Inhibition of Casein Kinase II by CX-4945, But Not Yes-associated protein (YAP) by Verteporfin,Enhances the Antitumor Efficacy of Temozolomide in Glioblastoma

Overcoming temozolomide (TMZ) resistance in glioma cancer cells remains a major challenge to the effective treatment of the disease. Increasing TMZ efficacy for patients with glioblastoma (GBM) is urgently needed because TMZ treatment is the standard chemotherapy protocol for adult patients with glioblastoma. O⁶-methylguanine-DNA-methyltransferase (MGMT) overexpression is associated with TMZ resistance, and low MGMT is a positive response marker for TMZ therapy. Here, we used 3 glioma cell lines (SF767, U373, and LN229), which had different levels of TMZ sensitivity. We found TMZ sensitivity is positively correlated with MGMT expression and multidrug-resistance protein ABC subfamily G member 2 (ABCG2) in these cells. CK2-STAT3 signaling and Hippo-YAP signaling are reported to regulate MGMT expression and ABCG2 expression, respectively. We combined CK2 inhibitor CX-4945 and YAP inhibitor verteporfin with TMZ treatment. We found that CX-4945 but not verteporfin can sensitize TMZ-resistant cells SF767 to TMZ and that CX-4945 and TMZ combinational treatment was effective for glioma treatment in mouse models compared with TMZ alone.ImplicationsA combination of CK2 inhibitor with TMZ may improve the therapeutic efficiency of TMZ toward GBM with acquired resistance.     

The interruption of atypical PKC signaling and Temozolomide combination therapy against glioblastoma

Current treatment options of glioblastoma include chemotherapy and limited surgical resection. Temozolomide (TMZ) is the current therapeutic choice for chemotherapy. Still, it has severe limitations due to the development of resistance that occurs by genetic modification and constitutive activation of several cell signaling pathways. Therefore, it is essential to develop combination therapy of TMZ with other novel compounds to prevent the development of chemo-resistance. In this study, we used two inhibitors; ICA, an inhibitor of PKC-ι and ζ-Stat, an inhibitor of PKC-ζ. T98G and U87MG glioblastoma cells were treated with either ICA or ζ-stat or TMZ monotherapies, as well as TMZ were combined with either ICA or ζ-stat for five consecutive days. Our in vitro results exhibited that ICA when combined with TMZ, significantly decreased the viability of cancerous cells compared with untreated or TMZ or ICA monotherapies. Additionally, glioblastoma cells were remarkably undergoing apoptosis against the combination treatment of TMZ and ICA nucleotide compared with untreated control cells, as suggested by our Annexin-V/PI flow cytometric analysis. Moreover, the combination of TMZ and ICA also decreased the invasion of glioblastoma cell lines by acting on FAK/Paxillin pathway, as evidenced by scratch assay, transwell invasion assay, Western blot and immunoprecipitation analysis. Furthermore, our in vivo data presented that the combination of ICA and TMZ also reduced glioblastoma tumor growth and volume in mice. These data suggest that atypical PKCs, particularly PKC-ι might be an important therapeutic target as adjuvant therapy in the treatment of glioblastoma.     

Lactate and Choline Metabolites Detected In Vitro by Nuclear Magnetic Resonance Spectroscopy Are Potential Metabolic Biomarkers for PI3K Inhibition in Pediatric Glioblastoma

