RESUMO
The mechanisms underlying stimuli-induced dynamic structural remodeling of RNAs for the maintenance of cellular physiological function and survival remain unclear. Here, we showed that in MGMT promoter-methylated glioblastoma (GBM), the RNA helicase DEAD-box helicase 46 (DDX46) is phosphorylated by temozolomide (TMZ)-activated checkpoint kinase 1 (CHK1), resulting in a dense-to-loose conformational change and an increase in DDX46 helicase activity. DDX46-mediated tertiary structural remodeling of LINC01956 exposes the binding motifs of LINC01956 to the 3' untranslated region of O6-methylguanine DNA methyltransferase (MGMT). This accelerates recruitment of MGMT mRNA to the RNA export machinery and transportation of MGMT mRNA from the nucleus to the cytoplasm, leading to increased MGMT abundance and TMZ resistance. Using patient-derived xenograft (PDX) and tumor organoid models, we found that treatment with the CHK1 inhibitor SRA737abolishes TMZ-induced structural remodeling of LINC01956 and subsequent MGMT up-regulation, resensitizing TMZ-resistant MGMT promoter-methylated GBM to TMZ. In conclusion, these findings highlight a mechanism underlying temozolomide-induced RNA structural remodeling and may represent a potential therapeutic strategy for patients with TMZ-resistant MGMT promoter-methylated GBM.
Assuntos
RNA Helicases DEAD-box , Metilases de Modificação do DNA , Resistencia a Medicamentos Antineoplásicos , Glioblastoma , RNA Longo não Codificante , Temozolomida , Proteínas Supressoras de Tumor , Glioblastoma/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/metabolismo , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Humanos , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Animais , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genética , RNA Helicases DEAD-box/metabolismo , RNA Helicases DEAD-box/genética , Metilases de Modificação do DNA/metabolismo , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Enzimas Reparadoras do DNA/genética , Regiões Promotoras Genéticas/genética , Metilação de DNA/genética , Metilação de DNA/efeitos dos fármacos , Quinase 1 do Ponto de Checagem/metabolismo , Quinase 1 do Ponto de Checagem/genética , Linhagem Celular Tumoral , Camundongos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Fosforilação/efeitos dos fármacosRESUMO
Solitary fibrous tumours (SFTs) and chronic myeloid leukaemia (CML) are both uncommon neoplasms with distinct chromosomal aberrations and clinical presentations. Here, we present a case of a male in his late 50s with a history of intracranial SFT who presented 8 years after subtotal resection and adjuvant radiotherapy with splenic infarcts, a white blood cell of 83 000 cells/mL, and liver masses. He was treated with dasatinib for CML and temozolomide/bevacizumab for SFT. This case emphasises the benefits of broad differential diagnoses that include multiple concurrent disease processes when confronted with unusual presentations. It highlights the need for interdisciplinary efforts and personalised approaches when managing patients with multiple primary malignancies.
Assuntos
Neoplasias Encefálicas , Leucemia Mielogênica Crônica BCR-ABL Positiva , Tumores Fibrosos Solitários , Humanos , Masculino , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Neoplasias Encefálicas/diagnóstico , Tumores Fibrosos Solitários/diagnóstico , Tumores Fibrosos Solitários/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Diagnóstico Diferencial , Dasatinibe/uso terapêutico , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/patologia , Temozolomida/uso terapêuticoRESUMO
Low-grade gliomas (LGG) are brain tumors of glial cells origin. They are grade 1 and grade 2 tumors according to the WHO classification. Diagnosis of LGG is made through imaging, histopathological analysis, and use of molecular markers. Imaging alone does not establish the grade of the tumor and thus a histopathological examination of tissue is crucial in establishing the definite histopathological diagnosis. Clinical presentation varies according to the location and size of the tumor. Surgical resection is strongly recommended in LGG over observation to improve overall survival as surgery leads to greater benefit due to progression-free survival. Radiation has shown benefits in LGG patients in randomized controlled trials and chemotherapy with temozolomide has also shown good results. This paper covers the principles of low-grade gliomas management and summarizes the recommendations for the LMICs.
