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1.
Anticancer Res ; 41(4): 1859-1870, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813391

RESUMEN

BACKGROUND/AIM: Demethoxycurcumin (DMC), one of the derivatives of curcumin, has been shown to induce apoptotic cell death in many human cancer cell lines. However, there is no available information on whether DMC inhibits metastatic activity in human glioblastoma cancer cells in vitro. MATERIALS AND METHODS: DMC at 1.0-3.0 µM significantly decreased the proliferation of GBM 8401 cells; thus, we used 2.0 µM for further investigation regarding anti-metastatic activity in human glioblastoma GBM 8401 cells. RESULTS: The internalized amount of DMC has reached the highest level in GBM 8401 cells after 3 h treatment. Wound healing assay was used to determine cell mobility and results indicated that DMC suppressed cell movement of GBM 8401 cells. The transwell chamber assays were used for measuring cell migration and invasion and results indicated that DMC suppressed cell migration and invasion in GBM 8401 cells. Gelatin zymography assay was used to examine gelatinolytic activity (MMP-2) in conditioned media of GBM 8401 cells treated by DMC and results demonstrated that DMC significantly reduced MMP-2 activity. Western blotting showed that DMC reduced the levels of p-EGFR(Tyr1068), GRB2, Sos1, p-Raf, MEK, p-ERK1/2, PI3K, p-Akt/PKBα(Thr308), p-PDK1, NF-κB, TIMP-1, MMP-9, MMP-2, GSK3α/ß, ß-catenin, N-cadherin, and vimentin, but it elevated Ras and E-cadherin at 24 h treatment. CONCLUSION: DMC inhibited cancer cell migration and invasion through inhibition of PI3K/Akt and NF-κB signaling pathways in GBM 8401 cells. We suggest that DMC may be used as a novel anti-metastasis agent for the treatment of human glioblastoma cancer in the future.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Diarilheptanoides/farmacología , Glioblastoma/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Glioblastoma/enzimología , Glioblastoma/patología , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , FN-kappa B/metabolismo , Invasividad Neoplásica , Transducción de Señal , beta Catenina/metabolismo
2.
Anticancer Res ; 41(3): 1445-1449, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788736

RESUMEN

BACKGROUND: Limited brain metastasis is treated definitively with stereotactic radiosurgery when surgical resection is not indicated. Although this has historically been performed in a single fraction, multi-fraction approaches such as fraction radiosurgery (FSRS) and staged radiosurgery (SSRS) have been recently examined as alternative approaches for larger lesions to permit better tumor control without increased toxicity. CASE REPORT: We present the case of a patient who developed symptomatic radionecrosis in two brain metastasis, 2.3 cm and 2.1 cm in size, which were treated with 18 Gy in one fraction, but no radionecrosis in a 3.3 cm lesion treated in two fractions of 15 Gy nor in two punctate lesions that were treated in one fraction of 20 Gy. Although she did not respond to steroids, she responded to bevacizumab symptomatically and on neuroimaging. CONCLUSION: Congruent with other recent studies, our report suggests that large brain metastasis should be considered for FSRS/SSRS.


Asunto(s)
Neoplasias Encefálicas/radioterapia , Encéfalo/efectos de la radiación , Fraccionamiento de la Dosis de Radiación , Radiocirugia/métodos , Adulto , Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Femenino , Humanos , Necrosis/radioterapia , Resultado del Tratamiento
3.
Nat Commun ; 12(1): 1912, 2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33771989

RESUMEN

Glioblastoma (GB) is a highly invasive type of brain cancer exhibiting poor prognosis. As such, its microenvironment plays a crucial role in its progression. Among the brain stromal cells, the microglia were shown to facilitate GB invasion and immunosuppression. However, the reciprocal mechanisms by which GB cells alter microglia/macrophages behavior are not fully understood. We propose that these mechanisms involve adhesion molecules such as the Selectins family. These proteins are involved in immune modulation and cancer immunity. We show that P-selectin mediates microglia-enhanced GB proliferation and invasion by altering microglia/macrophages activation state. We demonstrate these findings by pharmacological and molecular inhibition of P-selectin which leads to reduced tumor growth and increased survival in GB mouse models. Our work sheds light on tumor-associated microglia/macrophage function and the mechanisms by which GB cells suppress the immune system and invade the brain, paving the way to exploit P-selectin as a target for GB therapy.


