RESUMEN
T cell receptors (TCRs) enable T cells to specifically recognize mutations in cancer cells1-3. Here we developed a clinical-grade approach based on CRISPR-Cas9 non-viral precision genome-editing to simultaneously knockout the two endogenous TCR genes TRAC (which encodes TCRα) and TRBC (which encodes TCRß). We also inserted into the TRAC locus two chains of a neoantigen-specific TCR (neoTCR) isolated from circulating T cells of patients. The neoTCRs were isolated using a personalized library of soluble predicted neoantigen-HLA capture reagents. Sixteen patients with different refractory solid cancers received up to three distinct neoTCR transgenic cell products. Each product expressed a patient-specific neoTCR and was administered in a cell-dose-escalation, first-in-human phase I clinical trial ( NCT03970382 ). One patient had grade 1 cytokine release syndrome and one patient had grade 3 encephalitis. All participants had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease and the other eleven had disease progression as the best response on the therapy. neoTCR transgenic T cells were detected in tumour biopsy samples after infusion at frequencies higher than the native TCRs before infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs that recognize mutational neoantigens. Moreover, simultaneous knockout of the endogenous TCR and knock-in of neoTCRs using single-step, non-viral precision genome-editing are achieved. The manufacture of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene-edited neoTCR T cell products and the ability of the transgenic T cells to traffic to the tumours of patients are also demonstrated.
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Tratamiento Basado en Trasplante de Células y Tejidos , Edición Génica , Neoplasias , Medicina de Precisión , Receptores de Antígenos de Linfocitos T , Linfocitos T , Transgenes , Humanos , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Biopsia , Tratamiento Basado en Trasplante de Células y Tejidos/efectos adversos , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Síndrome de Liberación de Citoquinas/complicaciones , Progresión de la Enfermedad , Encefalitis/complicaciones , Técnicas de Sustitución del Gen , Técnicas de Inactivación de Genes , Genes Codificadores de la Cadena alfa de los Receptores de Linfocito T , Genes Codificadores de la Cadena beta de los Receptores de Linfocito T , Mutación , Neoplasias/complicaciones , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/terapia , Seguridad del Paciente , Medicina de Precisión/efectos adversos , Medicina de Precisión/métodos , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Transgenes/genética , Antígenos HLA/inmunología , Sistemas CRISPR-CasRESUMEN
The delivery of cancer care has never changed as rapidly and dramatically as we have seen with the coronavirus disease 2019 (COVID-19) pandemic. During the early phase of the pandemic, recommendations for the management of oncology patients issued by various professional societies and government agencies did not recognize the significant regional differences in the impact of the pandemic. California initially experienced lower than expected numbers of cases, and the health care system did not experience the same degree of the burden that had been the case in other parts of the country. In light of promising trends in COVID-19 infections and mortality in California, by late April 2020, discussions were initiated for a phased recovery of full-scale cancer services. However, by July 2020, a surge of cases was reported across the nation, including in California. In this review, the authors share the response and recovery planning experience of the University of California (UC) Cancer Consortium in an effort to provide guidance to oncology practices. The UC Cancer Consortium was established in 2017 to bring together 5 UC Comprehensive Cancer Centers: UC Davis Comprehensive Cancer Center, UC Los Angeles Jonsson Comprehensive Cancer Center, UC Irvine Chao Family Comprehensive Cancer Center, UC San Diego Moores Cancer Center, and the UC San Francisco Helen Diller Family Comprehensive Cancer Center. The interventions implemented in each of these cancer centers are highlighted, with a focus on opportunities for a redesign in care delivery models. The authors propose that their experiences gained during this pandemic will enhance pre-pandemic cancer care delivery.
