceous gland cells and hair follicle cells in etiology. Topical metronidazole, clindamycin, topical salicylic acid and tetracycline can be used in treatment. In case of severe acneiform eruption dose of erlotinib may be reduced or treatment of erlotinib may be delayed. Our case was 67 years old male presented with acneiform eruption on his face after erlotinib treatment for non-small cell lung cancer. We decide to report this case because early diagnosis and treatment of skin lesions related to erlotinib treatment is important for patient compliance with erlotinib treatment.

Research progress of ursolic acid’s anti-tumor actions

Ursolic acid (UA) is a sort of pentacyclic triterpenoid carboxylic acid purified from natural plant. UA has a series of biological effects such as sedative, anti-inflammatory, anti-bacterial, anti-diabetic, antiulcer, etc. It is discovered that UA has a broad-spectrum anti-tumor effect in recent years, which has attracted more and more scholars' attention. This review explained anti-tumor actions of UA, including (1) the protection of cells' DNA from different damages; (2) the anti-tumor cell proliferation by the inhibition of epidermal growth factor receptor/mitogen-activated protein kinase signal or of FoxM1 transcription factors, respectively; (3) antiangiogenesis, (4) the immunological surveillance to tumors; (5) the inhibition of tumor cell migration and invasion; (6) the effect of UA on caspase, cytochromes C, nuclear factor kappa B, cyclooxygenase, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or mammalian target of rapamycin signal to induce tumor cell apoptosis respectively, and etc. Moreover, UA has selective toxicity to tumor cells, basically no effect on normal cells. With further studies, UA would be one of the potential anti-tumor agents.

Daily baseline skin care in the prevention, treatment, and supportive care of skin toxicity in oncology patients: recommendations from a multinational expert panel

Skin reactions due to radiotherapy and chemotherapy are a significant problem for an important number of cancer patients. While effective for treating cancer, they disturb cutaneous barrier function, causing a reaction soon after initiation of treatment that impacts patient quality of life. Managing these symptoms with cosmetics and nonpharmaceutical skin care products for camouflage or personal hygiene may be important for increasing patient self-esteem. However, inappropriate product choice or use could worsen side effects. Although recommendations exist for the pharmaceutical treatment of skin reactions, there are no recommendations for the choice or use of dermatologic skin care products for oncology patients. The present guidelines were developed by a board of European experts in dermatology and oncology to provide cancer care professionals with guidance for the appropriate use of non-pharmaceutical, dermocosmetic skin care management of cutaneous toxicities associated with radiotherapy and systemic chemotherapy, including epidermal growth factor inhibitors and monoclonal antibodies. The experts hope that these recommendations will improve the management of cutaneous side effects and hence quality of life for oncology patients.

Regulation of Human Corneal Epithelial Mucins by Rebamipide

Purpose: Membrane-associated mucins (MAMs) play important roles in barrier function and tear stability, and their expression on the ocular surface is altered in dry eye disease. Rebamipide is a mucin secretagogue that promotes the production of mucin-like glycoproteins in human corneal epithelial (HCE) cells. However, the expression of MAMs on the corneal epithelia (MUC1, MUC4, MUC16), which is induced by rebamipide, is poorly understood. In this study, we investigated the effect of rebamipide on the regulation of MAM expression in HCE cells.Materials and Methods: MUC16, Ki67 and PCNA expression levels in HCE cells isolated at confluence and at 24 hours after confluence were examined by Western blotting to assess cell proliferation. HCE cells isolated at 24 hours after confluence were cultured in medium supplemented with 1–10 µM rebamipide or 0.3–30 nM of epidermal growth factor (EGF). Real-time PCR (RT-PCR) and Western blot analysis of MAMs were performed to evaluate the effect of rebamipide. Western blot analysis of cells treated with an EGF receptor inhibitor (AG1478) or MEK1/2 inhibitor (U0126) was performed to reveal the relationship between EGF receptor activation and rebamipide-induced MAM expression.Results: HCE cells isolated at 24 hours after confluence had lower cell proliferation activity and increased MUC16 expression compared with cells isolated at confluence. RT-PCR and Western blot analysis revealed that rebamipide increased MAM gene expression for 2 hours and protein expression for 24 hours in HCE cells. EGF inhibitor treatment led to reduced levels of all three MAMs that are normally induced by rebamipide, whereas EGF induced the expression of all three MAMs.Conclusions: We suggested that rebamipide increased MUC1, MUC4 and MUC16 expression levels through signals involved in EGF receptor activation in the human corneal epithelia. These data suggest that rebamipide may improve subjective symptoms of dry eye disease by upregulating MAM expression.

