RESUMO
BACKGROUND: Chordomas are rare tumors arising from the skull base and spine, with approximately 20 pediatric chordoma cases in the Unitedn States per year. The natural history and optimal treatment of pediatric chordomas, especially poorly differentiated and dedifferentiated subtypes, is incompletely understood. Herein, we present findings from our first National Cancer Institute (NCI) chordoma clinic and a retrospective analysis of published cases of pediatric poorly differentiated chordomas (PDC) and dedifferentiated chordomas (DC). METHODS: Patients less than 40 years old with chordoma were enrolled on the NCI Natural History and Biospecimens Acquisitions Study for Children and Adults with Rare Solid Tumors protocol (NCT03739827). Chordoma experts reviewed patient records, evaluated patients, and provided treatment recommendations. Patient-reported outcomes, biospecimens, and volumetric tumor analyses were collected. A literature review for pediatric PDC and DC was conducted. RESULTS: Twelve patients (median age: 14 years) attended the clinic, including four patients with active disease and three patients with PDC responsive to systemic therapy. Consensus treatment, management, and recommendations were provided to patients. Literature review returned 45 pediatric cases of PDC or DC with variable treatments and outcomes. CONCLUSIONS: A multidisciplinary expert clinic was feasible and successful in improving understanding of pediatric chordoma. While multimodal approaches have all been employed, treatment for PDC has been inconsistent and a recommended standardized treatment approach has not been defined. Centralized efforts, inclusive of specialized chordoma-focused clinics, natural history studies, and prospective analyses will help in the standardization of care for this challenging disease.
RESUMO
BACKGROUND: Brachyury is a transcription factor overexpressed in chordoma and is associated with chemotherapy resistance and epithelial-to-mesenchymal transition. GI-6301 is a recombinant, heat-killed Saccharomyces cerevisiae yeast-based vaccine targeting brachyury. A previous phase I trial of GI-6301 demonstrated a signal of clinical activity in chordomas. This trial evaluated synergistic effects of GI-6301 vaccine plus radiation. MATERIALS AND METHODS: Adults with locally advanced, unresectable chordoma were treated on a randomized, placebo-controlled trial. Patients received three doses of GI-6301 (80 × 107 yeast cells) or placebo followed by radiation, followed by continued vaccine or placebo until progression. Primary endpoint was overall response rate, defined as a complete response (CR) or partial response (PR) in the irradiated tumor site at 24 months. Immune assays were conducted to evaluate immunogenicity. RESULTS: Between May 2015 and September 2019, 24 patients enrolled on the first randomized phase II study in chordoma. There was one PR in each arm; no CRs were observed. Median progressive-free survival for vaccine and placebo arms was 20.6 months (95% confidence interval [CI], 5.7-37.5 months) and 25.9 months (95% CI, 9.2-30.8 months), respectively. Hazard ratio was 1.02 (95% CI, 0.38-2.71). Vaccine was well tolerated with no vaccine-related serious adverse events. Preexisting brachyury-specific T cells were detected in most patients in both arms. Most patients developed T-cell responses during therapy, with no difference between arms in frequency or magnitude of response. CONCLUSION: No difference in overall response rate was observed, leading to early discontinuation of this trial due to low conditional power to detect statistical difference at the planned end of accrual. IMPLICATIONS FOR PRACTICE: Chordoma is a rare neoplasm lacking effective systemic therapies for advanced, unresectable disease. Lack of clinically actionable somatic mutations in chordoma makes development of targeted therapy quite challenging. While the combination of yeast-brachyury vaccine (GI-6301) and standard radiation therapy did not demonstrate synergistic antitumor effects, brachyury still remains a good target for developmental therapeutics in chordoma. Patients and their oncologists should consider early referral to centers with expertise in chordoma (or sarcoma) and encourage participation in clinical trials.