The phosphoinositide 3-kinase (PI3K) pathway is believed to be of key importance in pediatric glioblastoma. Novel inhibitors of the PI3K pathway are being developed and are entering clinical trials. Our aim is to identify potential non-invasive biomarkers of PI3K signaling pathway inhibition in pediatric glioblastoma using in vitro nuclear magnetic resonance (NMR) spectroscopy, to aid identification of target inhibition and therapeutic response in early phase clinical trials of PI3K inhibitors in childhood cancer. Treatment of SF188 and KNS42 human pediatric glioblastoma cell lines with the dual pan-Class I PI3K/mTOR inhibitor PI-103, inhibited the PI3K signaling pathway and resulted in a decrease in phosphocholine (PC), total choline (tCho) and lactate levels (p<0.02) as detected by phosphorus (³¹P)- and proton (¹H)-NMR. Similar changes were also detected using the pan–Class I PI3K inhibitor GDC-0941 which lacks significant mTOR activity and is entering Phase II clinical trials. In contrast, the DNA damaging agent temozolomide (TMZ), which is used as current frontline therapy in the treatment of glioblastoma postoperatively (in combination with radiotherapy), increased PC, glycerophosphocholine (GPC) and tCho levels (p<0.04). PI-103-induced NMR changes were associated with alterations in protein expression levels of regulatory enzymes involved in glucose and choline metabolism including GLUT1, HK2, LDHA and CHKA. Our results show that by using NMR we can detect distinct biomarkers following PI3K pathway inhibition compared to treatment with the DNA-damaging anti-cancer agent TMZ. This is the first study reporting that lactate and choline metabolites are potential non-invasive biomarkers for monitoring response to PI3K pathway inhibitors in pediatric glioblastoma.     

Radiotherapy plus Concomitant Adjuvant Temozolomide for Glioblastoma: Japanese Mono-Institutional Results

This study was conducted to investigate the feasibility and survival benefits of combined treatment with radiotherapy and temozolomide (TMZ), which has been covered by the national health insurance in Japanese patients with glioblastoma since September 2006. Between September 2006 and December 2011, 47 patients with newly diagnosed and histologically confirmed glioblastoma received radiotherapy for 60 Gy in 30 fractions. Among them, 45 patients (TMZ group) received concomitant TMZ (75 mg/m²/day, every day) and adjuvant TMZ (200 mg/m²/day, 5 days during each 28-days). All 36 of the glioblastoma patients receiving radiotherapy between January 1988 and August 2006 were analyzed as historical controls (control group). All patients were followed for at least 1 year or until they died. The median survival was 15.8 months in the TMZ group and 12.0 months in the control group after a median follow-up of 14.0 months. The hazard ratio for death in the TMZ group relative to the control group was 0.52 (P<0.01); the 2-year survival rate was 27.7% in the TMZ group and 14.6% in the control group. Hematologic toxicity of grade 3 and higher was observed in 20.4% in the TMZ group. Multivariate analysis showed that extent of surgery had the strongest impact on survival (P<0.01), while the use of TMZ had the second largest impact on survival (P = 0.035). The results indicate that combined treatment with radiotherapy and TMZ has a significant survival benefit for Japanese patients with newly diagnosed glioblastoma with slightly higher toxicities than previously reported.     

Temozolomide Resistance in Glioblastoma Cell Lines: Implication of MGMT,MMR, P-Glycoprotein and CD133 Expression

Background

The use of temozolomide (TMZ) has improved the prognosis for glioblastoma multiforme patients. However, TMZ resistance may be one of the main reasons why treatment fails. Although this resistance has frequently been linked to the expression of O6-methylguanine-DNA methyltransferase (MGMT) it seems that this enzyme is not the only molecular mechanism that may account for the appearance of drug resistance in glioblastoma multiforme patients as the mismatch repair (MMR) complex, P-glycoprotein, and/or the presence of cancer stem cells may also be implicated.

Methods

Four nervous system tumor cell lines were used to analyze the modulation of MGMT expression and MGMT promoter methylation by TMZ treatment. Furthermore, 5-aza-2’-deoxycytidine was used to demethylate the MGMT promoter and O(6)-benzylguanine to block GMT activity. In addition, MMR complex and P-glycoprotein expression were studied before and after TMZ exposure and correlated with MGMT expression. Finally, the effect of TMZ exposure on CD133 expression was analyzed.

Results

Our results showed two clearly differentiated groups of tumor cells characterized by low (A172 and LN229) and high (SF268 and SK-N-SH) basal MGMT expression. Interestingly, cell lines with no MGMT expression and low TMZ IC₅₀ showed a high MMR complex expression, whereas cell lines with high MGMT expression and high TMZ IC₅₀ did not express the MMR complex. In addition, modulation of MGMT expression in A172 and LN229 cell lines was accompanied by a significant increase in the TMZ IC₅₀, whereas no differences were observed in SF268 and SK-N-SH cell lines. In contrast, P-glycoprotein and CD133 was found to be unrelated to TMZ resistance in these cell lines.

