RESUMEN
Brasilicardinâ A (1) consists of an unusual anti/syn/anti-perhydrophenanthrene skeleton with a carbohydrate side chain and an amino acid moiety. It exhibits potent immunosuppressive activity, yet its mode of action differs from standard drugs that are currently in use. Further pre-clinical evaluation of this promising, biologically active natural product is hampered by restricted access to the ready material, as its synthesis requires both a low-yielding fermentation process using a pathogenic organism and an elaborate, multi-step total synthesis. Our semi-synthetic approach included a) the heterologous expression of the brasilicardinâ A gene cluster in different non-pathogenic bacterial strains producing brasilicardinâ A aglycone (5) in excellent yield and b) the chemical transformation of the aglycone 5 into the trifluoroacetic acid salt of brasilicardinâ A (1 a) via a short and straightforward five-steps synthetic route. Additionally, we report the first preclinical data for brasilicardinâ A.
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Aminoglicósidos/metabolismo , Ingeniería Genética , Inmunosupresores/síntesis química , Transferasas Alquil y Aril/genética , Aminoglicósidos/síntesis química , Aminoglicósidos/química , Aminoglicósidos/farmacología , Animales , Productos Biológicos/síntesis química , Productos Biológicos/química , Productos Biológicos/metabolismo , Productos Biológicos/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Inmunosupresores/química , Inmunosupresores/metabolismo , Inmunosupresores/farmacología , Ratones , Plásmidos/genética , Plásmidos/metabolismo , Streptomyces/genética , Streptomyces/metabolismo , Terpenos/químicaRESUMEN
BACKGROUND: The relationship between pneumococcal conjugate vaccine-induced antibody responses and protection against community-acquired pneumonia (CAP) and acute otitis media (AOM) is unclear. This study assessed the impact of the ten-valent pneumococcal nontypable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) on these end points. The primary objective was to demonstrate vaccine efficacy (VE) in a per-protocol analysis against likely bacterial CAP (B-CAP: radiologically confirmed CAP with alveolar consolidation/pleural effusion on chest X-ray, or non-alveolar infiltrates and C-reactive protein ≥ 40 µg/ml); other protocol-specified outcomes were also assessed. METHODS AND FINDINGS: This phase III double-blind randomized controlled study was conducted between 28 June 2007 and 28 July 2011 in Argentine, Panamanian, and Colombian populations with good access to health care. Approximately 24,000 infants received PHiD-CV or hepatitis control vaccine (hepatitis B for primary vaccination, hepatitis A at booster) at 2, 4, 6, and 15-18 mo of age. Interim analysis of the primary end point was planned when 535 first B-CAP episodes, occurring ≥2 wk after dose 3, were identified in the per-protocol cohort. After a mean follow-up of 23 mo (PHiD-CV, n = 10,295; control, n = 10,201), per-protocol VE was 22.0% (95% CI: 7.7, 34.2; one-sided p = 0.002) against B-CAP (conclusive for primary objective) and 25.7% (95% CI: 8.4%, 39.6%) against World Health Organization-defined consolidated CAP. Intent-to-treat VE was 18.2% (95% CI: 5.5%, 29.1%) against B-CAP and 23.4% (95% CI: 8.8%, 35.7%) against consolidated CAP. End-of-study per-protocol analyses were performed after a mean follow-up of 28-30 mo for CAP and invasive pneumococcal disease (IPD) (PHiD-CV, n = 10,211; control, n = 10,140) and AOM (n = 3,010 and 2,979, respectively). Per-protocol VE was 16.1% (95% CI: -1.1%, 30.4%; one-sided p = 0.032) against clinically confirmed AOM, 67.1% (95% CI: 17.0%, 86.9%) against vaccine serotype clinically confirmed AOM, 100% (95% CI: 74.3%, 100%) against vaccine serotype IPD, and 65.0% (95% CI: 11.1%, 86.2%) against any IPD. Results were consistent between intent-to-treat and per-protocol analyses. Serious adverse events were reported for 21.5% (95% CI: 20.7%, 22.2%) and 22.6% (95% CI: 21.9%, 23.4%) of PHiD-CV and control recipients, respectively. There were 19 deaths (n = 11,798; 0.16%) in the PHiD-CV group and 26 deaths (n = 11,799; 0.22%) in the control group. A significant study limitation was the lower than expected number of captured AOM cases. CONCLUSIONS: Efficacy was demonstrated against a broad range of pneumococcal diseases commonly encountered in young children in clinical practice. TRIAL REGISTRATION: www.ClinicalTrials.gov NCT00466947.