Asunto(s)
Neoplasias Encefálicas/genética , Glioblastoma/genética , Macrófagos/metabolismo , Microglía/metabolismo , Selectina-P/genética , Animales , Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Células Cultivadas , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Células HEK293 , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones SCID , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Selectina-P/antagonistas & inhibidores , Selectina-P/metabolismo , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética
4.
Int J Mol Sci ; 22(4)2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670244

RESUMEN

The paired sialic acid-binding immunoglobulin like lectins (Siglecs) are characterized by similar cellular distribution and ligand recognition but opposing signalling functions attributed to different intracellular sequences. Since sialic acid-Siglec axis are known to control immune homeostasis, the imbalance between activatory and inhibitory mechanisms of glycan-dependent immune control is considered to promote pathology. The role of sialylation in cancer is described, however, its importance in immune regulation in gliomas is not fully understood. The experimental and clinical observation suggest that dexamethasone (Dex) and temozolomide (TMZ), used in the glioma management, alter the immunity within the tumour microenvironment. Using glioma-microglia/monocytes transwell co-cultures, we investigated modulatory action of Dex/TMZ on paired Siglecs. Based on real-time PCR and flow cytometry, we found changes in SIGLEC genes and their products. These effects were accompanied by altered cytokine profile and immune cells phenotype switching measured by arginases expression. Additionally, the exposure to Dex or TMZ increased the binding of inhibitory Siglec-5 and Siglec-11 fusion proteins to glioma cells. Our study suggests that the therapy-induced modulation of the interplay between sialoglycans and paired Siglecs, dependently on patient's phenotype, is of particular signification in the immune surveillance in the glioma management and may be useful in glioma patient's therapy plan verification.


Asunto(s)
Antígenos CD/farmacología , Antígenos de Diferenciación Mielomonocítica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Encefálicas , Glioma , Lectinas/farmacología , Proteínas de la Membrana/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Dexametasona/farmacología , Glioma/tratamiento farmacológico , Glioma/inmunología , Glioma/patología , Humanos , Factores Inmunológicos/farmacología , Células THP-1 , Temozolomida/farmacología
5.
JAMA Netw Open ; 4(2): e2037120, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33570575

RESUMEN

Importance: Despite approximately 40% of patients having Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores of at least 2 in the real world, most landmark clinical trials that led to the use of pembrolizumab as standard of care in advanced non-small cell lung cancer (NSCLC) excluded this group. Objective: To evaluate whether an ECOG PS score of at least 2 at the start of therapy is associated with progression-free survival (PFS) and overall survival (OS) in advanced NSCLC treated with pembrolizumab monotherapy. Design, Setting, and Participants: This cohort study included all consecutive patients with advanced NSCLC who underwent treatment with palliative pembrolizumab monotherapy from February 2016 to October 2019 at a single academic cancer center, with data censoring on January 15, 2020. Exposures: ECOG PS score at start of therapy, with 0 and 1 indicating fully active or restricted in strenuous activity and scores of 2 and higher indicating increasing disability. Main Outcomes and Measures: PFS and OS, measured from initiation of pembrolizumab monotherapy. Results: Of 74 patients (median [range] age, 68.5 [33-87] years; 36 [48.7%] women; 53 [71.6%] White individuals) with median follow-up of 19.5 (95% CI, 13.4-27.8) months, 45 (60.8%) had an ECOG PS of 0 or 1, while 29 (39.2%) had an ECOG PS of at least 2. There were no significant differences in the baseline characteristics, except in age. Compared with patients with PS scores of 0 or 1, those with PS scores of at least 2 had significantly lower disease control rates (38 [88.4%] vs 15 [53.6%]; P = .002), shorter median PFS (7.9 [95% CI, 4.6-15.4] months vs 2.3 [95% CI, 1.8-4.8] months; P = .004), and shorter median OS (23.2 [14.0 vs 35.7] months vs 4.1 [95% CI, 2.1-6.9] months; P < .001). Among those potentially eligible for subsequent cancer-directed therapy beyond pembrolizumab monotherapy, patients in the group with PS scores of at least 2 were less likely to receive it than those with PS scores of 0 or 1 (2 [8.3%] vs 14 [45.2%]; P = .003). Multivariable adjustment for baseline characteristics confirmed ECOG PS of at least 2 as an independent risk factor for worse PFS (HR, 2.02; 95% CI, 1.09-3.74; P = .03) and worse OS (HR, 2.87; 95% CI, 1.40-5.89; P = .004). Conclusions and Relevance: In this cohort study, having an ECOG PS score of at least 2 was associated with poorer prognosis for treatment of advanced NSCLC with palliative pembrolizumab monotherapy. Further prospective studies are needed to evaluate more objective and consistent measures of functional status to facilitate identification of patients with borderline performance status who may achieve durable clinical benefit from treatment with pembrolizumab monotherapy.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias de las Glándulas Suprarrenales/tratamiento farmacológico , Neoplasias de las Glándulas Suprarrenales/secundario , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/fisiopatología , Carcinoma de Pulmón de Células no Pequeñas/secundario , Estudios de Cohortes , Toma de Decisiones Conjunta , Femenino , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/fisiopatología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Cuidados Paliativos , Neoplasias Pleurales/tratamiento farmacológico , Neoplasias Pleurales/secundario , Pronóstico , Supervivencia sin Progresión , Tasa de Supervivencia
6.
Lancet Oncol ; 22(3): 370-380, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33587894