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COVID-19 , Instituciones Oncológicas/organización & administración , Atención a la Salud/organización & administración , Neoplasias/terapia , COVID-19/complicaciones , COVID-19/diagnóstico , COVID-19/epidemiología , COVID-19/prevención & control , Prueba de COVID-19 , California/epidemiología , Salud Global , Humanos , Control de Infecciones/métodos , Control de Infecciones/organización & administración , Neoplasias/complicaciones , Neoplasias/diagnóstico , Pandemias , Telemedicina/métodos , Telemedicina/organización & administraciónRESUMEN
BACKGROUND: Craniopharyngiomas, primary brain tumors of the pituitary-hypothalamic axis, can cause clinically significant sequelae. Treatment with the use of surgery, radiation, or both is often associated with substantial morbidity related to vision loss, neuroendocrine dysfunction, and memory loss. Genotyping has shown that more than 90% of papillary craniopharyngiomas carry BRAF V600E mutations, but data are lacking with regard to the safety and efficacy of BRAF-MEK inhibition in patients with papillary craniopharyngiomas who have not undergone previous radiation therapy. METHODS: Eligible patients who had papillary craniopharyngiomas that tested positive for BRAF mutations, had not undergone radiation therapy previously, and had measurable disease received the BRAF-MEK inhibitor combination vemurafenib-cobimetinib in 28-day cycles. The primary end point of this single-group, phase 2 study was objective response at 4 months as determined with the use of centrally determined volumetric data. RESULTS: Of the 16 patients in the study, 15 (94%; 95% confidence interval [CI], 70 to 100) had a durable objective partial response or better to therapy. The median reduction in the volume of the tumor was 91% (range, 68 to 99). The median follow-up was 22 months (95% CI, 19 to 30) and the median number of treatment cycles was 8. Progression-free survival was 87% (95% CI, 57 to 98) at 12 months and 58% (95% CI, 10 to 89) at 24 months. Three patients had disease progression during follow-up after therapy had been discontinued; none have died. The sole patient who did not have a response stopped treatment after 8 days owing to toxic effects. Grade 3 adverse events that were at least possibly related to treatment occurred in 12 patients, including rash in 6 patients. In 2 patients, grade 4 adverse events (hyperglycemia in 1 patient and increased creatine kinase levels in 1 patient) were reported; 3 patients discontinued treatment owing to adverse events. CONCLUSIONS: In this small, single-group study involving patients with papillary craniopharyngiomas, 15 of 16 patients had a partial response or better to the BRAF-MEK inhibitor combination vemurafenib-cobimetinib. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03224767.).
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Antineoplásicos , Craneofaringioma , Neoplasias Hipofisarias , Humanos , Craneofaringioma/tratamiento farmacológico , Craneofaringioma/genética , Progresión de la Enfermedad , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/genética , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Vemurafenib/efectos adversos , Vemurafenib/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Inducción de RemisiónRESUMEN
In continuation of our previous efforts for the development of potent small molecules against brain cancer, herein we synthesized seventeen new compounds and tested their anti-gliomapotential against established glioblastoma cell lines, namely, D54MG, U251, and LN-229 as well as patient derived cell lines (DB70 and DB93). Among them, the carboxamide derivatives, BT-851 and BT-892 were found to be the most active leads in comparison to our established hit compound BT#9.The SAR studies of our hit BT#9 compound resulted in the development of two new lead compounds by hit to lead strategy. The detailed biological studies are currently underway. The active compounds could possibly act as template for the future development of newer anti-glioma agents.
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Antineoplásicos , Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Glioblastoma/tratamiento farmacológico , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Línea Celular Tumoral , Proliferación CelularRESUMEN
Ubiquitin proteasome-mediated protein degradation has been implicated in posttranslational oncogenesis in medulloblastoma. Current research is evaluating the clinical implications of proteasome inhibition as a therapeutic target. In medulloblastoma cell lines, proteasome inhibitors induce apoptosis and inhibit cell proliferation via multiple pathways involving activation of caspase pathways, NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway inhibition, reduced AKT/mTOR pathway activity, and pro-apoptotic protein expression. Second-generation proteasome inhibitors demonstrate blood-brain barrier penetration while maintaining antitumor effect. This review summarizes the ubiquitin-proteasome system in the pathogenesis of medulloblastoma and the potential clinical implications.
