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1.
Nat Chem Biol ; 14(8): 768-777, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29942081

RESUMO

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer.


Assuntos
Antineoplásicos/farmacologia , Aurora Quinase A/antagonistas & inibidores , Azepinas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas de Plantas/metabolismo , Pirimidinas/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Aurora Quinase A/metabolismo , Azepinas/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas de Plantas/química , Pirimidinas/química
2.
Pediatr Blood Cancer ; 64(2): 374-380, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27615542

RESUMO

BACKGROUND: Quality of life in survivors of pediatric acute lymphocytic leukemia (ALL) can be compromised by chronic diseases including increased risk of second cancers, cardiovascular disease, and diabetes. Overweight or obesity further increases these risks. Steroids are a component of chemotherapy for ALL, and weight gain is a common side effect. To impact behaviors associated with weight gain, we conducted a randomized nutrition counseling intervention in ALL patients on treatment. PROCEDURE: ALL patients on a steroid-based treatment regimen at the MD Anderson Children's Cancer Hospital were recruited and randomized into control or intervention groups. The control group received standard care and nutrition education materials. The intervention group received monthly one-on-one nutrition counseling sessions, consisting of a baseline and 12 follow-up visits. Anthropometrics, dietary intake (3-day 24-hr dietary recalls) and oxidative stress measures were collected at baseline, 6 months, and postintervention. Dietary recall data were analyzed using the Nutrition Data System for Research. RESULTS: Twenty-two patients (median age 11.5 years), all in the maintenance phase of treatment, were recruited. The intervention group (n = 12) reported significantly lower calorie intake from baseline to 12-month follow-up and significant changes in glutamic acid and selenium intake (P < 0.05). Waist circumference was significantly associated with calorie, vitamin E, glutamic acid, and selenium intake. CONCLUSIONS: A year-long dietary intervention was effective at reducing caloric intake in pediatric ALL patients receiving steroid-based chemotherapy, indicating that this is a modality that can be built upon for obesity prevention and management.


Assuntos
Aconselhamento/métodos , Intervenção Educacional Precoce/métodos , Ingestão de Energia , Neoplasias/tratamento farmacológico , Estado Nutricional , Qualidade de Vida , Esteroides/farmacologia , Adolescente , Estudos de Casos e Controles , Criança , Dieta , Feminino , Seguimentos , Humanos , Masculino , Neoplasias/patologia , Obesidade/prevenção & controle , Prognóstico
3.
Sci Rep ; 14(1): 3694, 2024 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-38355954

RESUMO

Individual cancers are composed of heterogeneous tumor cells with distinct phenotypes and genotypes, with triple negative breast cancers (TNBC) demonstrating the most heterogeneity among breast cancer types. Variability in transcriptional phenotypes could meaningfully limit the efficacy of monotherapies and fuel drug resistance, although to an unknown extent. To determine if transcriptional differences between tumor cells lead to differential drug responses we performed single cell RNA-seq on cell line and PDX models of breast cancer revealing cell subpopulations in states associated with resistance to standard-of-care therapies. We found that TNBC models contained a subpopulation in an inflamed cellular state, often also present in human breast cancer samples. Inflamed cells display evidence of heightened cGAS/STING signaling which we demonstrate is sufficient to cause tumor cell resistance to chemotherapy. Accordingly, inflamed cells were enriched in human tumors taken after neoadjuvant chemotherapy and associated with early recurrence, highlighting the potential for diverse tumor cell states to promote drug resistance.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Linhagem Celular Tumoral , Transdução de Sinais , Fenótipo
4.
Nutrients ; 12(1)2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31892127

RESUMO

Over and under nutrition are associated with worse outcomes for children with leukemia and lymphoma; however, the molecular basis for this clinical observation is not well understood. Many chemotherapeutics used for leukemia treatment are known to generate oxidative stress in vitro; therefore, we evaluated redox status and diet in pediatric leukemia patients during therapy in order to ascertain relationships between nutrition and oxidative stress. Dietary intake and redox measures in peripheral blood mononuclear cells from 32 pediatric leukemia and lymphoma patients were collected over six months during treatment. Baseline measures when patients were off chemotherapy and subsequent assessments were collected after one, two and six months. Oxidative stress increased over time in all patients, consistent with chemotherapy-induced redox effects. Older and younger children showed significantly different baseline levels of reactive oxygen species, which increased over time in all age ranges. Diet was assessed at points proximal to oxidative stress measurements and revealed a novel association with consumption of animal protein, vegetable protein, and total protein intake. Our findings demonstrate that chemotherapy increases oxidative stress in pediatric leukemia patients, and raises the possibility that dietary protein or altered protein metabolism could contribute to clinical outcomes.


Assuntos
Antineoplásicos/efeitos adversos , Proteínas Alimentares/administração & dosagem , Leucemia/sangue , Linfoma/sangue , Estado Nutricional/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Leucemia/tratamento farmacológico , Leucócitos Mononucleares/química , Leucócitos Mononucleares/metabolismo , Linfoma/dietoterapia , Masculino , Oxirredução , Estresse Oxidativo/fisiologia , Projetos Piloto , Estudos Prospectivos , Espécies Reativas de Oxigênio/sangue
5.
Nat Med ; 25(1): 111-118, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30478424

RESUMO

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance.


Assuntos
Aurora Quinase A/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Contagem de Células , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação/genética , Neoplasia Residual/tratamento farmacológico , Proteínas Nucleares/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia
6.
Cancer Chemother Pharmacol ; 81(3): 483-495, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29313067

RESUMO

PURPOSE: Amongst the epigenetically targeted therapies, targeting of the histone deacetylases (HDACs) has yielded numerous drugs for clinical use in hematological malignancies, but none as yet for acute lymphocytic leukemia (ALL). Single agent activity of HDAC inhibitors (HDACi) has been elusive in ALL, and has prompted study of combinatorial strategies. Because several HDACi raise levels of intracellular oxidative stress, we evaluated combinations of two structurally distinct HDACi with the redox active compound adaphostin in ALL. METHODS: The HDACi vorinostat and entinostat were tested in combination with adaphostin in human ALL cell lines. DNA fragmentation, caspase activation, mitochondrial disruption and levels of  intracellular peroxides, superoxide and glutathione were measured in cells treated with the HDACi/adaphostin combinations. Antioxidant blockade of cell death induction and gene expression profiling of cells treated with vorinostat/adaphostin versus entinostat/adaphostin combinations were evaluated. RESULTS: Both combinations synergistically induced apoptotic DNA fragmentation, which was preceded by an increase in superoxide levels, a reduction in mitochondrial membrane potential, and an increase in caspase-9 activation. The antioxidant N-acetylcysteine (NAC) blocked superoxide generation and prevented reduction of mitochondrial membrane potential. NAC decreased DNA fragmentation and caspase activity in cells treated with adaphostin and vorinostat, but not in those treated with adaphostin and entinostat. Gene expression arrays revealed differential regulation of several redox genes prior to cell death induction. CONCLUSIONS: A redox modulatory agent, adaphostin, enhances efficacy of two HDACi, vorinostat or entinostat, but via different mechanisms indicating a point of divergence in the mechanisms of synergy between the two distinct HDACi and adaphostin.


Assuntos
Adamantano/análogos & derivados , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Fragmentação do DNA/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Hidroquinonas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Piridinas/farmacologia , Vorinostat/farmacologia , Adamantano/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Quimioterapia Combinada , Perfilação da Expressão Gênica , Histona Desacetilases/metabolismo , Humanos , Oxirredução
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