RESUMEN

BACKGROUND: Melanoma lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy. Cell-free circulating tumour DNA (ctDNA) is a promising biomarker; however, various detection methods have been used, and, to date, no large studies have examined the association between serial changes in ctDNA and survival after BRAF, MEK, or BRAF plus MEK inhibitor therapy. We aimed to evaluate whether baseline ctDNA concentrations and kinetics could predict survival outcomes. METHODS: In this clinical validation study, we used analytically validated droplet digital PCR assays to measure BRAFV600-mutant ctDNA in pretreatment and on-treatment plasma samples from patients aged 18 years or older enrolled in two clinical trials. COMBI-d (NCT01584648) was a double-blind, randomised phase 3 study of dabrafenib plus trametinib versus dabrafenib plus placebo in previously untreated patients with BRAFV600 mutation-positive unresectable or metastatic melanoma. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. COMBI-MB (NCT02039947) was an open-label, non-randomised, phase 2 study evaluating dabrafenib plus trametinib in patients with BRAFV600 mutation-positive metastatic melanoma and brain metastases. Patients in cohort A of COMBI-MB had asymptomatic brain metastases, no previous local brain-directed therapy, and an ECOG performance status of 0 or 1. Biomarker analysis was a prespecified exploratory endpoint in both trials and performed in the intention-to-treat populations in COMBI-d and COMBI-MB. We investigated the association between mutant copy number (baseline or week 4 or zero conversion status) and efficacy endpoints (progression-free survival, overall survival, and best overall response). We used Cox models, Kaplan-Meier plots, and log-rank tests to explore the association of pretreatment ctDNA concentrations with progression-free survival and overall survival. The effect of additional prognostic variables such as lactate dehydrogenase was also investigated in addition to the mutant copy number. FINDINGS: In COMBI-d, pretreatment plasma samples were available from 345 (82%) of 423 patients and on-treatment (week 4) plasma samples were available from 224 (53%) of 423 patients. In cohort A of COMBI-MB, pretreatment and on-treatment samples were available from 38 (50%) of 76 patients with intracranial and extracranial metastatic melanoma. ctDNA was detected in pretreatment samples from 320 (93%) of 345 patients (COMBI-d) and 34 (89%) of 38 patients (COMBI-MB). When assessed as a continuous variable, elevated baseline BRAFV600 mutation-positive ctDNA concentration was associated with worse overall survival outcome (hazard ratio [HR] 1·13 [95% CI 1·09-1·18], p<0·0001 by univariate analysis), independent of treatment group and baseline lactate dehydrogenase concentrations (1·08 [1·03-1·13], p=0·0020), in COMBI-d. A ctDNA cutoff point of 64 copies per mL of plasma stratified patients enrolled in COMBI-d as high risk or low risk with respect to survival outcomes (HR 1·74 [95% CI 1·37-2·21], p<0·0001 for progression-free survival; 2·23 [1·73-2·87], p<0·0001 for overall survival) and was validated in the COMBI-MB cohort (3·20 [1·39-7·34], p=0·0047 for progression-free survival; 2·94 [1·18-7·32], p=0·016 for overall survival). In COMBI-d, undetectable ctDNA at week 4 was significantly associated with extended progression-free and overall survival, particularly in patients with elevated lactate dehydrogenase concentrations (HR 1·99 [95% CI 1·08-3·64], p=0·027 for progression-free survival; 2·38 [1·24-4·54], p=0·0089 for overall survival). INTERPRETATION: Pretreatment and on-treatment BRAFV600-mutant ctDNA measurements could serve as independent, predictive biomarkers of clinical outcome with targeted therapy. FUNDING: Novartis.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/secundario , ADN Tumoral Circulante/genética , Melanoma/patología , Anciano , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , ADN Tumoral Circulante/análisis , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Imidazoles/administración & dosificación , Masculino , Melanoma/tratamiento farmacológico , Melanoma/genética , Persona de Mediana Edad , Oximas/administración & dosificación , Pronóstico , Piridonas/administración & dosificación , Pirimidinonas/administración & dosificación , Tasa de Supervivencia
7.
AAPS PharmSciTech ; 22(2): 71, 2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33575970