Assuntos
Neoplasias Encefálicas , Países em Desenvolvimento , Glioma , Humanos , Glioma/terapia , Glioma/patologia , Glioma/diagnóstico , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/diagnóstico , Gradação de Tumores , Temozolomida/uso terapêutico , Consenso , AdultoRESUMO
BACKGROUND: Glioblastoma (GBM) is the most aggressive primary malignant brain tumor. Temozolomide (TMZ) is the most used first-line chemotherapeutic agent for GBM after surgery, but acquired resistance to TMZ frequently leads to treatment failure and is a major challenge in the clinical treatment of GBM. Increasing evidence suggests that E2F transcription factor 6 (E2F6) is associated with a variety of tumor malignant biological behaviors and drug resistance, but its biological function and underlying molecular mechanisms in GBM are unknown. METHODS: The study investigated the levels of E2F6 in both TMZ-sensitive and TMZ-resistant GBM cells and tissues using Western blotting and immunofluorescence assays. In vitro experiments were conducted to explore the impact of E2F6 on TMZ resistance and glioma stem cell stemness. These experiments included Western blotting, colony formation assay, flow cytometry assay, and TdT-mediated dUTP nick-end labeling (TUNEL) assay. Bioinformatic analyses were conducted to investigate the mechanism behind the high expression of E2F6 in TMZ-resistant cells and its correlation with caspase recruitment domain 6 (CARD6) and disulfide-linked cell adhesion protein (POSTN). The study employed bioinformatic analyses, messenger RNA (mRNA) sequencing, chromatin immunoprecipitation sequencing assay, immunofluorescence, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. To examine the function of E2F6, an intracranial xenograft tumor mouse model was used for in vivo experiments. RESULTS: It was found that CARD6 and POSTN were significantly associated with TMZ resistance and survival of GBM patients. E2F6 was up-regulated in TMZ-resistant cells and tissues. Knockdown of E2F6 down-regulated the expression of CARD6, promoted TMZ-induced apoptosis, and enhanced chemo-sensitivity, whereas its overexpression significantly increased TMZ resistance in vitro and in vivo. In addition, E2F6 can promote TMZ resistance through stem-like properties acquisition. We identified a signaling pathway related to E2F6 and POSTN, which maintains the self-renewal of GBM stem cells (GSCs). E2F6 concentrates in the promoter region of POSTN, thereby regulating the expression of GSCs-related genes cluster of differentiation 133 (CD133), Nestin, and sex-determining region Y-box 2 (SOX2), which may be involved in tumor metabolism and drug resistance processes. Down-regulation of E2F6 down-regulated the expression of POSTN and inhibited tumor growth in nude mice. CONCLUSIONS: These results suggest that the E2F6-CARD6/POSTN signaling axis regulates the malignant biological behaviors of GBM and TMZ resistance. These findings are expected to provide promising therapeutic targets for CARD6 overcoming GBM TMZ resistance.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Glioblastoma , Temozolomida , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Humanos , Camundongos , Animais , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas Adaptadoras de Sinalização CARD/genética , Regiões Promotoras Genéticas , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Camundongos NusRESUMO
BACKGROUND: The low level of median survival rate after complete therapy (i.e., surgery and concomitant chemotherapy and radiotherapy) in high-grade glioma (HGG) patients reflects the needs for a better understanding about HGG pathogenesis, including the role of epigenetic in glioma. MicroRNA (miRNA), a small chain non-coding RNA, has been increasingly utilized in the management of other oncology cases and might possess an immense potential in HGG. The expression of miRNA-10b and miRNA-21 (i.e., two miRNAs that are frequently studied due to its involvement in glioma) are higher in HGG patients and their role in regulatory mechanism of glioma has been established. However, the influence of those miRNAs in toxicity, recurrence, and overall survival of HGG patients is still unclear. We aim to assess the predictive value of plasma miRNA-10b and miRNA-21 in the chemotherapy toxicity, recurrence, and overall survival of HGG patients. METHODS: This is an observational analytic study using hospital-based mixed cohort approach. The study is conducted in RSUP Dr. Sardjito, Yogyakarta, from