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Neoplasias Cerebelosas , Meduloblastoma , Inhibidores de Proteasoma , Apoptosis , Neoplasias Cerebelosas/tratamiento farmacológico , Humanos , Meduloblastoma/tratamiento farmacológico , Complejo de la Endopetidasa Proteasomal , Inhibidores de Proteasoma/uso terapéutico , UbiquitinaRESUMEN
BACKGROUND: Anthracyclines remain the cornerstone of the treatment in many cancers including lymphomas, leukemia and sarcomas, and breast cancer. The cardiomyopathy that develops from anthracyclines can lead to heart failure and decreased survival. Multiple mechanisms are involved in the pathophysiology of anthracycline-induced heart failure. STUDY QUESTION: We hypothesize that anthracycline-induced cardiac (AIC) pathology can be monitored using a panel of blood biomarkers including high-sensitive cardiac troponin T (hs-cTnT) for myocyte necrosis and N-terminal prohormone brain natriuretic peptide (NT-proBNP) for parietal stress. STUDY DESIGN: A prospective, institutionally approved study recruited all patients with cancer scheduled to start anthracycline chemotherapy in the Transylvania University cancer clinics. MEASURES AND OUTCOMES: Transthoracic 2D echocardiography and the measurements of NT-proBNP and hs-cTnT plasma levels were performed at the beginning of the study and 3 months and 6 months after anthracycline treatment initiation. RESULTS: The plasma levels of hs-cTnT at 3 months (rho = 0.439, P = 0.0001) and 6 months (rho = 0.490, P = 0.0001) are correlated with AIC occurrence. For a cutoff value of hs-cTnT at 3 months > 0.008 ng/mL, we obtained 66.7% sensitivity and 67.9% specificity for developing AIC at 6 months, with a 54.5% positive predictive value and a 87.8% negative predictive value. The NT-proBNP serum levels at 3 months (rho = 0.495, P = 0.0001) and 6 months (rho = 0.638, P = 0.0001) are correlated with an AIC diagnosis at 6 months. For a cutoff value of NT-proBNP at 3 months >118.5 pg/mL, we obtained 80% sensitivity and 79.2% specificity for evolution to AIC at 6 months, with 52.2% positive predictive value and 93.3% negative predictive value. CONCLUSIONS: In anthracycline-treated cancer patients, the increase in plasma levels of NT-proBNP and of hs-cTnT can predict the development of anthracycline-induced cardiomyopathy. Early identification of at-risk patients will potentially allow for targeted dose reductions and will diminish the number of patients developing cardiac pathology.
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Antraciclinas/efectos adversos , Antineoplásicos/efectos adversos , Cardiomiopatías/sangre , Cardiomiopatías/inducido químicamente , Péptido Natriurético Encefálico/sangre , Precursores de Proteínas/sangre , Troponina T/sangre , Adulto , Anciano , Antraciclinas/uso terapéutico , Antineoplásicos/uso terapéutico , Biomarcadores/sangre , Cardiomiopatías/diagnóstico por imagen , Doxorrubicina/efectos adversos , Ecocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Valor Predictivo de las Pruebas , Estudios Prospectivos , Volumen Sistólico , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: Magmas (mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) is a nuclear gene that encodes the mitochondrial import inner membrane translocase subunit Tim16. Magmas is highly conserved, ubiquitously expressed in mammalian cells, and is essential for cell viability. Magmas expression levels are increased in prostate cancers and pituitary adenomas. Moreover, silencing Magmas by RNAi sensitizes pituitary adenoma cells to pro-apoptotic stimuli and induces a G0/G1 accumulation. The aim of this study was to examine whether inhibition of Magmas by small molecule inhibitors could be beneficial for the treatment of malignant gliomas. METHODS: We evaluated the expression of Magmas in patient-derived glioblastoma tissue samples and xenograft models. We studied the feasibility of a small molecule Magmas inhibitor (BT#9) as a therapeutic agent in stable human glioma cell lines and high-grade patient derived glioma stem-like cells. RESULTS: Magmas was overexpressed in tissue sections from glioma patients and xenografts. In vivo studies revealed that BT#9 could cross the blood-brain barrier in the animal model. Magmas inhibition by BT#9 in glioma cell lines significantly decreased cell proliferation, induced apoptosis along with vacuole formation, and blocked migration and invasion. In addition, BT#9 treatment decreased the respiratory function of glioma cells, supporting the role that Magmas serves as a reactive oxygen species regulator. CONCLUSIONS: This is the first study on the role of Magmas in glioma. Our findings suggest that Magmas plays a key role in glioma cell survival and targeting Magmas by small molecule inhibitors may be a therapeutic strategy in gliomas.