RESUMEN

Glioblastoma multiforme (GBM) is the most aggressive type of malignant brain tumor. Current FDA-approved treatments include surgical resection, radiation, and chemotherapy, while hyperthermia, immunotherapy, and most relevantly, nanoparticle (NP)-mediated delivery systems or combinations thereof have shown promise in preclinical studies. Drug-carrying NPs are a promising approach to brain delivery as a result of their potential to facilitate the crossing of the blood-brain barrier (BBB) via two main types of transcytosis mechanisms: adsorptive-mediated transcytosis (AMT) and receptor-mediated transcytosis (RMT). Their ability to accumulate in the brain can thus provide local sustained release of tumoricidal drugs at or near the site of GBM tumors. NP-based drug delivery has the potential to significantly reduce drug-related toxicity, increase specificity, and consequently improve the lifespan and quality of life of patients with GBM. Due to significant advances in the understanding of the molecular etiology and pathology of GBM, the efficacy of drugs loaded into vectors targeting this disease has increased in both preclinical and clinical settings. Multitargeting NPs, such as those incorporating multiple specific targeting ligands, are an innovative technology that can lead to decreased off-target effects while simultaneously having increased accumulation and action specifically at the tumor site. Targeting ligands can include antibodies, or fragments thereof, and peptides or small molecules, which can result in a more controlled drug delivery system compared to conventional drug treatments. This review focuses on GBM treatment strategies, summarizing current options and providing a detailed account of preclinical findings with prospective NP-based approaches aimed at improving tumor targeting and enhancing therapeutic outcomes for GBM patients.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Glioblastoma/tratamiento farmacológico , Nanopartículas/química , Glioblastoma/patología , Humanos , Estudios Prospectivos
9.
Nat Commun ; 12(1): 801, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33547324

RESUMEN

Most trials do not release interim summaries on efficacy and toxicity of the experimental treatments being tested, with this information only released to the public after the trial has ended. While early release of clinical trial data to physicians and patients can inform enrollment decision making, it may also affect key operating characteristics of the trial, statistical validity and trial duration. We investigate the public release of early efficacy and toxicity results, during ongoing clinical studies, to better inform patients about their enrollment options. We use simulation models of phase II glioblastoma (GBM) clinical trials in which early efficacy and toxicity estimates are periodically released accordingly to a pre-specified protocol. Patients can use the reported interim efficacy and toxicity information, with the support of physicians, to decide which trial to enroll in. We describe potential effects on various operating characteristics, including the study duration, selection bias and power.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/psicología , Drogas en Investigación/uso terapéutico , Glioblastoma/psicología , Difusión de la Información/métodos , Modelación Específica para el Paciente , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Ensayos Clínicos como Asunto , Toma de Decisiones , Glioblastoma/tratamiento farmacológico , Glioblastoma/mortalidad , Glioblastoma/patología , Humanos , Difusión de la Información/ética , Seguridad del Paciente , Selección de Paciente/ética , Análisis de Supervivencia , Factores de Tiempo , Resultado del Tratamiento
12.
Am J Phys Med Rehabil ; 100(1): 100-104, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33534219