Postacute and Long-Term Care Teams Increasingly Participate in Cancer Care

Postacute and Long-Term Care Teams Increasingly Participate in Cancer Care

Switching from MAPK-dependent to MAPK-independent repression of the sodium-iodide symporter in 2D and 3D cultured normal thyroid cells

Loss of sodium-iodide symporter (NIS) expression in thyroid tumour cells primarily caused by constitutive MAPK pathway activation is often refractory to small molecule MAPK inhibitors. Suggested mechanisms are rebound MAPK signalling and activation of alternative signalling pathways. Here we provide evidence that failure to recover down-regulated NIS by MEK inhibition is not specific to tumour cells. NIS mRNA levels remained repressed in TSH-stimulated primary thyroid cells co-treated with epidermal growth factor (EGF) and pan-MEK inhibitor U0126 in the presence of 5% fetal bovine serum or, independently of serum, in 3D cultured thyroid follicles. This led to inhibited iodide transport and iodination. In contrast, U0126 restituted thyroglobulin synthesis in EGF-treated follicular cells. Serum potentiated TSH-stimulated NIS expression in 2D culture. U0126 blocked down-regulation of NIS only in serum-starved cells with a diminished TSH response. Together, this suggests that morphogenetic signals modify the expression of NIS and recovery response to MEK inhibition.

Synergistic inhibition of cell migration by tetraspanin CD82 and gangliosides occurs via the EGFR or cMet-activated Pl3K/Akt signalling pathway

The metastasis suppressor CD82/KAI-1, which is a member of the tetraspanin superfamily, has been proposed to exert its activity together with glycosphingolipids. However, the mechanism of CD82 inhibition has not been fully elucidated. The present study aimed to investigate the synergistic inhibition of cell migration by the tetraspanin CD82 and gangliosides and to correlate this inhibition with activation of epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (HGFR/cMet) in Hepa1-6 cell lines, whose motility and migration is stimulated by epidermal growth factor (EGF) and hepatocyte growth factor (HGF) in vitro. We found that Hepa1-6 cells transfected with the CD82 gene exhibited decreased migration in response to EGF and HGF. EGF-stimulated phosphorylation of EGFR at Tyr1173 was inhibited in these cells, which contributed to the attenuation of EGFR. Ectopic expression of CD82 in Hepa1-6 cells inhibited HGF-stimulated tyrosine phosphorylation of cMet at Tyr1313 and Tyr1365 without affecting the expression of cMet. These inhibitory effects were enhanced when CD82 was introduced with Ganglioside GM3 alone or GM2/GM3. Reduction of CD82 expression by RNA interference together with depletion of glycosphingolipids with P4 significantly enhanced cell motility and increased the expression of EGFR and its phosphorylation at Tyr1173 in response to EGF. Increased cell motility and HGF-dependent activation of cMet at Tyr1313 and Tyr1365 resulted from decreased CD82 levels and increased GM3. Furthermore, CD82 expression selectively attenuated EGFR and cMet signalling via phosphatidylinositol 3-kinase/Akt but had no affect on the activity of the MAPK signalling pathway. These results suggest that the synergistic effects of CD82 and GM3 or GM2/GM3 on EGFR expression and phosphorylation and cMet activation are responsible for CD82 inhibition of EGF- and HGF-dependent cell motility and migration of Hepa1-6 cells.

Effect of all-trans retinoic acid on the differentiation of U87 glioma stem/progenitor cells.

GSPCs (glioma stem/progenitor cells) were isolated from U87 glioma cell lines by serum-free neural stem cell medium. Four concentrations (1, 2, 4, and 8 μmol/L) of ATRA (all-trans retinoic acid) were used to induce the differentiation of GSPCs in the medium with or without growth factors. The effect of ATRA on the differentiation of GSPCs was analyzed by flow cytometry, real-time-PCR, and immunofluorescence. The differentiation of GSPCs could be induced by 1 or 2 μmol/L ATRA when GSPCs were cultured in growth factor-free medium. The detection of real-time-PCR showed that the level of GFAP (glial fibrillary acidic protein) mRNA of differentiated GSPCs in the growth factor-free medium containing 1 μmol/L ATRA group was significantly higher than that in the control group, and there was no significant difference in the level of TUBB-3 mRNA between the two groups. The GSPCs suffered apoptosis in the growth factor-free medium containing 4 or 8 μmol/L ATRA. The differentiation of GSPCs could not be induced by ATRA when GSPCs were cultured in the medium containing growth factors. The percentage of cells in G0/G1 phase was 84.26 ± 2.24 %, and the percentage of apoptosis was 18.95 ± 2.53 % in experimental groups which was similar to those in the control group. In conclusion, ATRA has certain capacity to induce differentiation of GSPCs, while its effective concentration should be controlled strictly. The differentiation of GSPCs induced by ATRA cannot antagonize the formidable differential inhibition of epidermal growth factor and basic fibroblast growth factor.

