RESUMEN
Breast cancer heterogeneity demands that prognostic models must be biologically driven and recent clinical evidence indicates that future prognostic signatures need evaluation in the context of early compared with late metastatic risk prediction. In pre-clinical studies, we and others have shown that various protein-protein interactions, pertaining to the actin microfilament-associated proteins, ezrin and cofilin, mediate breast cancer cell migration, a prerequisite for cancer metastasis. Moreover, as a direct substrate for protein kinase Cα, ezrin has been shown to be a determinant of cancer metastasis for a variety of tumour types, besides breast cancer; and has been described as a pivotal regulator of metastasis by linking the plasma membrane to the actin cytoskeleton. In the present article, we demonstrate that our tissue imaging-derived parameters that pertain to or are a consequence of the PKC-ezrin interaction can be used for breast cancer prognostication, with inter-cohort reproducibility. The application of fluorescence lifetime imaging microscopy (FLIM) in formalin-fixed paraffin-embedded patient samples to probe protein proximity within the typically <10 nm range to address the oncological challenge of tumour heterogeneity, is discussed.
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Neoplasias de la Mama/patología , Proteína Quinasa C-alfa/metabolismo , Factores Despolimerizantes de la Actina/metabolismo , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/metabolismo , Proteínas del Citoesqueleto/metabolismo , Femenino , Transferencia Resonante de Energía de Fluorescencia , Humanos , Metástasis de la Neoplasia , Fosforilación , Fracciones Subcelulares/metabolismo , Especificidad por Sustrato , Resultado del TratamientoRESUMEN
CD3 bispecific T-cell engagers (TCE), comprised of a tumor-targeting domain linked to a CD3 binding domain, function by bridging target-positive tumors and CD3-expressing effector T cells enabling redirected T cell-mediated killing of tumor cells. Although the majority of CD3 bispecific molecules in clinical development incorporate tumor-targeting antibody-based binding domains, many tumor-associated antigens derive from intracellular proteins and are not accessible to targeting via antibody. Intracellular proteins processed into short peptide fragments and presented on the cell surface by MHC proteins are recognized by T-cell receptors (TCR) on the surface of T cells. Here we describe the generation and preclinical evaluation of ABBV-184, a novel TCR/anti-CD3 bispecific composed of a highly selective soluble TCR that binds a peptide derived from the oncogene survivin (BIRC5) bound to the class I MHC allele human leukocyte antigen (HLA)-A*02:01 expressed on tumor cells, linked to a specific binder to the CD3 receptor on T cells. ABBV-184 drives an optimal distance between T cell and target cell thereby enabling sensitive recognition of low-density peptide/MHC targets. Consistent with the expression profile of survivin across a broad range of both hematologic and solid tumors, treatment of acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC) cell lines with ABBV-184 results in T-cell activation, proliferation, and potent redirected cytotoxicity of HLA-A2-positive target cell lines, both in vitro and in vivo, including patient-derived AML samples. These results indicate that ABBV-184 is an attractive clinical candidate for the treatment of patients with AML and NSCLC.
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Anticuerpos Biespecíficos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Hematológicas , Leucemia Mieloide Aguda , Neoplasias Pulmonares , Humanos , Linfocitos T , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Survivin/metabolismo , Neoplasias Pulmonares/metabolismo , Receptores de Antígenos de Linfocitos T , Complejo CD3 , Leucemia Mieloide Aguda/patología , Neoplasias Hematológicas/metabolismo , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/uso terapéuticoRESUMEN
PARP-1, the most abundant member of the PARP superfamily of nuclear enzymes, has emerged as a promising molecular target in the past decade particularly for the treatment of cancer. A number of PARP-1 inhibitors, including veliparab discovered at Abbott, have advanced into different stages of clinical trials. Herein we describe the development of a new tetrahydropyridopyridazinone series of PARP-1 inhibitors. Many compounds in this class, such as 20w, displayed excellent potency against the PARP-1 enzyme with a K(i) value of <1nM and an EC(50) value of 1nM in a C41 whole cell assay. The presence of the NH in the tetrahydropyridyl ring of the tetrahydropyridopyridazinone scaffold improved the pharmacokinetic properties over similar carbon based analogs. Compounds 8c and 20u are orally available, and have demonstrated significant efficacy in a B16 murine xenograft model, potentiating the efficacy of temozolomide (TMZ).
Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Piridazinas/farmacología , Piridinas/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/síntesis química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/síntesis química , Femenino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/enzimología , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/metabolismo , Piridazinas/síntesis química , Piridazinas/química , Piridinas/síntesis química , Piridinas/química , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Inhibitors of poly(ADP)-ribose polymerase (PARP) exploit defective DNA repair pathways existing in several forms of cancer, such as those with BRCA mutations, and have proven clinical efficacy as chemosensitizers. However, platinum-based chemopotentiation by PARP inhibitors (PARPi), particularly for non-small cell lung cancer (NSCLC), has only been confirmed in a few preclinical models and the molecular mechanisms that drive PARPi combinatorial synergy with chemotherapeutics remains poorly defined. To better understand these mechanisms, we characterized cisplatin and veliparib efficacy in A549 and Calu6 NSCLC in vivo tumor xenograft models and observed combinatorial synergy in the Calu6 model. Transcriptome-wide analysis of xenografts revealed several differentially expressed genes (DEGs) between untreated and cisplatin + veliparib-treated groups, which were unique from genes identified in either of the single-agent treatment arms. Particularly at 10- and 21-days post-treatment, these DEGs were enriched within pathways involved in DNA damage repair, cell cycle regulation, and senescence. Furthermore, TGF-ß- and integrin-related pathways were enriched in the combination treatment arm, while pathways involved in cholesterol metabolism were identified at earlier time points in both the combination and cisplatin-only groups. These data advance the biological underpinnings of PARPi combined with platinum-based chemotherapy and provides additional insight into the diverse sensitivity of NSCLC models.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Adenosina Difosfato , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Colesterol , Cisplatino , Humanos , Integrinas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Platino (Metal)/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Poli(ADP-Ribosa) Polimerasas/metabolismo , Ribosa/uso terapéutico , Transcriptoma , Factor de Crecimiento Transformador beta/genéticaRESUMEN
PURPOSE: We aimed to improve efficacy and reduce toxicity of high-risk human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) treatment by replacing taxanes and trastuzumab with trastuzumab emtansine (T-DM1). METHODS: The phase III KAITLIN study (NCT01966471) included adults with excised HER2-positive EBC (node-positive or node-negative, hormone receptor-negative, and tumor > 2.0 cm). Postsurgery, patients were randomly assigned 1:1 to anthracycline-based chemotherapy (three-four cycles) and then 18 cycles of T-DM1 plus pertuzumab (AC-KP) or taxane (three-four cycles) plus trastuzumab plus pertuzumab (AC-THP). Adjuvant radiotherapy/endocrine therapy was permitted. Coprimary end points were invasive disease-free survival (IDFS) in the intention-to-treat node-positive and overall populations with hierarchical testing. RESULTS: The median follow-up was 57.1 months (interquartile range, 52.1-60.1 months) for AC-THP (n = 918) and 57.0 months (interquartile range, 52.1-59.8 months) for AC-KP (n = 928). There was no significant IDFS difference between arms in the node-positive (n = 1,658; stratified hazard ratio [HR], 0.97; 95% CI, 0.71 to 1.32) or overall population (n = 1846; stratified HR, 0.98; 95% CI, 0.72 to 1.32). In the overall population, the three-year IDFS was 94.2% (95% CI, 92.7 to 95.8) for AC-THP and 93.1% (95% CI, 91.4 to 94.7) for AC-KP. Treatment completion rates (ie, 18 cycles) were 88.4% for AC-THP and 65.0% for AC-KP (difference driven by T-DM1 discontinuation because of laboratory abnormalities [12.5%]). Similar rates of grade ≥ 3 (55.4% v 51.8%) and serious adverse events (23.3% v 21.4%) occurred with AC-THP and AC-KP, respectively. KP decreased clinically meaningful deterioration in global health status versus THP (stratified HR, 0.71; 95% CI, 0.62 to 0.80). CONCLUSION: The primary end point was not met. Both arms achieved favorable IDFS. Trastuzumab plus pertuzumab plus chemotherapy remains the standard of care for high-risk HER2-positive EBC.