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Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteínas Mitocondriales/antagonistas & inhibidores , Proteínas Mitocondriales/metabolismo , Animales , Apoptosis/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Humanos , Masculino , Ratones Endogámicos BALB C , Mitocondrias/efectos de los fármacos , Mitocondrias/fisiología , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.
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BACKGROUND: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma. METHODS: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). RESULTS: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. CONCLUSIONS: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.
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Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/terapia , Vacunas contra el Cáncer/inmunología , Células Dendríticas/inmunología , Glioblastoma/inmunología , Glioblastoma/terapia , Adulto , Anciano , Neoplasias Encefálicas/diagnóstico , Vacunas contra el Cáncer/efectos adversos , Determinación de Punto Final , Femenino , Glioblastoma/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: The purpose of this review is to summarize advances in the molecular analysis of gliomas, the role genetics plays in MRI features, and how machine-learning approaches can be used to survey the tumoral environment. CONCLUSION: The genetic profile of gliomas influences the course of treatment and clinical outcomes. Though biopsy is the reference standard for determining tumor genetics, it can suffer diagnostic delays due to surgical planning and pathologic assessment. Radiogenomics may allow rapid, low-risk characterization of genetic heterogeneity.
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Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Heterogeneidad Genética , Glioblastoma/diagnóstico por imagen , Glioblastoma/genética , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Humanos , Imagen por Resonancia MagnéticaRESUMEN
Glioblastoma is the most common form of brain cancer in adults that produces severe damage to the brain leading to a very poor survival prognosis. The standard of care for glioblastoma is usually surgery, as well as radiotherapy followed by systemic temozolomide chemotherapy, resulting in a median survival time of about 12 to 15 months. Despite these therapeutic efforts, the tumor returns in the vast majority of patients. When relapsing, statistics suggest an imminent death dependent on the size of the tumor, the Karnofsky Performance Status, and the tumor localization. Following the standard of care, the administration of Bevacizumab, inhibiting the growth of the tumor vasculature, is an approved medicinal treatment option approved in the United States, but not in the European Union, as well as the recently approved alternating electric fields (AEFs) generator NovoTTF/Optune. However, it is clear that regardless of the current treatment regimens, glioma patients continue to have dismal prognosis and novel treatments are urgently needed. Here, we describe different approaches of recently developed therapeutic glioma brain cancer vaccines, which stimulate the patient's immune system to recognize tumor-associated antigens (TAA) on cancer cells, aiming to instruct the immune system to eventually attack and destroy the brain tumor cells, with minimal bystander damage to normal brain cells. These distinct immunotherapies may target particular glioma TAAs which are molecularly defined, but they may also target broad patient-derived tumor antigen preparations intentionally evoking a very broad polyclonal antitumor immune stimulation.