Acetylation of the Cell-Fate Factor Dachshund Determines p53 Binding and Signaling Modules in Breast Cancer

Breast cancer is a leading form of cancer in the world. The Drosophila Dac gene was cloned as an inhibitor of the hyperactive epidermal growth factor (EGFR), ellipse. Herein, endogenous DACH1 co-localized with p53 in a nuclear, extranucleolar compartment and bound to p53 in human breast cancer cell lines, p53 and DACH1 bound common genes in Chip-Seq. Full inhibition of breast cancer contact-independent growth by DACH1 required p53. The p53 breast cancer mutants R248Q and R273H, evaded DACH1 binding. DACH1 phosphorylation at serine residue (S439) inhibited p53 binding and phosphorylation at p53 amino-terminal sites (S15, S20) enhanced DACH1 binding. DACH1 binding to p53 was inhibited by NAD-dependent deacetylation via DACH1 K628. DACH1 repressed p21CIP1 and induced RAD51, an association found in basal breast cancer. DACH1 inhibits breast cancer cellular growth in an NAD and p53-dependent manner through direct protein-protein association.

Inhibition of TGF-β and EGF pathway gene expression and migration of oral carcinoma cells by mucosa-associated lymphoid tissue 1

Background:Expression of mucosa-associated lymphoid tissue 1 (MALT1) is inactivated in oral carcinoma patients with worse prognosis. However, the role in carcinoma progression is unknown. Unveiling genes under the control of MALT1 is necessary to understand the pathology of carcinomas.Methods:Gene data set differentially transcribed in MALT1-stably expressing and -marginally expressing oral carcinoma cells was profiled by the microarray analysis and subjected to the pathway analysis. Migratory abilities of cells in response to MALT1 were determined by wound-healing assay and time-lapse analysis.Results:Totally, 2933 genes upregulated or downregulated in MALT1-expressing cells were identified. The subsequent pathway analysis implicated the inhibition of epidermal growth factor and transforming growth factor-β signalling gene expression, and highlighted the involvement in the cellular movement. Wound closure was suppressed by wild-type MALT1 (66.4%) and accelerated by dominant-negative MALT1 (218.6%), and the velocities of cell migration were increased 0.2-fold and 3.0-fold by wild-type and dominant-negative MALT1, respectively.Conclusion:These observations demonstrate that MALT1 represses genes activating the aggressive phenotype of carcinoma cells, and suggest that MALT1 acts as a tumour suppressor and that the loss of expression stimulates oral carcinoma progression.

The role of maintenance therapy in metastatic colorectal cancer

During the last decade, numerous new agents were introduced into the therapy of metastatic colorectal cancer. Treatment duration and maintenance therapy, however, still remain a controversial issue. More and more results from clinical trials become available that assess the role of maintenance chemotherapy in combination with the angiogenesis inhibitor bevacizumab and epidermal growth factor inhibitors. Taken together, these data suggest that some form of maintenance therapy leads to a better patient outcome and is thus appropriate. Our challenge remains the need to identify and predict the required therapeutic intensity whether by biomarkers or clinical parameters. As also side effects may increase due to drug combinations, quality of life issues need to be carefully considered for each individual patient.

Integrating anti-EGFR therapies in metastatic colorectal cancer.

Colorectal cancer remains one of the most common causes of cancer diagnoses and mortality in the United States. The treatment of metastatic colorectal cancer has evolved significantly over the last decade with near-tripling of patient survival rate. A significant contribution to this outcome was the advent of novel targeted agents, such as the epidermal growth factor (EGFR) inhibitors. In an era of emphasis on refining therapy, the presence of KRAS mutation will predict for resistance and limit exposure to patients who are more likely to benefit. In contrast, the presence of BRAF mutations does not seem to have a predictive value. Agents that are thought to reverse resistance to EGFR inhibitors such as those targeting PI3K, c-MET or IGF-1R are currently under study. EGFR inhibitors have exhibited single agent activity, and seem to synergize very well with standard chemotherapy except for cetuximab and 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX). Preliminary data suggests that EGFR inhibitors have similar effectiveness to vascular endothelial growth factor (VEGF) inhibitors in the first line setting. Skin toxicity remains the main limiting factor for the utilization of EGFR inhibitors, but strategies including the use of agents such as minocycline or doxycycline added to topical care seem to limit the severity of the rash.