RESUMEN

ABSTRACT: The incidence of leptomeningeal disease (LMD) is believed to be increasing in part because of more effective chemotherapy treatments allowing cancer progression behind the blood-brain barrier. However, little has been published about the rehabilitation of this growing patient population. In this study, impairments and rehabilitation utilization by cytology-proven LMD patients receiving intrathecal chemotherapy at a cancer center are described. A total of 109 consecutive patients with pathology-confirmed LMD who received an intrathecal chemotherapy infusion from January 1, 2017, through October 31, 2017, were retrospectively reviewed. Of the 109 patients, 103 (95%) had impairments described in their medical record that could impact physical function, including 74 of 109 (68%) who had deconditioning or fatigue. Kaplan-Meier median survival from initial LMD diagnosis was 13.1 mos. The median number of hospital admissions and intrathecal chemotherapy administrations was both 8. Of the 109 patients, 43 (39%) had magnetic resonance imaging radiology interpreted LMD. Most LMD patients used rehabilitation services (95/109, 87%) and most were able to forego post-acute inpatient rehabilitation facilities (96/109, 88%). Additional research and education for rehabilitation professionals about this increasingly common syndrome are needed.


Asunto(s)
Neoplasias Encefálicas/rehabilitación , Fatiga/rehabilitación , Neoplasias Meníngeas/rehabilitación , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/tratamiento farmacológico , Fatiga/etiología , Femenino , Humanos , Inyecciones Espinales , Masculino , Neoplasias Meníngeas/complicaciones , Neoplasias Meníngeas/tratamiento farmacológico , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos
13.
BMJ Case Rep ; 14(2)2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-33526518

RESUMEN

Immune checkpoint inhibitors (ICIs) are increasingly used to treat certain malignancies due to their higher efficacy compared with conventional chemotherapy. As familiarity with these agents increases, it is becoming apparent that a significant number of patients treated with ICIs experience adverse events. With time, more immune-related adverse events (IRAEs) are being recognised. It is important to be vigilant for IRAEs and recognise that a patient may have multiple IRAEs affecting multiple organ systems. Common cardiovascular adverse events associated with ICIs include myocarditis, arrhythmias and pericarditis. This case report identifies a patient presenting with takotsubo syndrome followed by ketoacidosis (associated with sodium-glucose transport protein 2 (SGLT2) inhibitor) in the setting of combination ipilimumab and nivolumab therapy for metastatic melanoma.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Cetoacidosis Diabética/inducido químicamente , Melanoma/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Cardiomiopatía de Takotsubo/inducido químicamente , Anciano , Compuestos de Bencidrilo/efectos adversos , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/secundario , Angiografía Coronaria , Diabetes Mellitus Tipo 2/complicaciones , Cetoacidosis Diabética/complicaciones , Ecocardiografía , Glucósidos/efectos adversos , Humanos , Ipilimumab/efectos adversos , Imagen por Resonancia Magnética , Masculino , Melanoma/complicaciones , Melanoma/secundario , Nivolumab/efectos adversos , Cardiomiopatía de Takotsubo/complicaciones , Cardiomiopatía de Takotsubo/diagnóstico por imagen
14.
Nat Commun ; 12(1): 979, 2021 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-33579912