Assuntos
Cordoma , Vacinas , Adulto , Cordoma/radioterapia , Método Duplo-Cego , Proteínas Fetais/genética , Humanos , Saccharomyces cerevisiae/genética , Proteínas com Domínio TRESUMO
Cancer cells can switch between signaling pathways to regulate growth under different conditions. In the tumor microenvironment, this likely helps them evade therapies that target specific pathways. We must identify all possible states and utilize them in drug screening programs. One such state is characterized by expression of the transcription factor Hairy and Enhancer of Split 3 (HES3) and sensitivity to HES3 knockdown, and it can be modeled in vitro. Here, we cultured 3 primary human brain cancer cell lines under 3 different culture conditions that maintain low, medium, and high HES3 expression and characterized gene regulation and mechanical phenotype in these states. We assessed gene expression regulation following HES3 knockdown in the HES3-high conditions. We then employed a commonly used human brain tumor cell line to screen Food and Drug Administration (FDA)-approved compounds that specifically target the HES3-high state. We report that cells from multiple patients behave similarly when placed under distinct culture conditions. We identified 37 FDA-approved compounds that specifically kill cancer cells in the high-HES3-expression conditions. Our work reveals a novel signaling state in cancer, biomarkers, a strategy to identify treatments against it, and a set of putative drugs for potential repurposing.-Poser, S. W., Otto, O., Arps-Forker, C., Ge, Y., Herbig, M., Andree, C., Gruetzmann, K., Adasme, M. F., Stodolak, S., Nikolakopoulou, P., Park, D. M., Mcintyre, A., Lesche, M., Dahl, A., Lennig, P., Bornstein, S. R., Schroeck, E., Klink, B., Leker, R. R., Bickle, M., Chrousos, G. P., Schroeder, M., Cannistraci, C. V., Guck, J., Androutsellis-Theotokis, A. Controlling distinct signaling states in cultured cancer cells provides a new platform for drug discovery.
Assuntos
Glioblastoma/metabolismo , Proteínas Repressoras/metabolismo , Linhagem Celular Tumoral , Descoberta de Drogas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Glioblastoma/genética , Humanos , Interferência de RNA , Proteínas Repressoras/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
Although proteasome inhibitors (PIs) are used as anticancer drugs to treat various cancers, their relative therapeutic efficacy on stem cells vs. bulk cancers remains unknown. Here, we show that stem cells derived from gliomas, GSCs, are up to 1,000-fold more sensitive to PIs (IC50, 27-70 nM) compared with their differentiated controls (IC50, 47 to ¼100 µM). The stemness of GSCs correlates to increased ubiquitination, whose misregulation readily triggers apoptosis. PI-induced apoptosis of GSCs is independent of NF-κB but involves the phosphorylation of c-Jun N-terminal kinase as well as the transcriptional activation of endoplasmic reticulum (ER) stress-associated proapoptotic mediators. In contrast to the general notion that ER stress-associated apoptosis is signaled by prolonged unfolded protein response (UPR), GSC-selective apoptosis is instead counteracted by the UPR ATF3 is a key mediator in GSC-selective apoptosis. Pharmaceutical uncoupling of the UPR from its downstream apoptosis sensitizes GSCs to PIs in vitro and during tumorigenesis in mice. Thus, a combinational treatment of a PI with an inhibitor of UPR-coupled apoptosis may enhance targeting of stem cells in gliomas.