Correlation between development of rash and efficacy of EGFR inhibitors: A meta-regression analysis.

e13539 Background: Treatment with Epidermal Growth Factor (EGFR) inhibitors is frequently characterized by the presence of a rash. Previous research has suggested that developing this rash may be associated with improved outcomes. It has been difficult, however, to establish a direct link between occurrence of a rash and tumor response. Rashes are also likely to occur with greater drug exposure and it is possible that they exist as a confounder in the well established relationship between drug exposure/dosing and tumor response. The purpose of this meta-regression analysis is to define whether a correlation exists between the incidence of rash and clinical outcomes including response rate (RR), progression-free survival (PFS) and overall survival (OS) and then examine whether a similar relationship exists with other adverse events as that would suggest that rash occurrence is simply a function of drug dosing and not necessarily an indicator of tumor response. Methods: A literature search for RCT’s involving EGFR inhibitors in non-small cell lung cancer (NSCLC) identified 31 trials. This included 5 trials of Cetuximab, 13 trials of Gefitinib and 13 trials of Erlotinib. Multivariate meta-regression analysis was performed to evaluate whether all rashes (grades 1-5) and severe rashes (grades 3-5) as well as vomiting and neutropenia (two randomly chosen adverse events) may have influenced effect size (measured by RR, PFS and OS) across this cancer type. Results: The presence of severe rashes in the treatment arm was positively correlated with increased PFS (p<0.01) in NSCLC - a similar correlation was also found for risk of vomiting. Additionally, the presence of any rash in the treatment arm was positively correlated with increased OS (p=0.03) in NSCLC – a similar correlation was found for risk of vomiting and neutropenia. Conclusions: The presence of a rash seems to connote an increased likelihood of tumor response and/or survival in NSCLC. The fact that other adverse events (vomiting and neutropenia) are more evident in these responding patients suggests that rash occurrence may simply be a confounder in the EGFR inhibitors’ dose-response relationship as opposed to being independently associated with any tumor response.

EGFR Tyrosine Kinase Inhibitors: Difference in Efficacy and Resistance

Lung cancer will be diagnosed in 230,000 patients in the U.S. in 2013. Adenocarcinoma will be the most common histology, and 10% of lung cancers will be diagnosed in never or former light smokers. These patients will be those most likely to harbor targetable mutations, in particular, mutations in epidermal growth factor (EGFR). Preclinical work beginning in the 1980s led to the development of EGFR-targeted therapy in lung cancer patients. Analysis of the responders to gefitinib and erlotinib led to the discovery of activating mutations underlying sensitivity to EGFR-directed treatment. Although EGFR-mutant patients have higher response rates, better quality of life, and longer progression free survival, all patients eventually develop resistance. Mutations in the tyrosine kinase domain that render tumors resistant to erlotinib and gefitinib are the most common mechanism of resistance. A second generation of EGFR inhibitors are now making their way to the clinic, with hopes of thwarting these resistance mechanisms or providing more durable responses via irreversible inhibition, as well as targeting of additional HER receptors. Here we review the evolution of EGFR as a target in lung cancer, and the second generation of EGFR inhibitors in development.

Targeting Cancer Stem Cells for Treatment of Glioblastoma Multiforme

Cancer stem cells (CSCs) in glioblastoma multiforme (GBM) are radioresistant and chemoresistant, which eventually results in tumor recurrence. Targeting CSCs for treatment is the most crucial issue. There are five methods for targeting the CSCs of GBM. One is to develop a new chemotherapeutic agent specific to CSCs. A second is to use a radiosensitizer to enhance the radiotherapy effect on CSCs. A third is to use immune cells to attack the CSCs. In a fourth method, an agent is used to promote CSCs to differentiate into normal cells. Finally, ongoing gene therapy may be helpful. New therapeutic agents for targeting a signal pathway, such as epidermal growth factor (EGF) and vascular epidermal growth factor (VEGF) or protein kinase inhibitors, have been used for GBM but for CSCs the effects still require further evaluation. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as cyclooxygenase-2 (Cox-2) inhibitors have proven to be effective for increasing radiation sensitivity of CSCs in culture. Autologous dendritic cells (DCs) are one of the promising immunotherapeutic agents in clinical trials and may provide another innovative method for eradication of CSCs. Bone-morphogenetic protein 4 (BMP4) is an agent used to induce CSCs to differentiate into normal glial cells. Research on gene therapy by viral vector is also being carried out in clinical trials. Targeting CSCs by eliminating the GBM tumor may provide an innovative way to reduce tumor recurrence by providing a synergistic effect with conventional treatment. The combination of conventional surgery, chemotherapy, and radiotherapy with stem cell-orientated therapy may provide a new promising treatment for reducing GBM recurrence and improving the survival rate.