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Neoplasias Encefálicas/inmunología , Vacunas contra el Cáncer/inmunología , Glioblastoma/inmunología , Inmunización/métodos , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/patología , Neoplasias Encefálicas/tratamiento farmacológico , Vacunas contra el Cáncer/uso terapéutico , Glioblastoma/tratamiento farmacológico , Humanos , Sistema Inmunológico/efectos de los fármacos , Sistema Inmunológico/inmunología , Análisis de SupervivenciaRESUMEN
Adaptive homeostasis is defined as the transient expansion or contraction of the homeostatic range following exposure to subtoxic, non-damaging, signaling molecules or events, or the removal or cessation of such molecules or events (Mol. Aspects Med. (2016) 49, 1-7). Adaptive homeostasis allows us to transiently adapt (and then de-adapt) to fluctuating levels of internal and external stressors. The ability to cope with transient changes in internal and external environmental stress, however, diminishes with age. Declining adaptive homeostasis may make older people more susceptible to many diseases. Chronic oxidative stress and defective protein homeostasis (proteostasis) are two major factors associated with the etiology of age-related disorders. In the present paper, we review the contribution of impaired responses to oxidative stress and defective adaptive homeostasis in the development of age-associated diseases.
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Factores de Edad , Homeostasis/fisiología , Estrés Oxidativo/fisiología , Estrés Fisiológico/fisiología , Adaptación Biológica/fisiología , Animales , Humanos , Transducción de Señal/fisiologíaRESUMEN
Malignant gliomas (MG) are very aggressive tumors. In an effort to improve the outcome, the patients receive multi-modal therapies such as surgery, radiation and chemotherapy (temozolomide followed in many cases by bevacizumab). The survivors are affected by multiple learning and memory deficits. Greater deterioration over time in hippocampal specific cognitive tasks was shown in patients receiving bevacizumab in addition to radiation and temozolomide for a longer period of time (RTOG 0825). The rate of hippocampal atrophy in patients treated with radiation and temozolomide followed by bevacizumab is not yet determined, and is the goal of the present study. We used the serial MRIs obtained as parts of standard clinical care in patients with MG. Measurements were done using the Medical Image Processing, Analysis and Visualization (MIPAV) software. The hippocampus in the contralateral hemisphere was manually traced and measured, to avoid morphological structure changes induced by the tumor, radiation fields or surgical markers. We determined a longitudinal progression of hippocampal atrophy-with the maximum volume loss (33.26 %) for the patients that were on treatment for 5 years. There was no detectable hippocampal atrophy during the chemo-radiation followed by adjuvant temozolomide. A significant decrease in the absolute hippocampus volume was noted after 6 months of continuous bevacizumab treatment (p < 0.05). The hippocampal volume loss progressed over the next 3 years, and was higher than the one previously reported in Alzheimer disease patients. The hippocampal volume loss is minimal during the 1 month after diagnosis, when the patients receive chemo-radiation and adjuvant temozolomide. However, prolonged treatment including bevacizumab is associated with a significant rate of hippocampal volume loss.
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Neoplasias Encefálicas/patología , Glioma/patología , Hipocampo/patología , Resultado del Tratamiento , Adulto , Anciano , Antineoplásicos/uso terapéutico , Atrofia/diagnóstico por imagen , Atrofia/etiología , Atrofia/patología , Bevacizumab/uso terapéutico , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/terapia , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Femenino , Glioma/diagnóstico por imagen , Glioma/terapia , Hipocampo/diagnóstico por imagen , Hipocampo/efectos de los fármacos , Hipocampo/efectos de la radiación , Humanos , Procesamiento de Imagen Asistido por Computador , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Radioterapia/métodos , Estudios Retrospectivos , TemozolomidaRESUMEN
Retaspimycin hydrochloride (IPI-504), an Hsp90 (heat shock protein 90) inhibitor, has shown activity in multiple preclinical cancer models, such as lung, breast and ovarian cancers. However, its biological effects in gliomas and normal brain derived cellular populations remain unknown. In this study, we profiled the expression pattern of Hsp90α/ß mRNA in stable glioma cell lines, multiple glioma-derived primary cultures and human neural stem/progenitor cells. The effects of IPI-504 on cell proliferation, apoptosis, motility and expression of Hsp90 client proteins were evaluated in glioma cell lines. In vivo activity of IPI-504 was investigated in subcutaneous glioma xenografts. Our results showed Hsp90α and Hsp90ß expression levels to be patient-specific, higher in high-grade glioma-derived primary cells than in low-grade glioma-derived primary cells, and strongly correlated with CD133 expression and differentiation status of cells. Hsp90 inhibition by IPI-504 induced apoptosis, blocked migration and invasion, and significantly decreased epidermal growth factor receptor levels, mitogen-activated protein kinase and/or Akt activities, and secretion of vascular endothelial growth factor in glioma cell lines. In vivo study showed that IPI-504 could mildly attenuate tumor growth in immunocompromised mice. These findings suggest that targeting Hsp90 by IPI-504 has the potential to become an active therapeutic strategy in gliomas in a selective group of patients, but further research into combination therapies is still needed.