Conclusions

These results may be relevant in understanding the phenomenon of TMZ resistance, especially in glioblastoma multiforme patients laking MGMT expression, and may also aid in the design of new therapeutic strategies to improve the efficacy of TMZ in glioblastoma multiforme patients.     

MicroRNA-125b inhibitor sensitizes human primary glioblastoma cells to chemotherapeutic drug temozolomide on invasion

Malignant gliomas are treated with a combination of surgery, radiation, and temozolomide (TMZ), but these therapies ultimately fail due to tumor recurrence. In this study, we aimed to identify the combined effects of miR-125b and TMZ involved in the invasive pathogenesis of glioblastoma cells. The effects of miR-125b and TMZ on cell invasion were analyzed by Transwell assays. Unexpectedly, either overexpression or downregulation of miR-125b has no function on glioblastoma cell invasion. However, knockdown of miR-125b could enhance the effects of TMZ on glioblastoma cell invasion. Conversely, overexpression of miR-125b could decrease such effects of TMZ. Further research on the mechanism demonstrated that such function of miR-125b knockdown on enhancing the effects of TMZ was involved in downregulation of Notch1. Notch1 was overexpressed in glioblastoma cells, and found by us that downregulation of Notch1 expression decreased the cell invasion of glioblastoma cells. Knockdown of miR-125b combined with TMZ enhancely downregulated Notch1 and inhibited cell invasion of malignant glioblastoma. These findings indicate that the combination of miR-125b inhibitor and TMZ treatment could effectively inhibit the glioblastoma cell invasion by inhibiting Notch1 expression.     

DNA ligase IV as a new molecular target for temozolomide

Temozolomide (TMZ) is a methylating agent used in chemotherapy against glioblastoma. This work was designed to clarify details in repair pathways acting to remove DNA double-strand breaks (DSBs) induced by TMZ. Cultured mouse embryonic fibroblasts were used which were deficient in DSB repair genes such as homologous recombination repair-related genes X-ray repair cross-complementing group 2 (XRCC2)and radiation sensitive mutant54 (Rad54), non-homologous end joining repair-related gene DNAligase IV (Lig4). Cell sensitivity to drug treatments was assessed using colony forming assays. The most effective molecular target which was correlated with TMZ cell sensitivity was Lig4. In addition, it was found that small interference RNAs (siRNA) for Lig4 efficiently enhanced cell lethality induced by TMZ in human glioblastoma A172 cells. These findings suggest that down regulation of Lig4 might provide a useful tool for cell sensitization during TMZ chemotherapy.     

非小细胞肺癌低分割放疗研究进展

肺癌是全球发病率和死亡率第一的恶性肿瘤,虽然放疗在NSCLC的治疗中具有可观的局部疗效,但临床上仍有部分患者出现治疗失败。放疗失败的主要原因是局部未控、复发或远处转移。与常规分割相比,大分割放疗可在不增加放疗次数的情况下提高总的放疗剂量;对于接受相同BED照射的NSCLC患者,大分割放疗除了能带来局部控制率上的增加外,还可减少治疗次数,节省治疗时间和费用,增加病人的便捷,提高医用加速器的使用效率。L-Q模型的数据在预测大分割放疗疗效时存在许多局限。除经典L-Q模型所模拟的机制外,还可能有其他机制的参与。分子影像是无创性评价放疗疗效的可靠手段,利用不同分子显像剂结合胞内特定靶分子,能够对恶性肿瘤的代谢水平、乏氧状态、增殖能力等情况进行较为准确的评估,为大分割放疗提供良好的疗效评估手段并成为研究其特殊放射生物效应的有力工具。     