Assuntos
Glioma/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/tratamento farmacológico , Glioma/genética , Glioma/patologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Modelos Biológicos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Ubiquitinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Oncocytomas represent a subset of benign pituitary adenomas that are characterized by significant mitochondrial hyperplasia. Mitochondria are key organelles for energy generation and metabolic intermediate production for biosynthesis in tumour cells, so understanding the mechanism underlying mitochondrial biogenesis and its impact on cellular metabolism in oncocytoma is vital. Here, we studied surgically resected pituitary oncocytomas by using multi-omic analyses. Whole-exome sequencing did not reveal any nuclear mutations, but identified several somatic mutations of mitochondrial DNA, and dysfunctional respiratory complex I. Metabolomic analysis suggested that oxidative phosphorylation was reduced within individual mitochondria, and that there was no reciprocal increase in glycolytic activity. Interestingly, we found a reduction in the cellular lactate level and reduced expression of lactate dehydrogenase A (LDHA), which contributed to mitochondrial biogenesis in an in vitro cell model. It is of note that the hypoxia-response signalling pathway was not upregulated in pituitary oncocytomas, thereby failing to enhance glycolysis. Proteomic analysis showed that 14-3-3η was exclusively overexpressed in oncocytomas, and that 14-3-3η was capable of inhibiting glycolysis, leading to mitochondrial biogenesis in the presence of rotenone. In particular, 14-3-3η inhibited LDHA by direct interaction in the setting of complex I dysfunction, highlighting the role of 14-3-3η overexpression and inefficient oxidative phosphorylation in oncocytoma mitochondrial biogenesis. These findings deepen our understanding of the metabolic changes that occur within oncocytomas, and shine a light on the mechanism of mitochondrial biogenesis, providing a novel perspective on metabolic adaptation in tumour cells. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Assuntos
Proteínas 14-3-3/metabolismo , Adenoma Oxífilo/enzimologia , Metabolismo Energético , L-Lactato Desidrogenase/metabolismo , Mitocôndrias/enzimologia , Biogênese de Organelas , Neoplasias Hipofisárias/enzimologia , Proteínas 14-3-3/genética , Adenoma Oxífilo/genética , Adenoma Oxífilo/patologia , Adulto , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Feminino , Glicólise , Células HEK293 , Células HeLa , Humanos , L-Lactato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Mitocôndrias/patologia , Mutação , Fosforilação Oxidativa , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Transdução de Sinais , Microambiente TumoralRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICPIs) are being investigated in clinical trials for patients with glioblastoma. While these therapies hold great promise, management of the patients receiving such treatment can be complicated due to the challenges in recognizing immune-related adverse events caused by checkpoint inhibitor treatment. Brain imaging changes that are the consequence of an inflammatory response may be misinterpreted as disease progression leading to inappropriate premature cessation of treatment. The aim of this study was to, by way of a series of cases, underscore the challenges in determining the nature of contrast-enhancing masses that develop during the treatment of patients with glioblastoma treated with ICPIs. CASE PRESENTATION: We reviewed the clinical course and management of 4 patients on ICPIs who developed signs of tumor progression on imaging. These findings were examined in the context of Immunotherapy Response Assessment in Neuro-Oncology (iRANO) guidelines. Although all 4 patients had very similar imaging findings, 2 of the 4 patients were later found to have intense inflammatory changes (pseudoprogression) by pathologic examination. CONCLUSIONS: A high index of suspicion for pseudoprogression needs to be maintained when a patient with brain tumor on immunotherapy presents with worsening in an area of a pre-existing tumor or a new lesion in brain. Our findings strongly suggest that pathological diagnosis remains the gold standard for distinguishing tumor progression from pseudoprogression in patients receiving immunotherapy. There is a large unmet need to develop reliable non-invasive imaging diagnostic techniques. TRIAL REGISTRATION: ClinicalTrials.gov NCT02311920. Registered 8 December 2014.
Assuntos
Neoplasias Encefálicas/diagnóstico , Tomada de Decisão Clínica , Glioblastoma/diagnóstico , Imunoterapia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Antígeno CTLA-4/antagonistas & inibidores , Feminino , Glioblastoma/metabolismo , Glioblastoma/terapia , Humanos , Ipilimumab/farmacologia , Ipilimumab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Nivolumabe , Receptor de Morte Celular Programada 1/antagonistas & inibidoresRESUMO
Antiangiogenic therapies for malignant gliomas often result in transient response, and recurrent disease is characterized by adoption of invasive and hypoxic phenotype. The notch signaling pathway is activated in gliomas, and augments cell migration and hypoxic response. Here we report a clinical study of the combination of bevacizumab and RO4929097, an inhibitor of the notch signaling cascade. A phase I clinical trial was conducted through the Adult Brain Tumor Consortium in subjects with recurrent malignant glioma. Primary objectives were to assess safety and to define the maximum tolerated dose of RO4929097 in combination with bevacizumab. Secondary objectives were to determine overall survival, progression free survival, radiographic response, pharmacokinetic evaluation, and tissue biomarker analysis. Thirteen subjects were enrolled. Of the three subjects treated with the highest dose of RO4929097, one grade 3 toxicity and one grade 2 toxicity were observed. Definitive maximum tolerated dose of RO4929097 in combination with bevacizumab was not identified due to manufacturer's decision to halt drug production. 2 of 12 evaluable subjects demonstrated radiographic response; one subject experienced CR and the second PR. The median overall survival was 10.9 months with a median progression-free survival of 3.7 months. Two subjects remained free of disease progression at 6 months from treatment initiation. PK evaluation did not identify clinically significant drug-drug interactions. All analyzed tissue specimens revealed activation of notch signaling. Combination of RO4929097 and bevacizumab was well-tolerated. Given the compelling scientific rationale, additional studies of antiangiogenic and notch signaling inhibitors should be considered.