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Ado-Trastuzumab Emtansina/uso terapéutico , Antraciclinas/uso terapéutico , Antibióticos Antineoplásicos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Receptor ErbB-2/antagonistas & inhibidores , Trastuzumab/uso terapéutico , Ado-Trastuzumab Emtansina/efectos adversos , Adulto , Anciano , Antraciclinas/efectos adversos , Antibióticos Antineoplásicos/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Factores de Tiempo , Trastuzumab/efectos adversosRESUMEN
The antiapoptotic protein BCL2 plays critical roles in regulating lymphocyte development and immune responses, and has also been implicated in tumorigenesis and tumor survival. However, it is unknown whether BCL2 is critical for antitumor immune responses. We evaluated whether venetoclax, a selective small-molecule inhibitor of BCL2, would influence the antitumor activity of immune checkpoint inhibitors (ICI). We demonstrate in mouse syngeneic tumor models that venetoclax can augment the antitumor efficacy of ICIs accompanied by the increase of PD-1+ T effector memory cells. Venetoclax did not impair human T-cell function in response to antigen stimuli in vitro and did not antagonize T-cell activation induced by anti-PD-1. Furthermore, we demonstrate that the antiapoptotic family member BCL-XL provides a survival advantage in effector T cells following inhibition of BCL2. Taken together, these data provide evidence that venetoclax should be further explored in combination with ICIs for cancer therapy. SIGNIFICANCE: The antiapoptotic oncoprotein BCL2 plays critical roles in tumorigenesis, tumor survival, lymphocyte development, and immune system regulation. Here we demonstrate that venetoclax, the first FDA/European Medicines Agency-approved BCL2 inhibitor, unexpectedly can be combined preclinically with immune checkpoint inhibitors to enhance anticancer immunotherapy, warranting clinical evaluation of these combinations.This article is highlighted in the In This Issue feature, p. 1.
Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Linfocitos T , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Sulfonamidas/farmacologíaRESUMEN
Signaling through the erbB receptor family of tyrosine kinases contributes to the proliferation, differentiation, migration, and survival of a variety of cell types. Abnormalities in members of this receptor family have been shown to play a role in oncogenesis, thus making them attractive targets for anticancer treatments. PF-00299804 is a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor currently in phase I clinical trials. PF-00299804 is believed to irreversibly inhibit erbB tyrosine kinase activity through binding at the ATP site and covalent modification of nucleophilic cysteine residues in the catalytic domains of erbB family members. Oral administration of PF-00299804 causes significant antitumor activity, including marked tumor regressions in a variety of human tumor xenograft models that express and/or overexpress erbB family members or contain the double mutation (L858R/T790M) in erbB1 (EGFR) associated with resistance to gefitinib and erlotinib. Furthermore, PF-00299804 shows exceptional distribution to human tumor xenografts and excellent pharmacokinetic properties across species.
Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Quinazolinonas/farmacología , Quinazolinonas/farmacocinética , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto , Sustitución de Aminoácidos , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Receptores ErbB/metabolismo , Femenino , Humanos , Ratones , Ratones SCID , Mutación/genética , Fosforilación/efectos de los fármacos , Especificidad de la EspecieRESUMEN
PARP inhibitors have recently been approved as monotherapies for the treatment of recurrent ovarian cancer and metastatic BRCA-associated breast cancer, and ongoing studies are exploring additional indications and combinations with other agents. PARP inhibitors trap PARP onto damaged chromatin when combined with temozolomide and methyl methanesulfonate, but the clinical relevance of these findings remains unknown. PARP trapping has thus far been undetectable in cancer cells treated with PARP inhibitors alone. Here, we evaluate the contribution of PARP trapping to the tolerability and efficacy of PARP inhibitors in the monotherapy setting. We developed a novel implementation of the proximity ligation assay to detect chromatin-trapped PARP1 at single-cell resolution with higher sensitivity and throughput than previously reported methods. We further demonstrate that the PARP inhibitor-induced trapping appears to drive single-agent cytotoxicity in healthy human bone marrow, indicating that the toxicity of trapped PARP complexes is not restricted to cancer cells with homologous recombination deficiency. Finally, we show that PARP inhibitors with dramatically different trapping potencies exhibit comparable tumor growth inhibition at MTDs in a xenograft model of BRCA1-mutant triple-negative breast cancer. These results are consistent with emerging clinical data and suggest that the inverse relationship between trapping potency and tolerability may limit the potential therapeutic advantage of potent trapping activity. IMPLICATIONS: PARP trapping contributes to single-agent cytotoxicity of PARP inhibitors in both cancer cells and healthy bone marrow, and the therapeutic advantage of potent trapping activity appears to be limited.