The effect of Azo-dyes on glioblastoma cells in vitro

Despite the multidisciplinary standard treatment of glioblastoma (GB) consisting of maximal surgical resection, followed by radiotherapy (RT) plus concomitant chemotherapy with temozolomide (TMZ), the majority of patients experience tumor progression and almost universal mortality. In recent years, efforts have been made to create new agents for GB treatment, of which azo-dyes proved to be potential candidates, showing antiproliferative effects by inducing apoptosis and by inhibiting different signaling pathways. In this study we evaluated the antiproliferative the effect of six azo-dyes and TMZ on a low passage human GB cell line using MTT assay. We found that all compounds proved antiproliferative properties on GB cells. At equimolar concentrations azo-dyes induced more cytotoxic effect than TMZ. We found that Methyl Orange required the lowest IC₅₀ for 3 days of treatment (26.4684 μM), whilst for 7 days of treatment, two azo dyes proved to have the highest potency: Methyl Orange IC₅₀ = 13.8808 μM and Sudan I IC₅₀ = 12.4829 μM. The highest IC₅₀ was determined for TMZ under both experimental situations. Conclusions: Our research represents a novelty, by offering unique valuable data regarding the azo-dye cyototoxic effects in high grade brain tumors. This study may focus the attention on azo-dye agents that may represent an insufficient exploited source of agents for cancer treatment.     

Adyuvant fractionated radiotherapy after resection of intracranial hemangiopericytoma

AimReview of literature and adjuvant treatment in Hemangiopericytoma after complete resection.BackgroundIntracranial hemangiopericytoma (HPC) is an uncommon malignant vascular tumor arising from mesenchymal cells with pericytic differentiation. Surgery remains the mainstay treatment, and adjuvant radiation therapy appears to be appropriate for patients with high grade tumors or incomplete resection. We present our experience and review of the literature.Materials and methodsWe describe two cases of intracranial hemangiopericytoma located in the frontal lobe of the CNS. Both patients underwent complete tumor resection followed by adjuvant fractionated radiotherapy and completed treatment without interruptions.ResultsA local recurrence was observed in one of these cases and fractionated stereotactic radiotherapy was performed. Both patients are alive and disease has been under control up to date.ConclusionThe treatment of choice for intracranial hemangiopericytoma is a complete surgical resection as long as possible. Adjuvant radiotherapy of HPC can result in increased tumor control and should be considered as an effective treatment for patients with high grade or demonstrated residual tumor in the postoperative period. Salvage treatment using limited-field fractionated radiotherapy for local recurrence treatment is considered an acceptable option.     

Early Assessment of the Efficacy of Temozolomide Chemotherapy in Experimental Glioblastoma Using [18F]FLT-PET Imaging

Addition of temozolomide (TMZ) to radiation therapy is the standard treatment for patients with glioblastoma (GBM). However, there is uncertainty regarding the effectiveness of TMZ. Considering the rapid evolution of the disease, methods to assess TMZ efficacy early during treatment would be of great benefit. Our aim was to monitor early effects of TMZ in a mouse model of GBM using positron emission tomography (PET) with 3′-deoxy-3′-[¹⁸F]fluorothymidine ([¹⁸F]FLT).

Methods

Human glioma cells sensitive to TMZ (Gli36dEGFR-1) were treated with sub-lethal doses of TMZ to obtain cells with lower sensitivity to TMZ (Gli36dEGFR-2), as measured by growth and clonogenic assays. Gli36dEGFR-1 and Gli36dEGFR-2 cells were subcutaneously (s.c.) or intracranially (i.c.) xenografted into nude mice. Mice were treated for 7 days with daily injection of 25 or 50 mg/kg TMZ. Treatment efficacy was measured using [¹⁸F]FLT-PET before treatment and after 2 days. Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) were used to determine tumor volumes before treatment and after 7 days.

Results

A significant difference was observed between TMZ and DMSO treated tumors in terms of variations of [¹⁸F]FLT T/B ratio as soon as day 2 in the i.c. as well as in the s.c. mouse model. Variations of [¹⁸F]FLT T/B uptake ratio between days 0 and 2 correlated with variations of tumor size between days 0 and 7 (s.c. model: n_tumor = 17 in n_mice = 11, P<0.01; i.c. model: n_tumor/mice = 9, P<0.01).