RESUMEN

Glioblastoma (GBM) is a deadly cancer in which cancer stem cells (CSCs) sustain tumor growth and contribute to therapeutic resistance. Protein arginine methyltransferase 5 (PRMT5) has recently emerged as a promising target in GBM. Using two orthogonal-acting inhibitors of PRMT5 (GSK591 or LLY-283), we show that pharmacological inhibition of PRMT5 suppresses the growth of a cohort of 46 patient-derived GBM stem cell cultures, with the proneural subtype showing greater sensitivity. We show that PRMT5 inhibition causes widespread disruption of splicing across the transcriptome, particularly affecting cell cycle gene products. We identify a GBM splicing signature that correlates with the degree of response to PRMT5 inhibition. Importantly, we demonstrate that LLY-283 is brain-penetrant and significantly prolongs the survival of mice with orthotopic patient-derived xenografts. Collectively, our findings provide a rationale for the clinical development of brain penetrant PRMT5 inhibitors as treatment for GBM.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteína-Arginina N-Metiltransferasas/metabolismo , Animales , Apoptosis , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Epigenómica , Femenino , Regulación Neoplásica de la Expresión Génica , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/patología , Humanos , Ratones , Células Madre Neoplásicas/metabolismo , Proteína-Arginina N-Metiltransferasas/efectos de los fármacos , Proteína-Arginina N-Metiltransferasas/genética , Empalme del ARN , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Int J Nanomedicine ; 16: 185-199, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33447034

RESUMEN

Background: Therapy for glioblastoma (GBM) has always been very challenging, not only because of the presence of the blood-brain barrier (BBB) but also due to susceptibility to drug resistance. Recently, the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR/Cas9) has revolutionized gene editing technology and is capable of treating a variety of genetic diseases, including human tumors, but there is a lack of safe and effective targeting delivery systems in vivo, especially in the central nervous system (CNS). Methods: Lipid-polymer hybrid nanoparticles (LPHNs-cRGD) were constructed for efficient and targeting delivery of CRISPR/Cas9 plasmids targeting O6-methylguanine-DNA methyltransferase (MGMT), a drug-resistance gene to temozolomide (TMZ). Focused ultrasound (FUS)-microbubbles (MBs) were used to non-invasively and locally open the BBB to further facilitate gene delivery into glioblastoma in vivo. The gene editing efficiency and drug sensitivity changes were evaluated both in vitro and in vivo. Results: The gene-loaded LPHNs-cRGD were successfully synthesized and could protect pCas9/MGMT from enzyme degradation. LPHNs-cRGD could target GBM cells and mediate the transfection of pCas9/MGMT to downregulate the expression of MGMT, resulting in an increased sensitivity of GBM cells to TMZ. MBs-LPHNs-cRGD complexes could safely and locally increase the permeability of the BBB with FUS irradiation in vivo and facilitated the accumulation of nanoparticles at the tumor region in orthotopic tumor-bearing mice. Furthermore, the FUS-assisted MBs-LPHNspCas9/MGMT-cRGD enhanced the therapeutic effects of TMZ in glioblastoma, inhibited tumor growth, and prolonged survival of tumor-bearing mice, with a high level of biosafety. Conclusion: In this work, we constructed LPHNs-cRGD for targeting delivery of the CRISPR/Cas9 system, in combination with FUS-MBs to open the BBB. The MBs-LPHNs-cRGD delivery system could be a potential alternative for efficient targeting gene delivery for the treatment of glioblastoma.


Asunto(s)
Neoplasias Encefálicas/terapia , Resistencia a Antineoplásicos , Terapia Genética , Glioblastoma/terapia , Ultrasonido Enfocado de Alta Intensidad de Ablación , Lípidos/química , Nanopartículas/química , Polímeros/química , Animales , Barrera Hematoencefálica/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Línea Celular Tumoral , Desoxirribonucleasa I/metabolismo , Glioblastoma/tratamiento farmacológico , Humanos , Ratones Endogámicos NOD , Ratones SCID , Microburbujas , Nanopartículas/ultraestructura , Péptidos Cíclicos/química , Plásmidos/genética , Temozolomida/farmacología , Temozolomida/uso terapéutico , Distribución Tisular , Transfección
16.
Lancet Oncol ; 22(1): e7-e17, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33387511

