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Repurposing chlorpromazine in the treatment of glioblastoma multiforme: analysis of literature and forthcoming steps.

氯丙嗪治疗多形性胶质母细胞瘤的再利用: 文献分析和即将采取的步骤。

  • 影响因子:5.34
  • DOI:10.1186/s13046-020-1534-z
  • 作者列表:"Abbruzzese C","Matteoni S","Persico M","Villani V","Paggi MG
  • 发表时间:2020-01-31
Abstract

BACKGROUND:Glioblastoma multiforme is a CNS cancer characterized by diffuse infiltrative growth, aggressive clinical behavior and very poor prognosis. The state-of-art clinical approach to this disease consists of surgical resection followed by radiotherapy plus concurrent and adjuvant chemotherapy with temozolomide. Tumor recurrence occurs in virtually all cases, therefore, despite any treatment, the median survival is very low (14.6 months), which makes the approach to these patients a challenging clinical issue. MAIN BODY:The escalating costs and times required for new medications to reach the bedside make repurposing or repositioning of old drugs, when scientific bases allow their use in other pathologies, an appealing strategy. Here, we analyze a number of literature data concerning the antipsychotic chlorpromazine, the founder of the phenothiazines class of drugs, a medication widely used in the clinics for approximately 60 years. The drug exerts its effects on psychiatric patients by interfering with the dopamine receptor D2, although more recent pharmacodynamics studies ascribe chlorpromazine a series of biological effects on cancer cells, all converging in hindering also glioblastoma survival capabilities. SHORT CONCLUSIONS:On these bases, and assisted by the information on the well-established chlorpromazine toxicity and dosage in humans, we designed a Phase II clinical trial involving the combination of chlorpromazine with the standard treatment, temozolomide, in the adjuvant phase of the therapeutic protocol. Patients displaying hypo-methylation of the MGMT gene, and thus intrinsically resistant to temozolomide, will be enrolled. The endpoints of this study are the analysis of toxicity and clinical activity, as evaluated in terms of Progression-Free Survival, of the association of chlorpromazine with the first-line treatment for this very serious form of cancer.

摘要

背景: 多形性胶质母细胞瘤是一种以弥漫性浸润性生长、侵袭性临床行为和预后极差为特征的中枢神经系统肿瘤。该病的最新临床治疗方法包括手术切除后放疗加替莫唑胺同步和辅助化疗。几乎所有病例都有肿瘤复发,因此,尽管有任何治疗,中位生存期非常低 (14.6 个月),这使得治疗这些患者的方法成为一个具有挑战性的临床问题。 正文: 新药物到达床边所需的不断增加的成本和时间使旧药物重新利用或重新定位,当科学基础允许它们在其他病状中使用时,这是一个吸引人的策略。在此,我们分析了一些关于抗精神病药氯丙嗪的文献数据,该药物是吩噻嗪类药物的创始人,该药物在诊所广泛使用了大约 60 年。该药通过干扰多巴胺 D2 受体对精神病患者发挥作用,尽管最近的药效学研究将氯丙嗪归因于对癌细胞的一系列生物学作用, 所有这些都阻碍了胶质母细胞瘤的生存能力。 简短结论: 在这些基础上,并辅以关于氯丙嗪在人类中的毒性和剂量的信息, 我们设计了一项 II 期临床试验,涉及在治疗方案的辅助阶段将氯丙嗪与标准治疗替莫唑胺联合使用。将入组显示 MGMT 基因低甲基化,因此对替莫唑胺固有耐药的患者。本研究的终点是毒性和临床活性的分析,根据无进展生存期进行评价, 氯丙嗪与这种非常严重癌症的一线治疗的相关性。

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影响因子:4.01
发表时间:2020-01-30
DOI:10.1002/mrm.28183
作者列表:["Tiwari V","Mashimo T","An Z","Vemireddy V","Piccirillo S","Askari P","Hulsey KM","Zhang S","de Graaf RA","Patel TR","Pan E","Mickey BE","Maher EA","Bachoo RM","Choi C"]