Assuntos
Antineoplásicos/uso terapêutico , Benzazepinas/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Adulto , Neoplasias Encefálicas/mortalidade , Feminino , Glioma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
Astrocytes are the most abundant cell of the CNS and demonstrate contact inhibition in which a nonproliferative, nonmotile cellular state is achieved once stable intercellular contacts are formed between mature cells. Cellular injury disrupts these intercellular contacts, causing a loss of contact inhibition and the rapid initiation of healing. Dysregulation of the molecular pathways involved in this process is thought to lead to an aggressive cellular state associated with neoplasia. We investigated whether a comparable correlation exists between the response of astrocytes to injury and the malignant phenotype of astrocytomas. We discovered that the loss of contact inhibition plays a critical role in the initiation and regulation of reactive astrocytes in the healing of wounds. In particular, injury of the astrocytes interrupts and destabilizes the cadherin-catenin complexes at the cell membrane leading to nuclear translocation of ß-catenin and characteristic changes associated with the activation of astrocytes. Similar signaling pathways are found to be active--but dysregulated--in astrocytomas. Inhibition of ß-catenin signaling diminished both the response of astrocytes to injury and induction of the malignant phenotype of astrocytomas. The findings shed light on a unique mechanism associated with the pathogenesis of astrocytomas and provide a model for the loss of contact inhibition that may broadly apply to understanding the mechanisms of tissue repair and tumorigenesis in the brain.
Assuntos
Astrócitos/metabolismo , Astrocitoma/etiologia , Astrocitoma/metabolismo , beta Catenina/metabolismo , Animais , Astrocitoma/patologia , Proliferação de Células , Transformação Celular Neoplásica , Células Cultivadas , Técnicas de Silenciamento de Genes , Camundongos , Modelos Neurológicos , Fenótipo , RNA Interferente Pequeno , Transdução de Sinais , Células Tumorais Cultivadas , beta Catenina/antagonistas & inibidores , beta Catenina/genéticaRESUMO
Surgical resection followed by radiotherapy (RT) is recommended for malignant meningioma but poor outcome is unavoidable. To improve the efficacy of RT in malignant meningioma, a targeted radiosensitizer could be added. Nicotinamide phosphoribosyltransferase (NAMPT), highly expressed in high-grade meningiomas may have a role in determining the radioresponse. Here, we evaluated the impact of NAMPT inhibition on radiosensitivity in malignant meningioma in vivo and in vitro. IOMM-Lee and TTMM705 cells were treated with NAMPT inhibition (FK866 or shRNA NAMPT) before irradiation. The subsequent clonogenic assay demonstrated significantly increased radiosensitivity. Combination treatment with FK866 and irradiation significantly increased the number of G2/M-phase cells, the percentage of apoptotic cells and the γ-H2A.X level compared to FK866 or RT alone. We examined the effect of NAMPT inhibition on NMI and p53 expression in IOMM-Lee and TTMM705 cells. NAMPT inhibition by FK866 and shRNA treatment increased NMI, p53, CDKN1A and BAX expression. Additionally, we assessed the efficacy of FK866/RT combination treatment in vivo. The combination treatment exhibited increased antitumor efficacy compared to either treatment alone. The Ki-67 level was significantly lower and the p53 and γ-H2A.X level was significantly higher in the combination treatment group than in any of the other three groups. In conclusion, these results indicate that FK866 improves radiosensitivity in malignant meningioma, an effect that may be attributed to the increase in p53 expression.