RESUMEN

Breast cancer brain metastases are an increasing clinical problem. Studies have shown that brain metastases from breast cancer have a distinct genomic landscape to that of the primary tumour, including the presence of mutations that are absent in the primary breast tumour. In this Review, we aim to review and evaluate genomic sequencing data for breast cancer brain metastases by searching PubMed, Embase, and Scopus for relevant articles published in English between database inception and May 30, 2020. Extracted information includes data for mutations, receptor status (eg, immunohistochemistry and Prediction Analysis of Microarray 50 [PAM50]), and copy number alterations from published manuscripts and supplementary materials. Of the 431 articles returned by the database search, 13 (3%) breast cancer brain metastases sequencing studies, comprising 164 patients with sequenced brain metastases, met all our inclusion criteria. We identified 268 mutated genes that were present in two or more breast cancer brain metastases samples. Of these 268 genes, 22 (8%) were mutated in five or more patients and pathway enrichment analysis showed their involvement in breast cancer-related signalling pathways, regulation of gene transcription, cell cycle, and DNA repair. Actionability analysis using the Drug Gene Interaction Database revealed that 15 (68%) of these 22 genes are actionable drug targets. In addition, immunohistochemistry and PAM50 data showed receptor discordancy between primary breast cancers and their paired brain metastases. This systematic review provides a detailed overview of the most commonly mutated genes identified in samples of breast cancer brain metastases and their clinical relevance. These data highlight the differences between primary breast cancers and brain metastases and the importance of acquiring and analysing brain metastasis samples for further study.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Neoplasias de la Mama/genética , Variaciones en el Número de Copia de ADN , Dosificación de Gen , Mutación , Transducción de Señal/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Femenino , Redes Reguladoras de Genes , Predisposición Genética a la Enfermedad , Humanos , Terapia Molecular Dirigida , Fenotipo , Medicina de Precisión , Transducción de Señal/efectos de los fármacos
17.
J Med Chem ; 64(3): 1423-1434, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33502198

RESUMEN

Despite the recent advances in cancer therapeutics, highly aggressive cancer forms, such as glioblastoma (GBM), still have very low survival rates. The intracellular scaffold protein syntenin, comprising two postsynaptic density protein-95/discs-large/zona occludens-1 (PDZ) domains, has emerged as a novel therapeutic target in highly malignant phenotypes including GBM. Here, we report the development of a novel, highly potent, and metabolically stable peptide inhibitor of syntenin, KSL-128114, which binds the PDZ1 domain of syntenin with nanomolar affinity. KSL-128114 is resistant toward degradation in human plasma and mouse hepatic microsomes and displays a global PDZ domain selectivity for syntenin. An X-ray crystal structure reveals that KSL-128114 interacts with syntenin PDZ1 in an extended noncanonical binding mode. Treatment with KSL-128114 shows an inhibitory effect on primary GBM cell viability and significantly extends survival time in a patient-derived xenograft mouse model. Thus, KSL-128114 is a novel promising candidate with therapeutic potential for highly aggressive tumors, such as GBM.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Péptidos/química , Péptidos/farmacología , Sinteninas/efectos de los fármacos , Animales , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Humanos , Ligandos , Ratones , Microsomas/metabolismo , Modelos Moleculares , Mutación , Unión Proteica , Difracción de Rayos X , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Oncology ; 99(4): 215-224, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33472203

RESUMEN

INTRODUCTION: Gliomatosis cerebri (GC) is defined by diffuse, widespread glial tumor growth affecting three or more cerebral lobes. Previous studies in gliomas found no distinct histological or molecular GC subtype, yet the presence of GC is associated with worse median overall survival (OS). Here, we explored whether differing therapeutic strategies in first-line treatment could account for this. METHODS: From our University Cancer Center database, 47 patients with histological diagnosis of WHO grade II or III glioma and GC imaging pattern were identified. GC criteria were confirmed by independent review. Patients with WHO grade II or III glioma with non-GC pattern served as control cohort (n = 343). RESULTS: Within the GC patient cohort, lower WHO grade, mutated isocitrate dehydrogenase 1 (IDH1) status, and absence of contrast enhancement were associated with better OS. Compared to the control cohort, patients with GC had significantly shorter OS independent of histological diagnosis or IDH1 mutation status. Patients with GC preferentially received chemotherapy alone (62 vs. 18%), and less frequently radiochemotherapy (21 vs. 27%). OS was significantly shorter in the GC cohort compared to the non-GC cohort both for chemotherapy (3.9 vs. 7.6 years, p = 0.0085) and for combined radiochemotherapy (1.1 vs. 8.4 years, p < 0.0001). However, when only patients who received biopsy plus chemotherapy were analyzed, the differences lost statistical significance (3.5 vs. 6.6 years, p = 0.196). CONCLUSION: We found major differences in the selection of first-line therapies of GC versus non-GC patients. Our results suggest that these differences may partly account for the worse prognosis of GC patients.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/mortalidad , Glioma/tratamiento farmacológico , Glioma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/radioterapia , Estudios de Cohortes , Femenino , Glioma/patología , Glioma/radioterapia , Humanos , Isocitrato Deshidrogenasa/genética , Masculino , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Pronóstico , Tasa de Supervivencia , Resultado del Tratamiento , Adulto Joven
19.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-33435596