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Proteínas Bacterianas/inmunología , Proteínas Portadoras/inmunología , Haemophilus influenzae/inmunología , Inmunoglobulina D/inmunología , Lipoproteínas/inmunología , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas/inmunología , Streptococcus pneumoniae/inmunología , Vacunación , Vacunas Conjugadas/inmunología , Anticuerpos Antibacterianos/sangre , Preescolar , Método Doble Ciego , Infecciones por Haemophilus/microbiología , Humanos , Inmunización Secundaria , Lactante , Análisis de Intención de Tratar , América Latina , Otitis Media/inmunología , Otitis Media/microbiología , Otitis Media/prevención & control , Infecciones Neumocócicas/inmunología , Infecciones Neumocócicas/microbiología , Resultado del TratamientoRESUMEN
T-cell lymphomas are aggressive neoplasms characterized by poor responses to current chemotherapeutic agents. Expression of the l-type amino acid transporter 1 (LAT 1, SLC7A5) allows for the expansion of healthy T-cell counterparts, and upregulation of LAT1 has been reported in precursor T-cell acute leukemia. Therefore, the expression of LAT1 was evaluated in a cohort of cutaneous and peripheral T-cell lymphomas. The findings demonstrated that LAT1 is upregulated in aggressive variants and absent in low-grade or indolent disease such as mycosis fungoides. In addition, upregulated LAT1 expression was seen in a large proportion of aggressive peripheral T-cell lymphomas, including peripheral T-cell lymphoma not otherwise specific (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL). The anti-tumor effects of two novel non-cleavable and bifunctional compounds, QBS10072S and QBS10096S, that combine a potent cytotoxic chemotherapeutic domain (tertiary N-bis(2-chloroethyl)amine) with the structural features of a selective LAT1 substrate (aromatic ß-amino acid) were tested in vitro and in vivo in T-cell lymphoma cell lines. The findings demonstrated decreased survival of T-cell lymphoma lines with both compounds. Overall, the results demonstrate that LAT1 is a valuable biomarker for aggressive T-cell lymphoma counterparts and QBS10072S and QBS10096S are successful therapeutic options for these aggressive diseases.
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Introduction The standard treatment for glioblastoma (GBM) patients is surgical tumor resection, followed by radiation and chemotherapy with temozolomide (TMZ). Unfortunately, 60% of newly diagnosed GBM patients express high levels of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) and are TMZ-resistant, and all patients eventually become refractory to treatment. The blood-brain barrier (BBB) is an obstacle to the delivery of chemotherapeutic agents to GBM, and BBB-permeable agents that are efficacious in TMZ-resistant and refractory patients are needed. The large amino acid transporter 1 (LAT1) is expressed on the BBB and in GBM and is detected at much lower levels in normal brain tissue. A LAT1-selective therapeutic would potentially target brain tumors while avoiding uptake by healthy tissue. Methods We report a novel chemical entity (QBS10072S) that combines a potent cytotoxic chemotherapeutic domain (tertiary N-bis(2-chloroethyl)amine) with the structural features of a selective LAT1 substrate and tested it against GBM models in vitro and in vivo. For in vitro studies, DNA damage was assessed with a gamma H2A.X antibody and cell viability was assessed by WST-1 assay and/or CellTiter-Glo assay. For in vivo studies, QBS10072S (with or without radiation) was tested in orthotopic glioblastoma xenograft models, using overall survival and tumor size (as measured by bioluminescence), as endpoints. Results QBS10072S is 50-fold more selective for LAT1 vs. LAT2 in transport assays and demonstrates significant growth suppression in vitro of LAT1-expressing GBM cell lines. Unlike TMZ, QBS10072S is cytotoxic to cells with both high and low levels of MGMT expression. In orthotopic GBM xenografts, QBS10072S treatment significantly delayed tumorigenesis and prolonged animal survival compared to the vehicle without adverse effects. Conclusion QBS10072S is a novel BBB-permeable chemotherapeutic agent with the potential to treat TMZ-resistant and recurrent GBM as monotherapy or in combination with radiation treatment.