Asunto(s)
Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Animales , Médula Ósea , Citotoxicidad Inmunológica , Femenino , Humanos , Ratones , Ratones SCID , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacologíaRESUMEN
Many established cancer therapies involve DNA-damaging chemotherapy or radiotherapy. The DNA repair capacity of the tumor represents a common mechanism used by cancer cells to survive DNA-damaging therapy. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that is activated by DNA damage and has critical roles in DNA repair. Inhibition of PARP potentiates the activity of DNA-damaging agents such as temozolomide, topoisomerase inhibitors and radiation in both in vitro and in vivo preclinical models. Recently, several PARP inhibitors have entered clinical trials either as single agents or in combination with DNA-damaging chemotherapy. Because PARP inhibitors are not cytotoxic, a biomarker assay is useful to guide the selection of an optimal biological dose. We set out to develop an assay that enables us to detect 50% PAR reduction in human tumors with 80% power in a single-plate assay while assuring no more than a 10% false-positive rate. We have developed and optimized an enzyme-linked immunosorbent assay (ELISA) to measure PARP activity that meets the above-mentioned criterion. This robust assay is able to detect PAR levels of 30-2000 pg/ml in both tumor and peripheral blood monocyte samples. In a B16F10 mouse syngeneic tumor model, PARP inhibitor ABT-888 potentiates the effect of temozolomide in suppressing tumor growth, and PARP activity is greatly reduced by ABT-888 at efficacious doses. In summary, the ELISA assay described here is suitable for biomarker studies in clinical trials of PARP inhibitors.
Asunto(s)
Antineoplásicos/farmacología , Bencimidazoles/farmacología , Inhibidores Enzimáticos/farmacología , Ensayo de Inmunoadsorción Enzimática/métodos , Poli(ADP-Ribosa) Polimerasas/análisis , Animales , Bencimidazoles/química , Biomarcadores/análisis , Ensayos Clínicos como Asunto , Dacarbazina/análogos & derivados , Dacarbazina/farmacología , Modelos Animales de Enfermedad , Femenino , Humanos , Melanoma Experimental/enzimología , Ratones , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Poli(ADP-Ribosa) Polimerasas/metabolismo , TemozolomidaRESUMEN
This study is believed to be one of the first to assess the impact of urban VOC-(volatile organic compound) contaminated groundwater on river-water quality at the city scale. A network of riverbed piezometers was used to study the 7.4-km urbanised reach of the River Tame that flows across the groundwater-effluent unconfined Triassic sandstone aquifer underlying the city of Birmingham (UK). Aquifer groundwater contained significant chlorinated VOC contamination due to the city's industrial heritage. Chlorinated VOC-contaminated baseflow was widespread along the reach with trichloroethene (TCE) dominant. VOC concentrations in riverbed piezometers were in the range 0.1-100 microg/l with typical regulatory limits occasionally exceeded by an order of magnitude. Although anaerobic biodegradation products such as cis-dichloroethene were widespread, they were unlikely to have formed in the generally aerobic riverbed. The lack of anaerobic conditions was ascribed to insufficient accumulation of low-permeability, organic-carbon rich riverbed sediments in this medium-high energy river. Assumptions a priori that natural attenuation of chlorinated VOCs will occur via reductive dechlorination in urban riverbeds are likely in error, particularly where deposits of medium-high permeability exist transmitting much of the baseflow. Surface-water quality impacts were nevertheless still low with in-river TCE increasing by just 2 microg/l over the 7.4-km reach. Agreement of baseflow contaminant flux estimates based on five flow-concentration product methods was achieved to within an order of magnitude with 22-200 kg/yr of TCE estimated to discharge to the 7.4-km reach (equivalent to 0.8-7.5 mg/d/m2 of riverbed). Such uncertainty was not regarded as unreasonable when the large measurement scale and geological and chemical heterogeneities are considered. Improved flux estimation methods and greater monitoring densities are nevertheless warranted. Considering Birmingham's long industrial history and known incidence of VOC-contaminated groundwater, the city-scale impact of VOC-contaminated groundwater upon surface-water quality was judged to be relatively modest.