RESUMEN

Lung cancer is one of the most common malignant neoplasms. As a result of the disease's progression, patients may develop metastases to the central nervous system. The prognosis in this location is unfavorable; untreated metastatic lesions may lead to death within one to two months. Existing therapies-neurosurgery and radiation therapy-do not improve the prognosis for every patient. The discovery of Epidermal Growth Factor Receptor (EGFR)-activating mutations and Anaplastic Lymphoma Kinase (ALK) rearrangements in patients with non-small cell lung adenocarcinoma has allowed for the introduction of small-molecule tyrosine kinase inhibitors to the treatment of advanced-stage patients. The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein with tyrosine kinase-dependent activity. EGFR is present in membranes of all epithelial cells. In physiological conditions, it plays an important role in the process of cell growth and proliferation. Binding the ligand to the EGFR causes its dimerization and the activation of the intracellular signaling cascade. Signal transduction involves the activation of MAPK, AKT, and JNK, resulting in DNA synthesis and cell proliferation. In cancer cells, binding the ligand to the EGFR also leads to its dimerization and transduction of the signal to the cell interior. It has been demonstrated that activating mutations in the gene for EGFR-exon19 (deletion), L858R point mutation in exon 21, and mutation in exon 20 results in cancer cell proliferation. Continuous stimulation of the receptor inhibits apoptosis, stimulates invasion, intensifies angiogenesis, and facilitates the formation of distant metastases. As a consequence, the cancer progresses. These activating gene mutations for the EGFR are present in 10-20% of lung adenocarcinomas. Approximately 3-7% of patients with lung adenocarcinoma have the echinoderm microtubule-associated protein-like 4 (EML4)/ALK fusion gene. The fusion of the two genes EML4 and ALK results in a fusion gene that activates the intracellular signaling pathway, stimulates the proliferation of tumor cells, and inhibits apoptosis. A new group of drugs-small-molecule tyrosine kinase inhibitors-has been developed; the first generation includes gefitinib and erlotinib and the ALK inhibitor crizotinib. These drugs reversibly block the EGFR by stopping the signal transmission to the cell. The second-generation tyrosine kinase inhibitor (TKI) afatinib or ALK inhibitor alectinib block the receptor irreversibly. Clinical trials with TKI in patients with non-small cell lung adenocarcinoma with central nervous system (CNS) metastases have shown prolonged, progression-free survival, a high percentage of objective responses, and improved quality of life. Resistance to treatment with this group of drugs emerging during TKI therapy is the basis for the detection of resistance mutations. The T790M mutation, present in exon 20 of the EGFR gene, is detected in patients treated with first- and second-generation TKI and is overcome by Osimertinib, a third-generation TKI. The I117N resistance mutation in patients with the ALK mutation treated with alectinib is overcome by ceritinib. In this way, sequential therapy ensures the continuity of treatment. In patients with CNS metastases, attempts are made to simultaneously administer radiation therapy and tyrosine kinase inhibitors. Patients with lung adenocarcinoma with CNS metastases, without activating EGFR mutation and without ALK rearrangement, benefit from immunotherapy. This therapeutic option blocks the PD-1 receptor on the surface of T or B lymphocytes or PD-L1 located on cancer cells with an applicable antibody. Based on clinical trials, pembrolizumab and all antibodies are included in the treatment of non-small cell lung carcinoma with CNS metastases.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Acrilamidas/uso terapéutico , Compuestos de Anilina/uso terapéutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos/genética , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Pirimidinas/uso terapéutico , Sulfonas/uso terapéutico
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