January 2021 to December 2024. We prospectively assess the plasma miRNA level from HGG patients who met the inclusive and exclusive criteria. The consecutive sampling is used until the sample size is met. Statistical analysis will be conducted for temozolomide toxicity using Spearman's rank correlation, for recurrence using logistical regression, and for overall survival test. RESULTS: In this ongoing study, we plan to collect samples from 155 HGG patients. As of April 2024, we managed to collect 96 samples (median age of 49 years and 55% of male patients). Most of the patients were diagnosed with World Health Organization (WHO) grade IV tumors (69.3%), with the most common diagnosis was glioblastoma (62%). Most of the patients had unmethylated O6-methylguanine-DNA methyltransferase (MGMT) and wild-type isocitrate dehydrogenase (IDH) status (62% and 57%, respectively). There was no difference in miRNA-21 expression based on MGMT status (methylated or unmethylated), nor IDH status (wild type or mutant), with P=0.39 and P=0.25, respectively. Moreover, we found no significant difference in miRNA-10b expression in both MGMT status and both IDH status (P=0.19 and P=0.09). As for the data regarding toxicity, recurrence, and overall survival was still on the process of data collection. CONCLUSIONS: MiRNA is a promising epigenetic modulator that might be utilized in HGG management. A better understanding on the role of miRNA in HGG patients might be able to improve clinical outcome.
Assuntos
Glioma , MicroRNAs , Recidiva Local de Neoplasia , Temozolomida , Humanos , MicroRNAs/sangue , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Glioma/tratamento farmacológico , Glioma/sangue , Glioma/genética , Masculino , Feminino , Pessoa de Meia-Idade , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Alquilantes/farmacologia , Adulto , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/sangueRESUMO
BACKGROUND: Temozolomide (TMZ) resistance in glioblastoma (GBM) remains a challenge in clinical treatment and the mechanism is largely unknown. Emerging evidence shows that epigenetic modifications including DNA methylation and non-coding RNA were involved in diverse biological processes, including therapeutic resistance. However, the underlying mechanisms by which DNA methylation-mediated non-coding RNA regulates TMZ resistance remain poorly characterized. METHODS: RNA microarray and DNA methylation chips of TMZ-resistant and parental GBM cells were performed for the gain of unreported long non-coding RNA HSD52. Quantitative reverse transcription polymerase chain reaction (PCR) and fluorescence in situ hybridization assays were used to detect HSD52 levels in GBM cells and tissues. The investigation into HSD52's impact on TMZ resistance was conducted utilizing both in vitro assays and intracranial xenograft mouse models. The mechanism of HSD52 expression and its relationships with paraspeckle proteins, non-POU domain-containing octamer-binding protein (NONO) and splicing factor proline/glutamine rich (SFPQ), as well as alpha-thalassemia mental retardation X-linked (ATRX) mRNA were determined by pyrosequencing assay, chromatin immunoprecipitation, chromatin isolation by RNA purification, RNA immunoprecipitation, RNA pulldown, immunofluorescence, and western blot assays. RESULTS: HSD52 was highly expressed in high-grade glioma and TMZ-resistant GBM cells. Phosphorylated p38 mitogen-activated protein kinase (p38 MAPK)/ubiquitin specific peptidase 7 (USP7) axis mediates H3 ubiquitination, impairs the interaction between H3K23ub and DNA methyltransferase 1 (DNMT1) and the recruitment of DNMT1 at the HSD52 promoter to attenuate DNA methylation, which makes the transcription factor 12 (TCF12) more accessible to the promoter region to regulate HSD52 expression. Further analysis showed that HSD52 can serve as a scaffold to promote the interaction between NONO and SFPQ, and then increase the paraspeckle assembly and activate the paraspeckle/ataxia telangiectasia mutated (ATM) kinase pathway in GBM cells. In addition, HSD52 forms an RNA-RNA duplex with ATRX mRNA, and facilitates the association of heteromer of SFPQ and NONO with RNA duplex, thus leading to the increase of ATRX mRNA stability and level. In clinical patients, HSD52 is required for TMZ resistance and GBM recurrence. CONCLUSIONS: Our results reveal that HSD52 in GBM could serve as a therapeutic target to overcome TMZ resistance, enhancing the clinical benefits of TMZ chemotherapy.