Conclusions

Our results indicate that [¹⁸F]FLT-PET may be useful for an early evaluation of the response of GBM to TMZ chemotherapy in patients with glioma.     

Efficacy of cannabinoids against glioblastoma multiforme: A systematic review

IntroductionThe increased incidence of Glioblastoma Multiforme, the most aggressive and most common primary brain tumour, is evident worldwide. Survival rates are reaching only 15 months due to its high recurrence and resistance to current combination therapies including oncotomy, radiotherapy and chemotherapy. Light has been shed in the recent years on the anticancer properties of cannabinoids from Cannabis sativa.ObjectiveTo determine whether cannabinoids alone or in combination with radiotherapy and/or chemotherapy inhibit tumour progression, induce cancer cell death, inhibit metastasis and invasiveness and the mechanisms that underlie these actions.MethodPubMed and Web of Science were used for a systemic search to find studies on the anticancer effects of natural cannabinoids on glioma cancer cells in vitro and/or in vivo.ResultsA total of 302 papers were identified, of which 14 studies were found to fit the inclusion criteria. 5 studies were conducted in vitro, 2 in vivo and 7 were both in vivo and in vitro. 3 studies examined the efficacy of CBD, THC and TMZ, 1 study examined CBD and radiation, 2 studies examined efficacy of THC only and 3 studies examined the efficacy of CBD only. 1 study examined the efficacy of CBD, THC and radiotherapy, 2 studies examined the combination of CBD and THC and 2 more studies examined the efficacy of CBD and TMZ.ConclusionThe evidence in this systematic review leads to the conclusion that cannabinoids possess anticancer potencies against glioma cells, however this effect varies with the combinations and dosages used. Studies so far were conducted on cells in culture and on mice as well as a small number of studies that were conducted on humans. Hence in order to have more accurate results, higher quality studies mainly including human clinical trials with larger sample sizes are necessitated urgently for GBM treatment.     

替莫唑胺治疗胶质母细胞瘤的耐药性产生机制研究进展

胶质母细胞瘤作为胶质瘤中恶性程度最高的原发性脑部肿瘤,具有治愈率低、复发率高、呈浸润性生长等特点,在不使用化疗药物的情况下,患者中位生存期仅为12.1个月。胶质母细胞瘤患者的标准治疗方法以手术切除为主,放化疗为辅,其中替莫唑胺（temozolomide,TMZ）作为一种新型的口服烷化剂,是目前用于胶质瘤化学治疗的一线药物。但经过替莫唑胺治疗后,患者中位生存期仅提高了2个月,主要原因为胶质母细胞瘤可对TMZ产生耐药性。胶质母细胞瘤对TMZ产生的耐药机制主要为DNA修复机制,其包括了O⁶?甲基鸟嘌呤DNA甲基转移酶（O⁶?methyl guanine DNA methyltransferase,MGMT）对药物作用位点进行的直接修复、错配修复（mismatch repair,MMR）及碱基切除修复（base excision repair,BER）,这些修复机制可修复TMZ引起的DNA损伤,从而降低肿瘤细胞对TMZ敏感性。通过对近年来胶质母细胞瘤的TMZ耐药机制的研究进展进行介绍,旨在为发展新的治疗手段提供理论基础。     

PF化疗同步联合时辰放疗与常规放疗治疗局部晚期鼻咽癌的随机对照研究

目的:比较局部晚期鼻咽癌分别接受顺铂联合氟尿嘧啶方案(PF)化疗联合时辰放疗以及PF化疗联合常规放疗时的疗效和毒副反应。方法:将我科45例初治局部晚期鼻咽癌患者随机分为时辰放疗组和常规放疗组,分别为22例和23例。两组均采用相同放射治疗方法和治疗剂量,同步给予PF方案化疗。时辰放疗组放疗时间在20:00-22:00,而常规放疗组在8:00-10:00。结果:两组患者在放疗结束3个月和6个月进行时比较发现,时辰放疗组患者的鼻咽部及颈部的肿瘤完全消退率(CR率)均比常规放疗组高(P<0.05)。而时辰放疗组的各种急性副作用发生率较常规放疗组低,但无统计学差异。治疗后时辰组CD4/CD8升高,常规组CD4/CD8降低(P<0.05)。结论:时辰放疗联合PF同步化疗针对局部晚期鼻咽癌患者疗效好,毒副作用轻,同时可能有利于改善患者的免疫功能。     