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Glioma/tratamiento farmacológico , Glioma/fisiopatología , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/fisiopatología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Células Cultivadas , Receptores ErbB/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Glioma/patología , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Clasificación del Tumor , Trasplante de Neoplasias , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Big potassium (BK) ion channels have several spliced variants. One spliced variant initially described within human glioma cells is the glioma BK (gBK) channel. This isoform consists of 34 aa inserted into the intracellular region of the basic BK ion channel. PCR primers specific for this inserted region confirmed that human glioma cell lines and freshly resected surgical tissues from glioblastoma multiforme patients strongly expressed gBK mRNA. Normal human brain tissue very weakly expressed this transcript. An Ab specific for this gBK isoform confirmed that human glioma cells displayed this protein in the cell membrane, mitochondria, Golgi, and endoplasmic reticulum. Within the gBK region, two putative epitopes (gBK1 and gBK2) are predicted to bind to the HLA-A*0201 molecule. HLA-A*0201-restricted human CTLs were generated in vitro using gBK peptide-pulsed dendritic cells. Both gBK1 and gBK2 peptide-specific CTLs killed HLA-A2âº/gBK⺠gliomas, but they failed to kill non-HLA-A2-expressing but gBK⺠target cells in cytolytic assays. T2 cells loaded with exogenous gBK peptides, but not with the influenza M1 control peptide, were only killed by their respective CTLs. The gBK-specific CTLs also killed a variety of other HLA-A*0201⺠cancer cells that possess gBK, as well as HLA-A2⺠HEK cells transfected with the gBK gene. Of clinical relevance, we found that T cells derived from glioblastoma multiforme patients that were sensitized to the gBK peptide could also kill target cells expressing gBK. This study shows that peptides derived from cancer-associated ion channels maybe useful targets for T cell-mediated immunotherapy.
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Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/terapia , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/uso terapéutico , Glioma/inmunología , Glioma/terapia , Canales de Potasio de Gran Conductancia Activados por el Calcio/genética , Canales de Potasio de Gran Conductancia Activados por el Calcio/uso terapéutico , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Pruebas Inmunológicas de Citotoxicidad , Epítopos de Linfocito T/biosíntesis , Glioblastoma/inmunología , Glioblastoma/patología , Glioblastoma/terapia , Glioma/patología , Células Hep G2 , Humanos , Inmunoterapia Activa/métodos , Canales de Potasio de Gran Conductancia Activados por el Calcio/biosíntesis , Invasividad Neoplásica , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/patologíaRESUMEN
Cancer-related cognitive impairments (CRCI) are neurological complications associated with cancer treatment, and greatly affect cancer survivors' quality of life. Brain-derived neurotrophic factor (BDNF) plays an essential role in neurogenesis, learning and memory. The reduction of BDNF is associated with the decrease in cognitive function in various neurological disorders. Few pre-clinical studies have reported on the effects of chemotherapy and medical stress on BDNF levels and cognition. The present study aimed to compare the effects of medical stress and cisplatin on serum BDNF levels and cognitive function in 9-month-old female Sprague Dawley rats to age-matched controls. Serum BDNF levels were collected longitudinally during cisplatin treatment, and cognitive function was assessed by novel