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Development of metastases to central nervous system (CNS) is an increasing clinical issue following the diagnosis of advanced breast cancer. The propensity to metastasize to CNS varies by breast cancer subtype. Of the four breast cancer subtypes, triple-negative breast cancers (TNBC) have the highest rates of both parenchymal brain metastasis and leptomeningeal metastasis (LM). LM is rapidly fatal due to poor detection and limited therapeutic options. Therapy of TNBC brain metastasis and LM is challenged by multifocal brain metastasis and diffuse spread of LM, and must balance brain penetration, tumor cytotoxicity, and the avoidance of neurotoxicity. Thus, there is an urgent need for novel therapeutic options in TNBCs CNS metastasis. QBS10072S is a novel chemotherapeutic that leverages TNBC-specific defects in DNA repair and LAT1 (L-amino acid transporter type 1)-dependent transport into the brain. In our study, activity of QBS10072S was investigated in vitro with various cell lines including the human TNBC cell line MDA-MB-231 and its brain-tropic derivative MDA-MB-231-BR3. QBS10072S was preferentially toxic to TNBC cells. The efficacy of QBS10072S against brain metastasis and LM was tested using a model of brain metastasis based on the internal carotid injection of luciferase-expressing tumor cells into NuNu mice. The compound was well tolerated, delayed tumor growth and reduced leptomeningeal dissemination, resulting in significant extension of survival. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, QBS10072S is planned to be investigated in clinical trials as a therapeutic for TNBC LM. SIGNIFICANCE: TNBC brain metastasis often involves dissemination into leptomeninges. Treatment options for TNBC leptomeningeal metastasis are limited and are mostly palliative. Our study demonstrates significant efficacy of the brain-penetrating agent QBS10072S against TNBC brain metastasis and leptomeningeal spread.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Humanos , Ratones , Metástasis de la NeoplasiaRESUMEN
In KRAS-mutant lung adenocarcinoma, tumors with LKB1 loss (KL) are highly enriched for concurrent KEAP1 mutations, which activate the KEAP1/NRF2 pathway (KLK). Here, we investigated the biological consequences of these cooccurring alterations and explored whether they conferred specific therapeutic vulnerabilities. Compared with KL tumors, KLK tumors exhibited increased expression of genes involved in glutamine metabolism, the tricarboxylic acid cycle, and the redox homeostasis signature. Using isogenic pairs with knockdown or overexpression of LKB1, KEAP1, and NRF2, we found that LKB1 loss results in increased energetic and redox stress marked by increased levels of intracellular reactive oxygen species and decreased levels of ATP, NADPH/NADP+ ratio, and glutathione. Activation of the KEAP1/NRF2 axis in LKB1-deficient cells enhanced cell survival and played a critical role in the maintenance of energetic and redox homeostasis in a glutamine-dependent manner. LKB1 and the KEAP1/NRF2 pathways cooperatively drove metabolic reprogramming and enhanced sensitivity to the glutaminase inhibitor CB-839 in vitro and in vivo. Overall, these findings elucidate the adaptive advantage provided by KEAP1/NRF2 pathway activation in KL tumors and support clinical testing of glutaminase inhibitor in subsets of KRAS-mutant lung adenocarcinoma. SIGNIFICANCE: In KRAS-mutant non-small cell lung cancer, LKB1 loss results in enhanced energetic/redox stress, which is tolerated, in part, through cooccurring KEAP1/NRF2-dependent metabolic adaptations, thus enhancing glutamine dependence and vulnerability to glutaminase inhibition.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/13/3251/F1.large.jpg.