非小细胞肺癌的免疫治疗进展

肺癌是最致命的恶性肿瘤之一,也是男性肿瘤患者致死率最高的,5年生存率低于18%。尽管非小细胞肺癌(non-small cell lung cancer,NSCLC)在手术治疗、化疗、放疗以及靶向治疗方面均取得了一定的成果,但晚期NSCLC的预后依然很差。免疫治疗为NSCLC患者提供了一个新的治疗方向。免疫治疗目前主要研究方向在免疫检查点抑制剂(Ipilimumab、Nivolumab、MK-3475)和肿瘤疫苗(MAGE-A3,L-BLP25,TG4010,Belagenpumatucel-L)等。免疫治疗具有针对性强、副作用少、效率高的特点,并在Ⅱ、Ⅲ期临床试验中取得了较好的疗效,成为在手术、化疗、放疗以及靶向治疗后一种新的重要治疗手段。本文就当前非小细胞肺癌免疫治疗原理、临床试验及待解决问题作一综述。     

Hypofractionated radiation therapy with temozolomide versus standard chemoradiation in patients with glioblastoma multiforme (GBM): A prospective,single institution experience

Background and aim: the study aimed to determine whether hypofractionated radiotherapy (HFRT) with simultaneous and adjuvant temozolomide (TMZ) was feasible and could provide adequate disease control in primary GBM patients with poor prognostic factors including large tumor size, poor performance status, unresectable or multifocal lesions, poor imaging and inflammatory indices. Patients and methods: A total of 93 patients with glioblastoma multiforme were collected and distributed randomly as 1:1.7 of cases to controls; cases or arm (I) received HFRT with 45 Gy in 15 fractions over 3 weeks concurrently with TMZ. Controls or arm (II) received standard conventional fractionation radiotherapy of 60 Gy in 30 fractions over 6 weeks concurrently with TMZ. Results: 35 patients were recruited in arm I while 58 patients in arm II with significant difference in site of GBM, pattern of enhancement, type of surgery, and neutrophil to lymphocyte ratio, while no significant differences in tumor size, focality, responses, progression free survival, and overall survival (OS), only the type of surgery was an independent predictor for OS, no significant difference in the type and degree of toxicity between both arms. Conclusion: Our results showed that HFRT with concurrent TMZ is a feasible therapeutic approach in patients with GBM, especially those with poor prognostic factors, assuring high treatment compliance and low toxicity rates. Dose escalation and reduction in overall treatment time are clear advantages of HFRT, while at least the same survival rates as conventional fractionated RT are maintained.     

Factors influencing the use of adaptive radiation therapy in vulvar carcinoma

AimWe aim to evaluate the variables affecting the frequency of adaptive radiotherapy (ART) in vulvar cancer.BackgroundART may be needed throughout a definitive RT course for vulvar carcinoma due to changes in patient’s anatomy and tumor response.Materials and methodsCharts of patients charts who had been treated with definitive concurrent chemo-radiotherapy for vulvar carcinoma, between January 2015 and December 2019 were inquired. Radiation therapy was delivered using intensity modulated radiotherapy (IMRT) with daily image-guided radiotherapy (IGRT). ART was defined as re-simulation and re-planning based on deformation in the irradiated volume by more than 1 cm. Univariate analysis was conducted to study the impact of patient’s demographics as well as tumor characteristics on the frequency of ART.Results22 patients were eligible for analysis. Median age at diagnosis was 55 years (range 43–82). Radiotherapy dose was 60−66 Gy over 30–35 fractions (fx). Median primary tumor volume was 30cc (9–140). Median Body Mass Index (BMI) was 32 (range 21–40). Thirteen out of 22 patients (59%) required ART, with median timing at 25 fx (19–31). On univariate analysis, larger primary tumor volume (> = 30cc) was associated significantly with increased frequency of ART (p value = 0.0005). There was no significant impact of ART on the frequency with respect to patient’s age, BMI, tumor stage, grade and location.ConclusionChanges in radiation target volume are common among vulvar carcinoma patients who are treated with definitive radiotherapy, especially large primary tumors. This review highlights the importance of ART for patients with vulvar carcinoma treated with definitive radiotherapy.     