object recognition (NOR) 14 weeks post-cisplatin initiation. Terminal BDNF levels were collected 24 weeks after cisplatin initiation. In cultured hippocampal neurons, we screened three neuroprotective agents, riluzole (an approved treatment for amyotrophic lateral sclerosis), as well as the ampakines CX546 and CX1739. We assessed dendritic arborization by Sholl analysis and dendritic spine density by quantifying postsynaptic density-95 (PSD-95) puncta. Cisplatin and exposure to medical stress reduced serum BDNF levels and impaired object discrimination in NOR compared to age-matched controls. Pharmacological BDNF augmentation protected neurons against cisplatin-induced reductions in dendritic branching and PSD-95. Ampakines (CX546 and CX1739) and riluzole did not affect the antitumor efficacy of cisplatin in vitro. In conclusion, we established the first middle-aged rat model of cisplatin-induced CRCI, assessing the contribution of medical stress and longitudinal changes in BDNF levels on cognitive function, although future studies are warranted to assess the efficacy of BDNF enhancement in vivo on synaptic plasticity. Collectively, our results indicate that cancer treatment exerts long-lasting changes in BDNF levels, and support BDNF enhancement as a potential preventative approach to target CRCI with therapeutics that are FDA approved and/or in clinical study for other indications.
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Factor Neurotrófico Derivado del Encéfalo , Cisplatino , Ratas , Animales , Femenino , Cisplatino/toxicidad , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Ratas Sprague-Dawley , Regulación hacia Abajo , Calidad de Vida , Riluzol/farmacología , Hipocampo/metabolismo , Homólogo 4 de la Proteína Discs LargeRESUMEN
Medulloblastoma, the most common pediatric brain malignancy, has Sonic Hedgehog (SHH) and non-SHH group3 subtypes. MAGMAS (Mitochondrial Associated Granulocyte Macrophage colony-stimulating factor Signaling molecules) encode for mitochondrial import inner membrane translocase subunit and is responsible for translocation of matrix proteins across the inner membrane. We previously reported that a small molecule MAGMAS inhibitor, BT9, decreases cell proliferation, migration, and oxidative phosphorylation in adult glioblastoma cell lines. The aim of our study was to investigate whether the chemotherapeutic effect of BT9 can be extended to pediatric medulloblastoma. Methods: Multiple in vitro assays were performed using human DAOY (SHH activated tp53 mutant) and D425 (non-SHH group 3) cells. The impact of BT9 on cellular growth, death, migration, invasion, and metabolic activity were quantified using MTT assay, TUNEL staining, scratch wound assay, Matrigel invasion chambers, and seahorse assay, respectively. Survival following 50mg/kg BT9 treatment was assessed in vivo in immunodeficient mice intracranially implanted with D425 cells. Results: Compared to control, BT9 treatment led to a significant reduction in medulloblastoma cell growth (DAOY, 24hrs IC50: 3.6uM, 48hrs IC50: 2.3uM, 72hrs IC50: 2.1uM; D425 24hrs IC50: 3.4uM, 48hrs IC50: 2.2uM, 72hrs IC50: 2.1uM) and a significant increase in cell death (DAOY, 24hrs p=0.0004, 48hrs p<0.0001; D425, 24hrs p=0.0001, 48hrs p=0.02). In DAOY cells, 3uM BT9 delayed migration, and significantly decreased DAOY and D425 cells invasion (p < 0.0001). Our in vivo study, however, did not extend survival in xenograft mouse model of group3 medulloblastoma compared to vehicle-treated controls. Conclusions: Our in vitro data showed BT9 antitumor efficacy in DAOY and D425 cell lines suggesting that BT9 may represent a promising targeted therapeutic in pediatric medulloblastoma. These data, however, need to be further validated in animal models.