Assuntos
Metilação de DNA , Resistencia a Medicamentos Antineoplásicos , Temozolomida , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Humanos , Camundongos , Animais , Linhagem Celular Tumoral , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , RNA Longo não Codificante/genética , Glioblastoma/genética , Glioblastoma/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamento farmacológico , MasculinoRESUMO
Introduction: This is a prospective, rigorous inquiry into the systemic immune effects of standard adjuvant chemoradiotherapy, for WHO grade 4, glioblastoma. The purpose is to identify peripheral immunologic effects never yet reported in key immune populations, including myeloid-derived suppressor cells, which are critical to the immune suppressive environment of glioblastoma. We hypothesize that harmful immune-supportive white blood cells, myeloid derived suppressor cells, expand in response to conventionally fractionated radiotherapy with concurrent temozolomide, essentially promoting systemic immunity similar what is seen in chronic diseases like diabetes and heart disease. Methods: 16 patients were enrolled in a single-institution, observational, immune surveillance study where peripheral blood was collected and interrogated by flow cytometry and RNAseq. Tumor tissue from baseline assessment was analyzed with spatial proteomics to link peripheral blood findings to baseline tissue characteristics. Results: We identified an increase in myeloid-derived suppressor cells during the final week of a six-week treatment of chemoradiotherapy in peripheral blood of patients that were not alive at two years after diagnosis compared to those who were living. This was also associated with a decrease in CD8+ T lymphocytes that produced IFNγ, the potent anti-tumor cytokine. Discussion: These data suggest that, as in chronic inflammatory disease, systemic immunity is impaired following delivery of adjuvant chemoradiotherapy. Finally, baseline investigation of myeloid cells within tumor tissue did not differ between survival groups, indicating immune surveillance of peripheral blood during adjuvant therapy may be a critical missing link to educate our understanding of the immune effects of standard of care therapy for glioblastoma.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Células Supressoras Mieloides , Humanos , Glioblastoma/terapia , Glioblastoma/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Idoso , Quimiorradioterapia/métodos , Adulto , Temozolomida/uso terapêutico , Temozolomida/farmacologia , Linfócitos T CD8-Positivos/imunologia , Estudos Prospectivos , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND/AIM: To investigate the significance of the timing of chemoradiotherapy together with clinical and laboratory features in newly diagnosed glioblastoma. PATIENTS AND METHODS: Clinical and laboratory parameters of 209 patients with glioblastoma potentially influencing overall (OS) and progression-free (PFS) survival were analyzed in univariable and multivariable models. RESULTS: On univariable analyses, Karnofsky performance status (p<0.001), recursive partitioning analysis (RPA) class (p<0.001), O6-methylguanine-DNA methyltransferase (MGMT)-status (p<0.001), extent of resection (p<0.001), radiotherapy dose (p=0.01), and the number of adjuvant temozolomide (TMZ) cycles (p<0.001) were significantly associated with OS. Additionally, MGMT-status (p<0.001), extent of resection (p=0.03), surgical site infections (p=0.02), and the number of adjuvant TMZ cycles (p<0.001) were significantly associated with PFS. Multivariable analysis identified radiotherapy dose as the only independent predictor (p=0.049) of OS. MGMT-status (p=0.02) and the number of adjuvant TMZ cycles (p<0.001) were independent predictors of PFS. CONCLUSION: The timing of chemoradiotherapy did not play a prognostic role. For OS, the radiotherapy dose, and for PFS, MGMT-status and the number of adjuvant TMZ cycles were identified as independent prognostic factors.