RESUMO
Background: Gliosarcoma, an isocitrate dehydrogenase wildtype (IDH-WT) variant of glioblastoma, is defined by clonal biphasic differentiation into gliomatous and sarcomatous components. While the transformation from a glioblastoma to gliosarcoma is uncommon, the subsequent transformation to osteosarcoma is rare but may provide additional insights into the biology of these typically distinct cancers. We observed a patient initially diagnosed with glioblastoma, that differentiated into gliosarcoma at recurrence, and further evolved to osteosarcoma at the second relapse. Our objective was to characterize the molecular mechanisms of tumor progression associated with this phenotypic transformation. Methods: Tumor samples were collected at all 3 stages of disease and RNA sequencing was performed to capture their transcriptomic profiles. Sequential clonal evolution was confirmed by the maintenance of an identical PTEN mutation throughout the tumor differentiation using the TSO500 gene panel. Publicly available datasets and the Nanostring nCounter technology were used to validate the results. Results: The glioblastoma tumor from this patient possessed mixed features of all 3 TCGA-defined transcriptomic subtypes of an IDH-WT glioblastoma and a proportion of osteosarcoma signatures were upregulated in the original tumor. Analysis showed that enhanced transforming growth factor-ß (TGF-ß) and bone morphogenic protein signaling was associated with tumor transformation. Regulatory network analysis revealed that TGF-ß family signaling committed the lineage tumor to osteogenesis by stimulating the expression of runt-related transcription factor 2 (RUNX2), a master regulator of bone formation. Conclusions: This unusual clinical case provided an opportunity to explore the modulators of longitudinal sarcomatous transformation, potentially uncovering markers indicating predisposition to this change and identification of novel therapeutic targets.
RESUMO
Despite strides in immunotherapy, glioblastoma multiforme (GBM) remains challenging due to low inherent immunogenicity and suppressive tumor microenvironment. Converting "cold" GBMs to "hot" is crucial for immune activation and improved outcomes. This study comprehensively characterized a therapeutic vaccination strategy for preclinical GBM models. The vaccine consists of Mannan-BAM-anchored irradiated whole tumor cells, Toll-like receptor ligands [lipoteichoic acid (LTA), polyinosinic-polycytidylic acid (Poly (I:C)), and resiquimod (R-848)], and anti-CD40 agonistic antibody (rWTC-MBTA). Intracranial GBM models (GL261, SB28 cells) are used to evaluate the vaccine efficacy. A substantial number of vaccinated mice exhibited complete regression of GBM tumors in a T-cell-dependent manner, with no significant toxicity. Long-term tumor-specific immune memory is confirmed upon tumor rechallenge. In the vaccine-draining lymph nodes of the SB28 model, rWTC-MBTA vaccination triggered a major rise in conventional dendritic cell type 1 (cDC1) 12 h post-treatment, followed by an increase in conventional dendritic cell type 2 (cDC2), monocyte-derived dendritic cell (moDC), and plasmacytoid dendritic cell (pDC) on Day 5 and Day 13. Enhanced cytotoxicity of CD4+ and CD8+ T cells in vaccinated mice is verified in co-culture with tumor cells. Analyses of immunosuppressive signals (T-cell exhaustion, myeloid-derived suppressor cells (MDSC), M2 macrophages) in the GBM microenvironment suggest potential combinations with other immunotherapies for enhanced efficacy. In conclusion, the authors findings demonstrate that rWTC-MBTA induces potent and long-term adaptive immune responses against GBM.