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Adenocarcinoma del Pulmón/patología , Reprogramación Celular , Glutamina/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular , Metabolismo Energético , Femenino , Regulación Neoplásica de la Expresión Génica , Glutaminasa/metabolismo , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Redes y Vías Metabólicas , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Mutación , Factor 2 Relacionado con NF-E2/genética , Estrés Oxidativo , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We previously reported 10-valent pneumococcal non-typeable Haemophilus influenzae (NTHi) protein D conjugate vaccine (PHiD-CV) efficacy in a double-blind randomized trial (ClinicalTrials.gov: NCT00466947) against various diseases, including acute otitis media (AOM). Here, we provide further analyses. In the Panamanian subset, 7,359 children were randomized (1:1) to receive PHiD-CV or control vaccine at age 2/4/6 and 15-18 months. Of these, 2,000 had nasopharyngeal swabs collected. AOM cases were captured when parents sought medical attention for children with AOM symptoms; surveillance was enhanced approximately 2 y into the study through regular telephone calls or home visits by study personnel, who advised parents to visit the clinic if their child had AOM symptoms. Mean follow-up was 31.4 months. Clinical AOM (C-AOM) cases were assessed by physicians and confirmed by otorhinolaryngologists. Middle ear fluid samples, taken from children with C-AOM after specific informed consent, and nasopharyngeal samples were cultured for pathogen identification. For 7,359 children, 2,574 suspected AOM cases were assessed by a primary healthcare physician; 649 cases were C-AOM cases as per protocol definition. From the 503 MEF samples collected, 158 resulted in a positive culture. In the intent-to-treat cohort (7,214 children), PHiD-CV showed VE against first C-AOM (24.0% [95% CI: 8.7, 36.7]) and bacterial (B-AOM) episodes (48.0% [20.3, 66.1]) in children <24 months, which declined thereafter with age. Pre-booster VE against C-AOM was 30.7% [12.9, 44.9]; post-booster, -6.7% [-36.4, 16.6]. PHiD-CV VE was 17.7% [-6.1, 36.2] against moderate and 32.7% [-20.5, 62.4] against severe C-AOM. VE against vaccine-serotype pneumococcal NPC was 31.2% [5.3, 50.3] 3 months post-booster, and 25.6% [12.7, 36.7] across all visits. NTHi colonization rates were low and no significant reduction was observed. PHiD-CV showed efficacy against C-AOM and B-AOM in children younger than 24 months, and reduced vaccine-serotype NPC.
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Proteínas Bacterianas/inmunología , Proteínas Portadoras/inmunología , Portador Sano/prevención & control , Infecciones por Haemophilus/prevención & control , Vacunas contra Haemophilus/inmunología , Inmunoglobulina D/inmunología , Lipoproteínas/inmunología , Otitis Media/prevención & control , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas/inmunología , Método Doble Ciego , Oído Medio/microbiología , Exudados y Transudados/microbiología , Femenino , Estudios de Seguimiento , Vacunas contra Haemophilus/administración & dosificación , Humanos , Lactante , Masculino , Nasofaringe/microbiología , Panamá , Vacunas Neumococicas/administración & dosificación , Resultado del TratamientoRESUMEN
Cancer cells exhibit increased use of nutrients, including glucose and glutamine, to support the bioenergetic and biosynthetic demands of proliferation. We tested the small-molecule inhibitor of glutaminase CB-839 in combination with erlotinib on epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) as a therapeutic strategy to simultaneously impair cancer glucose and glutamine utilization and thereby suppress tumor growth. Here, we show that CB-839 cooperates with erlotinib to drive energetic stress and activate the AMP-activated protein kinase (AMPK) pathway in EGFR (del19) lung tumors. Tumor cells undergo metabolic crisis and cell death, resulting in rapid tumor regression in vivo in mouse NSCLC xenografts. Consistently, positron emission tomography (PET) imaging with 18F-fluoro-2-deoxyglucose (18F-FDG) and 11C-glutamine (11C-Gln) of xenografts indicated reduced glucose and glutamine uptake in tumors following treatment with CB-839 + erlotinib. Therefore, PET imaging with 18F-FDG and 11C-Gln tracers can be used to non-invasively measure metabolic response to CB-839 and erlotinib combination therapy.