Assuntos
Neoplasias Encefálicas , Quimiorradioterapia , Glioblastoma , Temozolomida , Humanos , Glioblastoma/terapia , Glioblastoma/mortalidade , Feminino , Masculino , Pessoa de Meia-Idade , Quimiorradioterapia/métodos , Idoso , Adulto , Prognóstico , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/tratamento farmacológico , Temozolomida/uso terapêutico , Adulto Jovem , Idoso de 80 Anos ou mais , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Fatores de Tempo , Intervalo Livre de Progressão , Proteínas Supressoras de Tumor , Enzimas Reparadoras do DNAAssuntos
Bevacizumab , Neoplasias Encefálicas , Glioblastoma , Temozolomida , Humanos , Bevacizumab/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/terapia , Temozolomida/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/terapia , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Alquilantes/administração & dosagemRESUMO
As the most common and aggressive primary malignant brain tumor, glioblastoma is still lacking a satisfactory curative approach. The standard management consisting of gross total resection followed by radiotherapy and chemotherapy with temozolomide only prolongs patients' life moderately. In recent years, many therapeutics have failed to give a breakthrough in GBM treatment. In the search for new treatment solutions, we became interested in the repurposing of existing medicines, which have established safety profiles. We focused on the possible implementation of well-known drugs, metformin, and arginine. Metformin is widely used in diabetes treatment, but arginine is mainly a cardiovascular protective drug. We evaluated the effects of metformin and arginine on total DNA methylation, as well as the oxidative stress evoked by treatment with those agents. In glioblastoma cell lines, a decrease in 5-methylcytosine contents was observed with increasing drug concentration. When combined with temozolomide, both guanidines parallelly increased DNA methylation and decreased 8-oxo-deoxyguanosine contents. These effects can be explained by specific interactions of the guanidine group with m5CpG dinucleotide. We showed that metformin and arginine act on the epigenetic level, influencing the foreground and potent DNA regulatory mechanisms. Therefore, they can be used separately or in combination with temozolomide, in various stages of disease, depending on desired treatment effects.
Assuntos
Arginina , Metilação de DNA , Reposicionamento de Medicamentos , Glioblastoma , Metformina , Temozolomida , Metformina/farmacologia , Metformina/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Humanos , Arginina/metabolismo , Reposicionamento de Medicamentos/métodos , Metilação de DNA/efeitos dos fármacos , Linhagem Celular Tumoral , Temozolomida/uso terapêutico , Temozolomida/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , 5-Metilcitosina/metabolismo , 5-Metilcitosina/análogos & derivadosRESUMO
BACKGROUND: Patients diagnosed with glioblastoma multiforme (GBM) often undergo concurrent temozolomide and radiation therapy. Antineoplastic medication nonadherence continues to be an issue for patients with cancer. OBJECTIVES: This quality improvement project aimed to institute an evidence-based standardized educational tool for patients with GBM undergoing concurrent temozolomide and radiation therapy. METHODS: To assess medication adherence, patients completed the Brief Adherence Rating Scale at the end of the last radiation therapy visit. Patients and providers completed satisfaction surveys. FINDINGS: Data analysis from the administered Brief Adherence Rating Scale demonstrated a mean of 99.3% (N = 13) medication adherence among participants. Median medication adherence was demonstrated to be 100%, with scores ranging from 93% to 100%.