RESUMEN
BACKGROUND: Standard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT) and temozolomide (TMZ) chemotherapy (TMZ/RTâTMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood brain barrier. METHODS: EORTC 1709/CCTG CE.8 was a multicenter, randomized, controlled, open label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RTâTMZ with patients receiving only standard treatment in the whole population, and in the subgroup of patients with MGMT promoter-unmethylated tumors. RESULTS: The trial was opened at 82 institutions in Europe, Canada and the US. A total of 749 patients (99.9% of planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs 16.5 months; HR=1.04; p=0.64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR=0.97; p=0.67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs 15.1 months, HR=1.13; p=0.27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm. CONCLUSIONS: Adding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma.
RESUMEN
Cancer-related cognitive impairments (CRCI) are debilitating consequences of cancer treatment with platinum agents (e.g., cisplatin) that greatly alter cancer survivors' health-related quality of life. Brain-derived neurotrophic factor (BDNF) plays an essential role in neurogenesis, learning, and memory, and the reduction of BDNF is associated with the development of cognitive impairment in various neurological disorders, including CRCI. Our previous CRCI rodent studies have shown that cisplatin reduces hippocampal neurogenesis and BDNF expression and increases hippocampal apoptosis, which is associated with cognitive impairments. Few studies have reported on the effects of chemotherapy and medical stress on serum BDNF levels and cognition in middle-aged female rat models. The present study aimed to compare the effects of medical stress and cisplatin on serum BDNF levels and cognitive performance in 9-month-old female Sprague Dawley rats to age-matched controls. Serum BDNF levels were collected longitudinally during cisplatin treatment, and cognitive function was assessed by novel object recognition (NOR) 14 weeks post-cisplatin initiation. Terminal BDNF levels were collected ten weeks after cisplatin completion. We also screened three BDNF-augmenting compounds, riluzole, ampakine CX546, and CX1739, for their neuroprotective effects on hippocampal neurons, in vitro . We assessed dendritic arborization by Sholl analysis and dendritic spine density by quantifying postsynaptic density-95 (PSD95) puncta. Cisplatin and exposure to medical stress reduced serum BDNF levels and impaired object discrimination in NOR compared to age-matched controls. Pharmacological BDNF augmentation protected neurons against cisplatin-induced reductions in dendritic branching and PSD95. Ampakines (CX546 and CX1739) but not riluzole altered the antitumor efficacy of cisplatin in two human ovarian cancer cell lines, OVCAR8 and SKOV3.ip1, in vitro. In conclusion, we established the first middle-aged rat model of cisplatin-induced CRCI, assessing the contribution of medical stress and longitudinal changes in BDNF levels with cognitive function. We conducted an in vitro screening of BDNF-enhancing agents to evaluate their potential neuroprotective effects against cisplatin-induced neurotoxicity and their effect on ovarian cancer cell viability.
RESUMEN
Malignant astroctyoma and glioblastoma are diffuse CNS tumors that have markedly similar features, including microvascular proliferation and necrosis, and the latter presents higher grade and poorer survival. The Isocitrate dehydrogenase 1/2 (IDH) mutation further predicts improved survival and is present in oligodendroglioma and astrocytoma. The latter are more prevalent in younger populations with a median age of 37 years at diagnosis as compared to glioblastoma with a median age of 641,2. These tumors frequently have co-occurring ATRX and/or TP53 mutations (Brat et al., 2021). The IDH mutation is known to cause dysregulation of the hypoxia response broadly in CNS tumors and subsequent reduction in both tumor growth and treatment resistance. The frequency of tumor recurrence is high for diffuse CNS tumors. Understanding the mechanism and potential molecular targets enhancing treatment resistance and local invasion in IDH mutant diffuse glioma is necessary for developing new treatment strategies for better tumor control and improving overall survival. Recent evidence highlights the importance of local foci in IDH mutant glioma with an accelerated stress response as responsible for recurrence in these tumors. Here, we demonstrate that LonP1 drives NRF2 and subsequent proneural mesenchymal transition interdependent with the IDH mutation in response to stress and other tumor microenvironment cues. Our findings provide further evidence that targeting LonP1 may be a crucial strategy for improving the standard-of-care treatment in IDH mutant diffuse astrocytoma.