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Ciudades , Monitoreo del Ambiente , Hidrocarburos Clorados/análisis , Contaminantes Químicos del Agua/análisis , Abastecimiento de Agua , Aerobiosis , Anaerobiosis , Biodegradación Ambiental , Geografía , Hidrocarburos Clorados/metabolismo , Medición de Riesgo , Ríos , Aguas del Alcantarillado , Tricloroetileno/análisis , Tricloroetileno/metabolismo , Reino Unido , Volatilización , Movimientos del Agua , Contaminantes Químicos del Agua/metabolismoRESUMEN
Groundwater-river exchanges in an urban setting have been investigated through long term field monitoring and detailed modelling of a 7 km reach of the Tame river as it traverses the unconfined Triassic Sandstone aquifer that lies beneath the City of Birmingham, UK. Field investigations and numerical modelling have been completed at a range of spatial and temporal scales from the metre to the kilometre scale and from event (hourly) to multi-annual time scales. The objective has been to quantify the spatial and temporal flow distributions governing mixing processes at the aquifer-river interface that can affect the chemical activity in the hyporheic zone of this urbanised river. The hyporheic zone is defined to be the zone of physical mixing of river and aquifer water. The results highlight the multi-scale controls that govern the fluid exchange distributions that influence the thickness of the mixing zone between urban rivers and groundwater and the patterns of groundwater flow through the bed of the river. The morphologies of the urban river bed and the adjacent river bank sediments are found to be particularly influential in developing the mixing zone at the interface between river and groundwater. Pressure transients in the river are also found to exert an influence on velocity distribution in the bed material. Areas of significant mixing do not appear to be related to the areas of greatest groundwater discharge and therefore this relationship requires further investigation to quantify the actual remedial capacity of the physical hyporheic zone.
Asunto(s)
Ciudades , Monitoreo del Ambiente , Sedimentos Geológicos/análisis , Movimientos del Agua , Contaminantes Químicos del Agua/análisis , Abastecimiento de Agua/análisis , Medición de Riesgo , Ríos , Factores de Tiempo , Reino Unido , Contaminantes Químicos del Agua/metabolismo , Contaminantes Químicos del Agua/toxicidadRESUMEN
PURPOSE: The rare association between breast cancer and pregnancy means that few oncologists gain an expertise in this area. In particular, there are few published data concerning the use of chemotherapy for breast cancer during pregnancy. In this retrospective case series, we describe the experiences of five hospitals in London, United Kingdom, and how they manage this condition. PATIENTS AND METHODS: Retrospective searches were performed at five London hospitals in order to identify women who received chemotherapy for breast cancer while pregnant. RESULTS: Twenty-eight women were identified who had received chemotherapy for breast cancer during pregnancy. Twenty-four women received adjuvant or neoadjuvant chemotherapy for early breast cancer, and four women received palliative chemotherapy for metastatic disease. A total of 116 cycles of chemotherapy were administered during pregnancy. Sixteen women were treated with anthracycline-based chemotherapy and 12 received cyclophosphamide, methotrexate, and fluorouracil. All but one of the women were treated after the first trimester. One spontaneous abortion occurred in the woman treated during her first trimester; otherwise, there were no serious adverse consequences for the mothers or neonates. CONCLUSION: These data provide evidence that in terms of peripartum complications and immediate fetal outcome, chemotherapy can be safely administered to women during the second and third trimesters of pregnancy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Complicaciones Neoplásicas del Embarazo/tratamiento farmacológico , Adulto , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Epirrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Londres , Metotrexato/administración & dosificación , Terapia Neoadyuvante , Embarazo , Complicaciones Neoplásicas del Embarazo/patología , Complicaciones Neoplásicas del Embarazo/cirugía , Resultado del Embarazo , Estudios RetrospectivosRESUMEN
Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of alkynamide analogues of quinazoline- and pyrido[3,4-d]pyrimidine-based compounds. The compounds were prepared by coupling the appropriate 6-aminoquinazolines or 6-aminopyrido[3,4-d]pyrimidines with alkynoic acids, using EDCI.HCl in pyridine. The compounds showed pan-erbB enzyme inhibition but were on average about 10-fold more potent against erbB1 than against erbB2 and erbB4. For cellular inhibition, the nature of the alkylating side chains was an important determinant, with 5-dialkylamino-2-pentynamide type Michael acceptors providing the highest potency. This is suggested to be due to an improved ability of the amine to participate in an autocatalysis of the Michael reaction with enzyme cysteine residues. Pyrido[3,4-d]pyrimidine analogue 39 was selected for in vivo evaluation and achieved tumor regressions at 10 mg/kg in the A431 human epidermoid carcinoma and at 40 mg/kg for the SF767 human glioblastoma and the SKOV3 human ovarian carcinoma. Complete stasis was observed at 40 mg/kg in the BXPC3 human pancreatic carcinoma as well as in the H125 human non-small-cell lung carcinoma.
Asunto(s)
Alquinos/síntesis química , Amidas/síntesis química , Antineoplásicos/síntesis química , Pirimidinas/síntesis química , Quinazolinas/síntesis química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Alquinos/química , Alquinos/farmacología , Amidas/química , Amidas/farmacocinética , Amidas/farmacología , Compuestos de Anilina/síntesis química , Compuestos de Anilina/química , Compuestos de Anilina/farmacocinética , Compuestos de Anilina/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular , Perros , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Haplorrinos , Humanos , Ratones , Ratones Desnudos , Ratones SCID , Fosforilación , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/farmacología , Ratas , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Receptor ErbB-4 , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Integrated understanding of urban land, groundwater (shallow and deep), baseflow and surface-water quality relationships is required for effective urban water-quality management. Chemical quality data from across these media have been collected for the Birmingham (UK) aquifer--River Tame conurbation to assess chemical transport from contaminated land to groundwater to baseflow to surface water. Although metals concentrations were high in soils, low leachability and attenuation caused concentrations in groundwaters and baseflow discharging to surface water to be generally low with only sporadic elevated concentrations attributed to localised point sources. Hydrocarbon VOCs (volatile organic compounds) were similarly absent or at low concentration attributable to their ready natural attenuation. Chlorinated VOCs, however, were widely encountered in groundwater, discharging as baseflow to surface water and impacting surface-water quality. This is attributed to their DNAPL (dense nonaqueous-phase liquid) properties and relative recalcitrance although there was some evidence of biodegradation, albeit insufficient to protect surface water and groundwater abstraction receptors. Some inorganic trends were evident across the various media; nitrate was the most significant quality concern. Generic conclusions are drawn on urban water-quality management and the need for risk-based management strategies to optimise use of urban, sporadically contaminated groundwater in conjunction with surface water highlighted.