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Apoptosis/efectos de los fármacos , Bencenoacetamidas/toxicidad , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib/toxicidad , Glutaminasa/antagonistas & inhibidores , Tiadiazoles/toxicidad , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Autofagia/efectos de los fármacos , Bencenoacetamidas/uso terapéutico , Radioisótopos de Carbono/química , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Receptores ErbB/genética , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib/uso terapéutico , Fluorodesoxiglucosa F18/química , Glutaminasa/metabolismo , Glutamina/química , Glutamina/metabolismo , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ratones , Ratones SCID , Mutación , Interferencia de ARN , Radiofármacos/química , Tiadiazoles/uso terapéutico , Trasplante HeterólogoRESUMEN
BACKGROUND: Myeloid cells are an abundant leukocyte in many types of tumors and contribute to immune evasion. Expression of the enzyme arginase 1 (Arg1) is a defining feature of immunosuppressive myeloid cells and leads to depletion of L-arginine, a nutrient required for T cell and natural killer (NK) cell proliferation. Here we use CB-1158, a potent and orally-bioavailable small-molecule inhibitor of arginase, to investigate the role of Arg1 in regulating anti-tumor immunity. METHODS: CB-1158 was tested for the ability to block myeloid cell-mediated inhibition of T cell proliferation in vitro, and for tumor growth inhibition in syngeneic mouse models of cancer as a single agent and in combination with other therapies. Tumors from animals treated with CB-1158 were profiled for changes in immune cell subsets, expression of immune-related genes, and cytokines. Human tumor tissue microarrays were probed for Arg1 expression by immunohistochemistry and immunofluorescence. Cancer patient plasma samples were assessed for Arg1 protein and L-arginine by ELISA and mass spectrometry, respectively. RESULTS: CB-1158 blocked myeloid cell-mediated suppression of T cell proliferation in vitro and reduced tumor growth in multiple mouse models of cancer, as a single agent and in combination with checkpoint blockade, adoptive T cell therapy, adoptive NK cell therapy, and the chemotherapy agent gemcitabine. Profiling of the tumor microenvironment revealed that CB-1158 increased tumor-infiltrating CD8+ T cells and NK cells, inflammatory cytokines, and expression of interferon-inducible genes. Patient tumor samples from multiple histologies expressed an abundance of tumor-infiltrating Arg1+ myeloid cells. Plasma samples from cancer patients exhibited elevated Arg1 and reduced L-arginine compared to healthy volunteers. CONCLUSIONS: These results demonstrate that Arg1 is a key mediator of immune suppression and that inhibiting Arg1 with CB-1158 shifts the immune landscape toward a pro-inflammatory environment, blunting myeloid cell-mediated immune evasion and reducing tumor growth. Furthermore, our results suggest that arginase blockade by CB-1158 may be an effective therapy in multiple types of cancer and combining CB-1158 with standard-of-care chemotherapy or other immunotherapies may yield improved clinical responses.
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Arginasa/metabolismo , Células Mieloides/citología , Neoplasias/tratamiento farmacológico , Pirrolidinas/administración & dosificación , Bibliotecas de Moléculas Pequeñas/administración & dosificación , Microambiente Tumoral/efectos de los fármacos , Animales , Arginasa/antagonistas & inhibidores , Arginina/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Células Hep G2 , Humanos , Células K562 , Masculino , Ratones , Células Mieloides/efectos de los fármacos , Células Mieloides/enzimología , Neoplasias/inmunología , Neoplasias/metabolismo , Pirrolidinas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Tuberculoid (TT) and lepromatous leprosy (LL) develop in the human host depending on his ability to trigger a specific cellular immune response(CIR). Different genes have been demonstrated in susceptibility/protection and may explain the forms of leprosy. The major histocompatibility complex (MHC) play an important role. The aim of the study was to explore the contribution of human leukocyte antigen (HLA) DRB1, DQA1, DQB1 and DQ promoter genes in LL Mexican patients. Six families (26 LL, three TT patients and 27 controls) were analyzed; 114 unrelated patients were compared with 204 controls. Class I typing was done by the standard microlymphocytotoxicity and class II typing using PCR-SSOP. Haplotype segregation correlated with specific CIR in vivo and in vitro using lepromin. Haplotype sharing was significantly deviated in the affected sibs (p=0.01). Six healthy sibs were non-responders to lepromin and four of them were DQ1 homozgotes. DQ1 was significantly associated with LL and with non-responders. We set up macrophage activation experiments after infecting these cells with 5x10(6) bacilli to demonstrate if elimination occurred in the context or DQ1. When DQ1 was present on macrophages and on T cells, bacteria were poorly eliminated from the cell (32%) while when absent, 76% of the individuals were able to eliminate the bacilli (p=0.03). DRB1*1501 DQA1*0102-DQB1*0602 (DQ1 subtype) was significantly increased in the patients, indicating its participation in susceptibility. QBP 5.11/5.12 promoter present in the mentioned haplotype, and QAP 1.4, linked to DRB1*1301/02 haplotypes were also associated. Two mechanisms are suggested: the promoter polymorphisms may influence allele expression and thus the amount of peptides presented to the T-cell receptor, leading to a deficient CIR: HLA restriction is important for vaccine design; the way peptides anchor the DRB1*1501 groove may be relevant to the activation of TH1 cells, which contribute to an efficient presentation of peptides inducing a protective T-cell response.