BET bromodomain proteins are required for glioblastoma cell proliferation

Epigenetic proteins have recently emerged as novel anticancer targets. Among these, bromodomain and extra terminal domain (BET) proteins recognize lysine-acetylated histones, thereby regulating gene expression. Newly described small molecules that inhibit BET proteins BRD2, BRD3, and BRD4 reduce proliferation of NUT (nuclear protein in testis)-midline carcinoma, multiple myeloma, and leukemia cells in vitro and in vivo. These findings prompted us to determine whether BET proteins may be therapeutic targets in the most common primary adult brain tumor, glioblastoma (GBM). We performed NanoString analysis of GBM tumor samples and controls to identify novel therapeutic targets. Several cell proliferation assays of GBM cell lines and stem cells were used to analyze the efficacy of the drug I-BET151 relative to temozolomide (TMZ) or cell cycle inhibitors. Lastly, we performed xenograft experiments to determine the efficacy of I-BET151 in vivo. We demonstrate that BRD2 and BRD4 RNA are significantly overexpressed in GBM, suggesting that BET protein inhibition may be an effective means of reducing GBM cell proliferation. Disruption of BRD4 expression in glioblastoma cells reduced cell cycle progression. Similarly, treatment with the BET protein inhibitor I-BET151 reduced GBM cell proliferation in vitro and in vivo. I-BET151 treatment enriched cells at the G1/S cell cycle transition. Importantly, I-BET151 is as potent at inhibiting GBM cell proliferation as TMZ, the current chemotherapy treatment administered to GBM patients. Since I-BET151 inhibits GBM cell proliferation by arresting cell cycle progression, we propose that BET protein inhibition may be a viable therapeutic option for GBM patients suffering from TMZ resistant tumors.     

Subgroup economic analysis for glioblastoma in a health resource-limited setting

Background

The aim of this research was to evaluate the economic outcomes of radiotherapy (RT), temozolomide (TMZ) and nitrosourea (NT) strategies for glioblastoma patients with different prognostic factors.

Methodology/Principal Findings

A Markov model was developed to track monthly patient transitions. Transition probabilities and utilities were derived primarily from published reports. Costs were estimated from the perspective of the Chinese healthcare system. The survival data with different prognostic factors were simulated using Weibull survival models. Costs over a 5-year period and quality-adjusted life years (QALYs) were estimated. Probabilistic sensitivity and one-way analyses were performed. The baseline analysis in the overall cohort showed that the TMZ strategy increased the cost and QALY relative to the RT strategy by $25,328.4 and 0.29, respectively; and the TMZ strategy increased the cost and QALY relative to the NT strategy by $23,906.5 and 0.25, respectively. Therefore, the incremental cost effectiveness ratio (ICER) per additional QALY of the TMZ strategy, relative to the RT strategy and the NT strategy, amounts to $87,940.6 and $94,968.3, respectively. Subgroups with more favorable prognostic factors achieved more health benefits with improved ICERs. Probabilistic sensitivity analyses confirmed that the TMZ strategy was not cost-effective. In general, the results were most sensitive to the cost of TMZ, which indicates that better outcomes could be achieved by decreasing the cost of TMZ.

Conclusions/Significance

In health resource-limited settings, TMZ is not a cost-effective option for glioblastoma patients. Selecting patients with more favorable prognostic factors increases the likelihood of cost-effectiveness.