Assuntos
Antineoplásicos Alquilantes , Neoplasias Encefálicas , Glioblastoma , Educação de Pacientes como Assunto , Temozolomida , Humanos , Temozolomida/uso terapêutico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/tratamento farmacológico , Masculino , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Glioblastoma/terapia , Pessoa de Meia-Idade , Educação de Pacientes como Assunto/métodos , Antineoplásicos Alquilantes/uso terapêutico , Idoso , Adulto , Adesão à Medicação , Quimiorradioterapia , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêuticoAssuntos
Neoplasias Encefálicas , Glioblastoma , Temozolomida , Glioblastoma/tratamento farmacológico , Glioblastoma/mortalidade , Temozolomida/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Humanos , Biguanidas/uso terapêutico , Animais , Antineoplásicos Alquilantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Metanálise como AssuntoRESUMO
BACKGROUND: For treating recurrent glioblastoma, for which there is no established treatment, the antiangiogenic antibody, bevacizumab, is used alone or with irinotecan. This study was aimed at comparing the survival of patients with recurrent glioblastoma receiving bevacizumab monotherapy and those receiving bevacizumab plus irinotecan combination therapy (B+I) by using a nationwide population-based dataset. METHODS: Patients matching the International Classification of Diseases code C71.x were screened from the Health Insurance Review and Assessment Service database. From January 2008 to November 2021, patients who underwent surgery or biopsy and subsequent standard concurrent chemoradiation with temozolomide were included. Among them, those who received bevacizumab monotherapy or B+I were selected. Demographic characteristics, inpatient stay, prescription frequency, survival outcomes, and steroid prescription duration were compared between these two groups. RESULTS: Eight hundred and forty-six patients who underwent surgery or biopsy and received concurrent chemoradiotherapy with temozolomide were included. Of these, 450 and 396 received bevacizumab monotherapy and B+I, respectively. The corresponding median overall survival from the initial surgery was 22.60 months (95% confidence interval [CI], 20.50-24.21) and 20.44 months (95% CI, 18.55-22.60; P = 0.508, log-rank test). The B+I group had significantly more bevacizumab prescriptions (median 5 times; BEV group: median 3 times). Cox analysis, based on the postsurgery period, revealed that male sex (hazard ratio [HR], 1.28; P = 0.002), older age (HR, 1.01; P = 0.042), and undergoing biopsy instead of surgery (HR, 1.79; P < 0.0001) were significantly associated with decreased survival. Fewer radiotherapy cycles correlated with improved survival outcomes (HR, 0.63; P = 0.001). Cox analysis, conducted from the start of chemotherapy including bevacizumab, showed that male sex was the only variable significantly associated with decreased survival (HR, 1.18; P = 0.044). CONCLUSION: We found no significant difference in overall survival between the bevacizumab monotherapy and B+I groups. Considering the additional potential toxicity associated with irinotecan, bevacizumab monotherapy could be a suitable treatment option for treating recurrent glioblastoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Glioblastoma , Irinotecano , Recidiva Local de Neoplasia , Humanos , Bevacizumab/uso terapêutico , Bevacizumab/administração & dosagem , Irinotecano/uso terapêutico , Masculino , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/mortalidade , Glioblastoma/terapia , Glioblastoma/patologia , Pessoa de Meia-Idade , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/mortalidade , Temozolomida/uso terapêutico , Estimativa de Kaplan-Meier , Estudos Retrospectivos , Quimiorradioterapia , Bases de Dados FactuaisRESUMO
Background: Glioblastoma (GBM) is a poor prognosis grade 4 glioma. After surgical resection, the standard therapy consists of concurrent radiotherapy (RT) and temozolomide (TMZ) followed by TMZ alone. Our previous data on melanoma patients showed that Dendritic Cell vaccination (DCvax) could increase the amount of intratumoral-activated cytotoxic T lymphocytes. Methods: This is a single-arm, monocentric, phase II trial in two steps according to Simon's design. The trial aims to evaluate progression-free survival (PFS) at three months and the safety of a DCvax integrated with standard therapy in resected GBM patients. DCvax administration begins after completion of RT-CTwith weekly administrations for 4 weeks, then is alternated monthly with TMZ cycles. The primary endpoints are PFS at three months and safety. One of the secondary objectives is to evaluate the immune response both in vitro and in vivo (DTH skin test). Results: By December 2022, the first pre-planned step of the study was concluded with the enrollment, treatment and follow up of 9 evaluable patients. Two patients had progressed within three months after leukapheresis, but none had experienced DCvax-related G3-4 toxicities Five patients experienced a positive DTH test towards KLH and one of these also towards autologous tumor homogenate. The median PFS from leukapheresis was 11.3 months and 12.2 months from surgery. Conclusions: This combination therapy is well-tolerated, and the two endpoints required for the first step have been achieved. Therefore, the study will proceed to enroll the remaining 19 patients. (Eudract number: 2020-003755-15 https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-003755-15/IT).