METHODS:PURPOSE:To generate a preclinical model of isocitrate dehydrogenase (IDH) mutant gliomas from glioma patients and design a MRS method to test the compatibility of 2-hydroxyglutarate (2HG) production between the preclinical model and patients. METHODS:Five patient-derived xenograft (PDX) mice were generated from two glioma patients with IDH1 R132H mutation. A PRESS sequence was tailored at 9.4 T, with computer simulation and phantom analyses, for improving 2HG detection in mice. 2HG and other metabolites in the PDX mice were measured using the optimized MRS at 9.4 T and compared with 3 T MRS measurements of the metabolites in the parental-tumor patients. Spectral fitting was performed with LCModel using in-house basis spectra. Metabolite levels were quantified with reference to water. RESULTS:The PRESS TE was optimized to be 96 ms, at which the 2HG 2.25 ppm signal was narrow and inverted, thereby leading to unequivocal separation of the 2HG resonance from adjacent signals from other metabolites. The optimized MRS provided precise detection of 2HG in mice compared to short-TE MRS at 9.4 T. The 2HG estimates in PDX mice were in excellent agreement with the 2HG measurements in the patients. CONCLUSION:The similarity of 2HG production between PDX models and parental-tumor patients indicates that PDX tumors retain the parental IDH metabolic fingerprint and can serve as a preclinical model for improving our understanding of the IDH-mutation associated metabolic reprogramming.

影响因子:3.29
发表时间:2020-01-31
来源期刊:BMC cancer
DOI:10.1186/s12885-020-6536-x
作者列表:["Ang SYL","Lee L","See AAQ","Ang TY","Ang BT","King NKK"]

METHODS:BACKGROUND:Gliomas consist of a heterogeneous group of tumors. This study aimed to report the incidences of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, 1p19q co-deletion, isocitrate dehydrogenase (IDH) gene mutations, and inactivating mutations of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) in high-grade gliomas in an ethnically diverse population. METHODS:Records of patients who underwent surgery for high-grade gliomas from January 2013 to March 2017 at our institution were obtained. The patients' age, gender, ethnicity, Karnofsky Performance Scale (KPS) score, ability to perform activities of daily living (ADLs), tumor location and biomarkers status were recorded. Data were analyzed using chi-square and Mann-Whitney U tests, Kaplan-Meier estimates and log-rank test. RESULTS:181 patients were selected (56 with grade III gliomas, 125 with grade IV gliomas). In the grade III group, 55% had MGMT promoter methylation, 41% had 1p19q co-deletion, 35% had IDH1 mutation and none had ATRX loss. In the grade IV group, 30% had MGMT promoter methylation, 2% had 1p19q co-deletion, 15% had IDH1 mutation and 8% had ATRX loss. After adjusting for effects of age, surgery and pre-operative ADL statuses, only MGMT promoter methylation was found to be significantly associated with longer overall survival time in grade III (p = 0.024) and IV patients (p = 0.006). CONCLUSIONS:The incidences of MGMT promoter methylation and IDH1 mutation were found to be comparable to globally reported rates, but those of 1p19q co-deletion and ATRX loss seemed to be lower in our cohort. MGMT promoter methylation was associated with increased overall survival in our cohort and might serve as favorable prognostic factor.

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影响因子:5.34
发表时间:2020-01-31
DOI:10.1186/s13046-020-1534-z
作者列表:["Abbruzzese C","Matteoni S","Persico M","Villani V","Paggi MG"]

METHODS:BACKGROUND:Glioblastoma multiforme is a CNS cancer characterized by diffuse infiltrative growth, aggressive clinical behavior and very poor prognosis. The state-of-art clinical approach to this disease consists of surgical resection followed by radiotherapy plus concurrent and adjuvant chemotherapy with temozolomide. Tumor recurrence occurs in virtually all cases, therefore, despite any treatment, the median survival is very low (14.6 months), which makes the approach to these patients a challenging clinical issue. MAIN BODY:The escalating costs and times required for new medications to reach the bedside make repurposing or repositioning of old drugs, when scientific bases allow their use in other pathologies, an appealing strategy. Here, we analyze a number of literature data concerning the antipsychotic chlorpromazine, the founder of the phenothiazines class of drugs, a medication widely used in the clinics for approximately 60 years. The drug exerts its effects on psychiatric patients by interfering with the dopamine receptor D2, although more recent pharmacodynamics studies ascribe chlorpromazine a series of biological effects on cancer cells, all converging in hindering also glioblastoma survival capabilities. SHORT CONCLUSIONS:On these bases, and assisted by the information on the well-established chlorpromazine toxicity and dosage in humans, we designed a Phase II clinical trial involving the combination of chlorpromazine with the standard treatment, temozolomide, in the adjuvant phase of the therapeutic protocol. Patients displaying hypo-methylation of the MGMT gene, and thus intrinsically resistant to temozolomide, will be enrolled. The endpoints of this study are the analysis of toxicity and clinical activity, as evaluated in terms of Progression-Free Survival, of the association of chlorpromazine with the first-line treatment for this very serious form of cancer.

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