Assuntos
Glioblastoma , Vacinas , Camundongos , Animais , Glioblastoma/metabolismo , Linfócitos T CD8-Positivos , Vacinas/metabolismo , Células Dendríticas , Imunidade , Microambiente TumoralRESUMO
Chordoma is a primary bone cancer arising on the midline from the skull base to the sacrum. Diagnosis is often delayed because of insidious onset and nonspecific symptoms. Chordomas appear histologically low-grade but are highly invasive and often recur locally. Management centers primarily on radical en bloc surgical resection when possible. Radiation therapy using protons and/or photons is often necessary because complete resection is seldom possible due to critical location and invasion of the cancer cells into surrounding structures. No approved medical therapy exists. The high rate of recurrence is reflected by a median survival of 6 to 7 years. This article reviews the clinical management of chordoma and discusses ongoing research in the field.
Assuntos
Cordoma/diagnóstico , Cordoma/terapia , Cordoma/epidemiologia , Cordoma/etiologia , HumanosRESUMO
In Parkinson's disease, multiple cell types in many brain regions are afflicted. As a consequence, a therapeutic strategy that activates a general neuroprotective response may be valuable. We have previously shown that Notch ligands support neural precursor cells in vitro and in vivo. Here we show that neural precursors express the angiopoietin receptor Tie2 and that injections of angiopoietin2 activate precursors in the adult brain. Signaling downstream of Tie2 and the Notch receptor regulate blood vessel formation. In the adult brain, angiopoietin2 and the Notch ligand Dll4 activate neural precursors with opposing effects on the density of blood vessels. A model of Parkinson's disease was used to show that angiopoietin2 and Dll4 rescue injured dopamine neurons with motor behavioral improvement. A combination of growth factors with little impact on the vasculature retains the ability to stimulate neural precursors and protect dopamine neurons. The cellular and pharmacological basis of the neuroprotective effects achieved by these single treatments merits further analysis.
Assuntos
Encéfalo/patologia , Dopamina/metabolismo , Neurônios/patologia , Células-Tronco/citologia , Indutores da Angiogênese/farmacologia , Inibidores da Angiogênese/farmacologia , Animais , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Morte Celular/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor TIE-2/metabolismo , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismoRESUMO
Neurological immune-related adverse events (irAEs) are rare toxicities that occur following immune checkpoint inhibitor therapy. We propose that patients with thymic malignancies and graft-versus-host disease (GVHD) are predisposed to irAEs. We present two asymptomatic patients, one with thymoma and another with GVHD, who developed abnormal brain MRIs after treatment with programmed cell death protein 1 inhibitors. The first patient, with thymic cancer and thymoma, developed pontine enhancing MRI lesions following treatment with pembrolizumab. The second patient, with prior GVHD, developed pachymeningeal enhancement following treatment with nivolumab. IrAEs with abnormal MRI studies, despite asymptomatology, have significant impact on the treatment strategy for these patients.
Assuntos
Neoplasias Encefálicas/etiologia , Doença Enxerto-Hospedeiro/imunologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Meningite/etiologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Timoma/imunologia , Neoplasias do Timo/imunologia , Corticosteroides/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias Encefálicas/diagnóstico por imagem , Tronco Encefálico/diagnóstico por imagem , Feminino , Doença Enxerto-Hospedeiro/terapia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Meningite/diagnóstico por imagem , Meningite/tratamento farmacológico , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Timoma/terapia , Neoplasias do Timo/terapiaRESUMO
In spite of increasing attention on targeted therapeutics in the treatment of glioblastoma multiforme, radiation therapy remains the most clinically effective treatment modality. However, radiotherapy only offers palliation, with hypoxia representing a major mechanism of tumor resistance. Traditional strategies to overcome the therapeutic barrier to irradiation imposed by tumor tissue hypoxia consist of improving tumor oxygenation and administering agents that increase the tumor cell sensitivity to irradiation (radiosensitizers). There is also increasing evidence that tumor tissue is composed of diverse populations of cells with heterogeneous sensitivities to irradiation. The radioresistant tumor-initiating CD133-positive glioblastoma cancer stem cells are preferentially expanded in hypoxic conditions. Therefore, identifying therapies that can specifically target the glioblastoma cancer stem cells will lead to more durable responses to radiation therapy.