Assuntos
Neoplasias Encefálicas , Vacinas Anticâncer , Células Dendríticas , Glioblastoma , Humanos , Glioblastoma/terapia , Glioblastoma/imunologia , Glioblastoma/mortalidade , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Células Dendríticas/imunologia , Células Dendríticas/transplante , Pessoa de Meia-Idade , Feminino , Masculino , Adulto , Idoso , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/mortalidade , Temozolomida/uso terapêutico , Temozolomida/administração & dosagem , Intervalo Livre de ProgressãoRESUMO
Glioblastoma (GBM) represents a primary malignant brain tumor. Temozolomide resistance is a major hurdle in GBM treatment. Proteins encoded by circular RNAs (circRNAs) can modulate the sensitivity of multiple tumor chemotherapies. However, the impact of circRNA-encoded proteins on GBM sensitivity to temozolomide remains unknown. Herein, we discover a circRNA (circCOPA) through the circRNA microarray profile in GBM samples, which can encode a novel 99 amino acid protein (COPA-99aa) through its internal ribosome entry site. Functionally, circCOPA overexpression in GBM cells inhibits cell proliferation, migration, and invasion in vitro and growth in vivo. Rather than itself, circCOPA mainly functions as a suppressive effector by encoding COPA-99aa. Moreover, we reveal that circCOPA is downregulated in GBM tissues and high expression of circCOPA is related to a better prognosis in GBM patients. Mechanistically, a heteromer of SFPQ and NONO is required for double-strand DNA break repair. COPA-99aa disrupts the dimerization of NONO and SFPQ by separately binding with the NONO and SFPQ proteins, thus resulting in the inhibition of proliferation or invasion and the increase of temozolomide-induced DNA damage in GBM cells. Collectively, our data suggest that circCOPA mainly contributes to inhibiting the GBM malignant phenotype through its encoded COPA-99aa and that COPA-99aa increases temozolomide-induced DNA damage by interfering with the dimerization of NONO and SFPQ. Restoring circCOPA or COPA-99aa may increase the sensitivity of patients to temozolomide.
Assuntos
Neoplasias Encefálicas , Proliferação de Células , Glioblastoma , RNA Circular , Proteínas de Ligação a RNA , Temozolomida , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , RNA Circular/genética , RNA Circular/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Proliferação de Células/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Animais , Fator de Processamento Associado a PTB/metabolismo , Fator de Processamento Associado a PTB/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Fenótipo , Movimento Celular/efeitos dos fármacos , Camundongos , Reparo do DNA/efeitos dos fármacos , Camundongos Nus , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Antineoplásicos Alquilantes/farmacologiaRESUMO
Glioblastoma (GBM) is the most aggressive and common malignant and CNS tumor, accounting for 47.7% of total cases. Glioblastoma has an incidence rate of 3.21 cases per 100,000 people. The regulation of autophagy, a conserved cellular process involved in the degradation and recycling of cellular components, has been found to play an important role in GBM pathogenesis and response to therapy. Autophagy plays a dual role in promoting tumor survival and apoptosis, and here we discuss the complex interplay between autophagy and GBM. We summarize the mechanisms underlying autophagy dysregulation in GBM, including PI3K/AKT/mTOR signaling, which is most active in brain tumors, and EGFR and mutant EGFRvIII. We also review potential therapeutic strategies that target autophagy for the treatment of GBM, such as autophagy inhibitors used in combination with the standard of care, TMZ. We discuss our current understanding of how autophagy is involved in TMZ resistance and its role in glioblastoma development and survival.