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Ciudades , Contaminantes Químicos del Agua/análisis , Abastecimiento de Agua , Aniones/análisis , Arsénico/análisis , Conservación de los Recursos Naturales , Monitoreo del Ambiente , Hidrocarburos/análisis , Metales Pesados/análisis , Éteres Metílicos/análisis , Ríos , Contaminantes del Suelo/análisis , Reino Unido , Movimientos del AguaRESUMEN
Adjuvant hormonal therapy results in substantial improvements in disease-free and overall survival for women with operable breast cancer. Use of an aromatase inhibitor (AI) is expected to replace tamoxifen as standard care for many patients. Aromatase is the enzyme responsible for the final step in estrogen biosynthesis. This is the conversion of the androgens testosterone and androstenedione to the estrogens estrone and estradiol. AIs are potent inhibitors of estrogen production and thus one of the major concerns over their use is their effect on bone health and their potential to increase the incidence of osteoporosis and risk of fracture. The American Society of Clinical Oncology has recognized that these patients are at high risk of developing osteoporosis and has published guidelines to aid in their management. These recommend that all patients have an initial dual-energy X-ray absorptiometry (DEXA) bone scan to assess bone mineral density and are offered calcium and vitamin D supplements as well as lifestyle advice. Patients with osteoporosis should be treated with a bisphosphonate to reduce the incidence of fracture. Osteonecrosis of the jaws is a recently described adverse side-effect of bisphosphonate therapy and has been described in women with metastatic breast cancer. Oversuppression of bone turnover is probably the primary mechanism for the development of this condition. The degree of risk for osteonecrosis with bisphosphonates is uncertain and warrants careful monitoring.
Asunto(s)
Inhibidores de la Aromatasa/efectos adversos , Densidad Ósea/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Osteoporosis/terapia , Inhibidores de la Aromatasa/uso terapéutico , Femenino , Humanos , Osteoporosis/inducido químicamente , PosmenopausiaRESUMEN
Overexpression of HER2 is an important prognostic marker, and the only predictive biomarker of response to HER2-targeted therapies in invasive breast cancer. HER2-HER3 dimer has been shown to drive proliferation and tumor progression, and targeting of this dimer with pertuzumab alongside chemotherapy and trastuzumab, has shown significant clinical utility. The purpose of this study was to accurately quantify HER2-HER3 dimerisation in formalin fixed paraffin embedded (FFPE) breast cancer tissue as a novel prognostic biomarker.FFPE tissues were obtained from patients included in the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) study. HER2-HER3 dimerisation was quantified using an improved fluorescence lifetime imaging microscopy (FLIM) histology-based analysis. Analysis of 131 tissue microarray cores demonstrated that the extent of HER2-HER3 dimer formation as measured by Förster Resonance Energy Transfer (FRET) determined through FLIM predicts the likelihood of metastatic relapse up to 10 years after surgery (hazard ratio 3.91 (1.61-9.5), p = 0.003) independently of HER2 expression, in a multivariate model. Interestingly there was no correlation between the level of HER2 protein expressed and HER2-HER3 heterodimer formation. We used a mathematical model that takes into account the complex interactions in a network of all four HER proteins to explain this counterintuitive finding.Future utility of this technique may highlight a group of patients who do not overexpress HER2 protein but are nevertheless dependent on the HER2-HER3 heterodimer as driver of proliferation. This assay could, if validated in a group of patients treated with, for instance pertuzumab, be used as a predictive biomarker to predict for response to such targeted therapies.
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Mama/patología , Transferencia Resonante de Energía de Fluorescencia/métodos , Microscopía Fluorescente/métodos , Receptor ErbB-2/análisis , Receptor ErbB-3/análisis , Adulto , Anciano , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Dimerización , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Modelos Teóricos , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Pronóstico , Modelos de Riesgos Proporcionales , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismoRESUMEN
Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7-substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents, respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation.