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Vacunas Bacterianas , Genes MHC Clase II , Predisposición Genética a la Enfermedad , Lepra/genética , Vacunas Sintéticas , Humanos , Lepra/prevención & controlRESUMEN
Glutamine serves as an important source of energy and building blocks for many tumor cells. The first step in glutamine utilization is its conversion to glutamate by the mitochondrial enzyme glutaminase. CB-839 is a potent, selective, and orally bioavailable inhibitor of both splice variants of glutaminase (KGA and GAC). CB-839 had antiproliferative activity in a triple-negative breast cancer (TNBC) cell line, HCC-1806, that was associated with a marked decrease in glutamine consumption, glutamate production, oxygen consumption, and the steady-state levels of glutathione and several tricarboxylic acid cycle intermediates. In contrast, no antiproliferative activity was observed in an estrogen receptor-positive cell line, T47D, and only modest effects on glutamine consumption and downstream metabolites were observed. Across a panel of breast cancer cell lines, GAC protein expression and glutaminase activity were elevated in the majority of TNBC cell lines relative to receptor positive cells. Furthermore, the TNBC subtype displayed the greatest sensitivity to CB-839 treatment and this sensitivity was correlated with (i) dependence on extracellular glutamine for growth, (ii) intracellular glutamate and glutamine levels, and (iii) GAC (but not KGA) expression, a potential biomarker for sensitivity. CB-839 displayed significant antitumor activity in two xenograft models: as a single agent in a patient-derived TNBC model and in a basal like HER2(+) cell line model, JIMT-1, both as a single agent and in combination with paclitaxel. Together, these data provide a strong rationale for the clinical investigation of CB-839 as a targeted therapeutic in patients with TNBC and other glutamine-dependent tumors.
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Antineoplásicos/administración & dosificación , Bencenoacetamidas/farmacología , Inhibidores Enzimáticos/administración & dosificación , Glutaminasa/antagonistas & inhibidores , Neoplasias Basocelulares/tratamiento farmacológico , Tiadiazoles/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Administración Oral , Animales , Antineoplásicos/uso terapéutico , Bencenoacetamidas/uso terapéutico , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Neoplasias Mamarias Experimentales , Ratones , Ratones SCID , Persona de Mediana Edad , Neoplasias Basocelulares/patología , Sulfuros/administración & dosificación , Sulfuros/uso terapéutico , Tiadiazoles/administración & dosificación , Tiadiazoles/uso terapéutico , Neoplasias de la Mama Triple Negativas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Se estudia una población de 40 trabajadores de una industria metalúrgica, que laboran en un ambiente de trabajo ruidoso, cuyos niveles de presión sonora superan el límite máximo permisible (85 dB). El 85% de la población trabajadora, perteneciente al sexo masculino y al área de producción, padecen de diferentes grados de TA atribuible al ruido industrial. Se hace énfasis en la vulnerabilidad de las células neurales sensitivas de las vías auditivas a los desórderes y deprivaciones metabólicas orgánicas como lo son el oxígeno y la glucosa, reflejándose en el audiograma una imagen muy similar a las descritas en los casos de TA superficial medio. Como resultado de esta experiencia se resalta la importancia de una cuidadosa historia en la investigación relativa a pérdidas auditivas por exposición al ruido y la necesidad de la implementación de normas de Higiene y Seguridad Laboral, medidas que deben ser respaldadas por una legislación laboral armónica con nuestra realidad