Assuntos
Autofagia , Resistencia a Medicamentos Antineoplásicos , Glioblastoma , Temozolomida , Humanos , Autofagia/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/genética , Glioblastoma/metabolismo , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/genética , Transdução de Sinais/efeitos dos fármacos , AnimaisRESUMO
Drug resistance is one of the biggest challenges in the fight against cancer. In particular, in the case of glioblastoma, the most lethal brain tumour, resistance to temozolomide (the standard of care drug for chemotherapy in this tumour) is one of the main reasons behind treatment failure and hence responsible for the poor prognosis of patients diagnosed with this disease. In this work, we combine the power of three-dimensional in vitro experiments of treated glioblastoma spheroids with mathematical models of tumour evolution and adaptation. We use a novel approach based on internal variables for modelling the acquisition of resistance to temozolomide that was observed in experiments for a group of treated spheroids. These internal variables describe the cell's phenotypic state, which depends on the history of drug exposure and affects cell behaviour. We use model selection to determine the most parsimonious model and calibrate it to reproduce the experimental data, obtaining a high level of agreement between the in vitro and in silico outcomes. A sensitivity analysis is carried out to investigate the impact of each model parameter in the predictions. More importantly, we show how the model is useful for answering biological questions, such as what is the intrinsic adaptation mechanism, or for separating the sensitive and resistant populations. We conclude that the proposed in silico framework, in combination with experiments, can be useful to improve our understanding of the mechanisms behind drug resistance in glioblastoma and to eventually set some guidelines for the design of new treatment schemes.
Assuntos
Neoplasias Encefálicas , Resistencia a Medicamentos Antineoplásicos , Glioblastoma , Modelos Biológicos , Temozolomida , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Glioblastoma/tratamento farmacológico , Humanos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Alquilantes/farmacologia , Linhagem Celular Tumoral , Esferoides Celulares/efeitos dos fármacos , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Dacarbazina/farmacologia , Simulação por Computador , Adaptação FisiológicaRESUMO
Glioblastoma multiforme (GBM) is the most frequent primary brain malignancy in adults. Despite improvements in imaging and therapy, the prognosis remains poor. To evaluate and compare the impact of combining bevacizumab with temozolomide and radiotherapy on progression-free survival (PFS) and overall survival (OS) in patients diagnosed with GBM. A comprehensive search was conducted across multiple databases, including PubMed, Embase, Scopus, and The Cochrane Library, covering the period from their inception to December 2022. The collected data underwent analysis employing appropriate statistical methods. Six articles were included in this systematic review and meta-analysis. The addition of bevacizumab to the combination of temozolomide/radiotherapy did not increase the OS in GBM patients. The pooled odds ratio (OR) was 0.843 (95% CI: 0.615-1.156, P = 0.290). The addition of bevacizumab to radiotherapy/temozolomide did not increase the PFS in patients with GBM. The pooled OR was 0.829 (95% CI: 0.561-1.224, P = 0.346). The funnel plot demonstrated the absence of the alleged pleiotropic effects by showing no evidence of observable variability across the estimations. This study does not support the benefit of the addition of bevacizumab to temozolomide and radiotherapy in improving OS and PFS in GBM patients.
Assuntos
Bevacizumab , Neoplasias Encefálicas , Glioblastoma , Temozolomida , Glioblastoma/radioterapia , Glioblastoma/tratamento farmacológico , Glioblastoma/terapia , Temozolomida/uso terapêutico , Humanos , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/mortalidade , Antineoplásicos Alquilantes/uso terapêutico , Quimiorradioterapia/métodos , Resultado do TratamentoRESUMO
The serine/threonine phosphatase family is important in tumor progression and survival. Due to the high conserved catalytic domain, designing selective inhibitors is challenging. Herein, we obtained compound 28a with 38-fold enhanced PP5 selectivity (PP2A/5 IC50 = 33.8/0.9 µM) and improved drug-like properties (favorable stability and safety, F = 82.0%) by rational drug design based on a phase II PP2A/5 dual target inhibitor LB-100. Importantly, we found the spatial conformational restriction of the 28a indole fragment was responsible for the selectivity of PP5. Thus, 28a activated p53 and downregulated cyclin D1 and MGMT, which showed potency in cell cycle arrest and reverse temozolomide (TMZ) resistance in the U87 MG cell line. Furthermore, oral administration of 28a and TMZ was well tolerated to effectively inhibit tumor growth (TGI = 87.7%) in the xenograft model. Collectively, these results implicate 28a could be a drug candidate by reversing TMZ resistance with a selective PP5 inhibition manner.