Asunto(s)
Antineoplásicos/química , Receptores ErbB/antagonistas & inhibidores , Morfolinas/química , Piridinas/química , Pirimidinas/química , Quinazolinas/química , Quinazolinonas/química , Administración Oral , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Perros , Xenoinjertos , Humanos , Inyecciones Intravenosas , Macaca fascicularis , Masculino , Ratones Desnudos , Morfolinas/síntesis química , Morfolinas/farmacocinética , Morfolinas/farmacología , Trasplante de Neoplasias , Fosforilación , Piridinas/síntesis química , Piridinas/farmacocinética , Piridinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Quinazolinas/síntesis química , Quinazolinas/farmacocinética , Quinazolinas/farmacología , Quinazolinonas/síntesis química , Quinazolinonas/farmacocinética , Quinazolinonas/farmacología , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The taxanes docetaxel and paclitaxel have established roles as two of the most active agents in the treatment of metastatic breast cancer. These two drugs are now being incorporated into the management of early breast cancer. A first generation of trials has explored whether the addition of taxanes either sequentially or in combination with adjuvant anthracycline-based chemotherapy improves outcome for patients with early breast cancer. A second generation of trials are now underway which are based on the assumption that taxanes are beneficial in the adjuvant setting, and are comparing the different taxanes, dosing regimens and the addition of further agents. Trials in the neoadjuvant setting have recently demonstrated improved response rates with the addition of taxanes into existing anthracycline-based regimes. This review critically appraises these trials and provides an overview of ongoing research in the area.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Paclitaxel/uso terapéutico , Taxoides/uso terapéutico , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Ensayos Clínicos como Asunto , Docetaxel , Femenino , Humanos , Terapia Neoadyuvante , Estadificación de NeoplasiasRESUMEN
The aromatase enzyme catalyses the last step in estrogen biosynthesis. There are two classes of third-generation aromatase inhibitors: irreversible steroidal inhibitors (e.g. exemestane) and reversible non-steroidal inhibitors (e.g. anastrozole, letrozole). All three agents have been found to be equivalent or superior to megestrol acetate as second-line therapy for metastatic breast cancer. In the first-line setting, large phase III trials have shown that all three are equivalent or superior to tamoxifen in women with metastatic disease. Several large trials with varying study designs have been launched to analyse their role in the adjuvant setting. The four that have reported found longer average disease-free survival for women who received an aromatase inhibitor than for those who did not. In addition, one trial, MA.17, has shown a survival advantage associated with the use of an aromatase inhibitor in node-positive patients. Guidelines produced by the American Society of Clinical Oncology suggest that adjuvant therapy for postmenopausal women with hormone-receptor-positive breast cancer should include an aromatase inhibitor. However, the long-term consequences of estrogen deprivation in postmenopausal women remain uncertain, particularly with regard to bone and cardiovascular health. The advantages and disadvantages of different hormonal strategies should therefore be carefully considered in each individual case.
Asunto(s)
Antineoplásicos/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/prevención & control , Anastrozol , Androstadienos/uso terapéutico , Neoplasias de la Mama/patología , Ensayos Clínicos como Asunto , Femenino , Humanos , Letrozol , Nitrilos/uso terapéutico , Posmenopausia , Triazoles/uso terapéuticoRESUMEN
PURPOSE: PARP inhibitors are being developed as therapeutic agents for cancer. More than six compounds have entered clinical trials. The majority of these compounds are ß-nicotinamide adenine dinucleotide (NAD(+))-competitive inhibitors. One exception is iniparib, which has been proposed to be a noncompetitive PARP inhibitor. In this study, we compare the biologic activities of two different structural classes of NAD(+)-competitive compounds with iniparib and its C-nitroso metabolite. EXPERIMENTAL DESIGN: Two chemical series of NAD(+)-competitive PARP inhibitors, iniparib and its C-nitroso metabolite, were analyzed in enzymatic and cellular assays. Viability assays were carried out in MDA-MB-436 (BRCA1-deficient) and DLD1(-/-) (BRCA2-deficient) cells together with BRCA-proficient MDA-MB-231 and DLD1(+/+) cells. Capan-1 and B16F10 xenograft models were used to compare iniparib and veliparib in vivo. Mass spectrometry and the (3)H-labeling method were used to monitor the covalent modification of proteins. RESULTS: All NAD(+)-competitive inhibitors show robust activity in a PARP cellular assay, strongly potentiate the activity of temozolomide, and elicit robust cell killing in BRCA-deficient tumor cells in vitro and in vivo. Cell killing was associated with an induction of DNA damage. In contrast, neither iniparib nor its C-nitroso metabolite inhibited PARP enzymatic or cellular activity, potentiated temozolomide, or showed activity in a BRCA-deficient setting. We find that the nitroso metabolite of iniparib forms adducts with many cysteine-containing proteins. Furthermore, both iniparib and its nitroso metabolite form protein adducts nonspecifically in tumor cells. CONCLUSIONS: Iniparib nonselectively modifies cysteine-containing proteins in tumor cells, and the primary mechanism of action for iniparib is likely not via inhibition of PARP activity.