Assuntos
Neoplasias Encefálicas/metabolismo , Hipóxia Celular/fisiologia , Glioblastoma/metabolismo , Tolerância a Radiação/fisiologia , Animais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Hipóxia Celular/efeitos da radiação , Glioblastoma/patologia , Glioblastoma/radioterapia , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/efeitos da radiaçãoRESUMO
RATIONALE: Primary central nervous system lymphoma (PCNSL) involving the choroid plexus is exceedingly rare. The differential diagnosis for choroid plexus enhancing lesions in addition to lymphoma includes infections, sarcoidosis, tuberculosis, papilloma, meningioma, subependymoma, and metastatic lesions. PATIENT CONCERNS: A 71-year-old man presented with 3 days of episodic memory loss and gait disturbance. Brain magnetic resonance imaging showed homogenously enhancing lesions with mildly restricted diffusion and T2 hypointensity in the lateral ventricles, as well as T2 hyperintensity and enhancement in the right hippocampus. His episodic memory loss was thought to be secondary to subclinical focal seizures, supported by EEG revealing right temporal lobe epileptiform discharges. DIAGNOSES: Large B-cell lymphoma, nongerminal center type was revealed on pathological examination. INTERVENTIONS: Stereotactic biopsy of his right thalamic lesion was performed. OUTCOMES: The patient underwent induction therapy with high-dose methotrexate, temozolomide, and rituximab, which resulted in complete resolution of the enhancing lesions. He then underwent conditioning chemotherapy with carmustine and thiotepa, followed by autologous stem cell transplantation. His PCNSL remains in remission 42 weeks after the onset of symptoms. LESSONS: We report a patient with multifocal PCNSL involving the choroid plexus, who presented with abnormal gait and episodic confusion and memory loss. PCNSL should be considered in the differential diagnosis of acute encephalopathy among immunocompetent older individuals who have choroid plexus enhancing lesions.
Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico , Linfoma não Hodgkin/diagnóstico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Neoplasias do Sistema Nervoso Central/terapia , Diagnóstico Diferencial , Eletroencefalografia , Transplante de Células-Tronco Hematopoéticas , Humanos , Linfoma não Hodgkin/terapia , Imageamento por Ressonância Magnética , MasculinoRESUMO
We examined the efficacy of selective inhibition of cyclin-dependent kinase 5 (CDK5) in glioblastoma by TP5. We analyzed its impact in vitro on CDK5 expression and activity, cell survival, apoptosis and cell cycle. DNA damage was analyzed using the expression of γH2A.X and phosphorylated ATM. Its tolerance and efficacy were assessed on in vivo xenograft mouse models. We showed that TP5 decreased the activity but not the expression of CDK5 and p35. TP5 alone impaired cell viability and colony formation of glioblastoma cell lines and induced apoptosis. TP5 increased DNA damage by inhibiting the phosphorylation of ATM, leading to G1 arrest. Whereas CDK5 activity is increased by DNA-damaging agents such as temozolomide and irradiation, TP5 was synergistic with either temozolomide or irradiation due to an accumulation of DNA damage. Concomitant use of TP5 and either temozolomide or irradiation reduced the phosphorylation of ATM, increased DNA damage, and inhibited the G2/M arrest induced by temozolomide or irradiation. TP5 alone suppressed the tumor growth of orthotopic glioblastoma mouse model. The treatment was well tolerated. Finally, alone or in association with irradiation or temozolomide, TP5 prolonged mouse survival. TP5 alone or in association with temozolomide and radiotherapy is a promising therapeutic option for glioblastoma.
RESUMO
Patients with Muir-Torre syndrome, an autosomal-dominant familial tumor condition caused by germline mutation of the DNA mismatch repair genes, MSH2 or MLH1, present with tumors of the sebaceous gland and visceral malignancies characterized by microsatellite instability. Here we show development of glioblastoma multiforme in a patient with Muir-Torre syndrome. Immunohistochemical analysis of the brain tumor and colon cancer revealed loss of the DNA mismatch repair gene detected by the genetic test, suggesting a pathogenic link.