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1.
N Engl J Med ; 389(10): 911-921, 2023 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-37672694

RESUMO

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a poor prognosis and no established therapy. Recently, encouraging responses to immune checkpoint inhibitors have been reported. METHODS: We conducted an investigator-initiated, multicenter, single-group, phase 2 study of the anti-programmed death ligand 1 (PD-L1) agent atezolizumab in adult and pediatric patients with advanced ASPS. Atezolizumab was administered intravenously at a dose of 1200 mg (in patients ≥18 years of age) or 15 mg per kilogram of body weight with a 1200-mg cap (in patients <18 years of age) once every 21 days. Study end points included objective response, duration of response, and progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, as well as pharmacodynamic biomarkers of multistep drug action. RESULTS: A total of 52 patients were evaluated. An objective response was observed in 19 of 52 patients (37%), with 1 complete response and 18 partial responses. The median time to response was 3.6 months (range, 2.1 to 19.1), the median duration of response was 24.7 months (range, 4.1 to 55.8), and the median progression-free survival was 20.8 months. Seven patients took a treatment break after 2 years of treatment, and their responses were maintained through the data-cutoff date. No treatment-related grade 4 or 5 adverse events were recorded. Responses were noted despite variable baseline expression of programmed death 1 and PD-L1. CONCLUSIONS: Atezolizumab was effective at inducing sustained responses in approximately one third of patients with advanced ASPS. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03141684.).


Assuntos
Anticorpos Monoclonais Humanizados , Antígeno B7-H1 , Sarcoma Alveolar de Partes Moles , Adolescente , Adulto , Criança , Humanos , Recém-Nascido , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Peso Corporal , Sarcoma Alveolar de Partes Moles/tratamento farmacológico , Administração Intravenosa
2.
Mol Cell ; 69(1): 3-4, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29304332

RESUMO

For optimal growth, plants must tightly control the switch between stress responses and regrowth upon restoration of favorable conditions. In this issue of Molecular Cell, Wang et al. (2017) reveal that reciprocal regulation of growth-promoting TOR and stress-activated SnRK2 facilitates plant adaptation to environmental variations.


Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis , Ácido Abscísico , Regulação da Expressão Gênica de Plantas , Fosfatidilinositol 3-Quinases , Proteínas Serina-Treonina Quinases/genética , Serina-Treonina Quinases TOR
3.
Mol Cell ; 58(3): 549-56, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25936805

RESUMO

The mammalian target of rapamycin complex 1 (mTORC1) is regulated, in part, by the endogenous inhibitor DEPTOR. However, the mechanism of DEPTOR regulation with regard to rapid mTORC1 activation remains unknown. We report that DEPTOR is rapidly and temporarily dissociated from mTORC1 upon mitogenic stimulation, suggesting a mechanism underlying acute mTORC1 activation. This mitogen-stimulated DEPTOR dissociation is blocked by inhibition or depletion of the mTORC1 regulator, phospholipase D (PLD), and recapitulated with the addition of the PLD product phosphatidic acid (PA). Our mass spectrometry analysis has independently identified DEPTOR as an mTOR binding partner dissociated by PA. Interestingly, only PA species with unsaturated fatty acid chains, such as those produced by PLD, are capable of displacing DEPTOR and activating mTORC1, with high affinity for the FRB domain of mTOR. Our findings reveal a mechanism of mTOR regulation and provide a molecular explanation for the exquisite specificity of PA function.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mitógenos/metabolismo , Complexos Multiproteicos/metabolismo , Ácidos Fosfatídicos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Células 3T3 , Animais , Ligação Competitiva/efeitos dos fármacos , Western Blotting , Linhagem Celular , Meios de Cultura/farmacologia , Células HEK293 , Células HeLa , Humanos , Insulina/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Espectrometria de Massas , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Mitógenos/farmacologia , Complexos Multiproteicos/genética , Ácidos Fosfatídicos/farmacologia , Fosfolipase D/metabolismo , Ligação Proteica/efeitos dos fármacos , Interferência de RNA , Soro , Serina-Treonina Quinases TOR/genética , Acetato de Tetradecanoilforbol/farmacologia
4.
Artigo em Inglês | MEDLINE | ID: mdl-33928209

RESUMO

This trial assessed the utility of applying tumor DNA sequencing to treatment selection for patients with advanced, refractory cancer and somatic mutations in one of four signaling pathways by comparing the efficacy of four study regimens that were either matched to the patient's aberrant pathway (experimental arm) or not matched to that pathway (control arm). MATERIALS AND METHODS: Adult patients with an actionable mutation of interest were randomly assigned 2:1 to receive either (1) a study regimen identified to target the aberrant pathway found in their tumor (veliparib with temozolomide or adavosertib with carboplatin [DNA repair pathway], everolimus [PI3K pathway], or trametinib [RAS/RAF/MEK pathway]), or (2) one of the same four regimens, but chosen from among those not targeting that pathway. RESULTS: Among 49 patients treated in the experimental arm, the objective response rate was 2% (95% CI, 0% to 10.9%). One of 20 patients (5%) in the experimental trametinib cohort had a partial response. There were no responses in the other cohorts. Although patients and physicians were blinded to the sequencing and random assignment results, a higher pretreatment dropout rate was observed in the control arm (22%) compared with the experimental arm (6%; P = .038), suggesting that some patients may have had prior tumor mutation profiling performed that led to a lack of participation in the control arm. CONCLUSION: Further investigation, better annotation of predictive biomarkers, and the development of more effective agents are necessary to inform treatment decisions in an era of precision cancer medicine. Increasing prevalence of tumor mutation profiling and preference for targeted therapy make it difficult to use a randomized phase II design to evaluate targeted therapy efficacy in an advanced disease setting.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzimidazóis/uso terapêutico , Carboplatina/uso terapêutico , DNA de Neoplasias/análise , Método Duplo-Cego , Everolimo/uso terapêutico , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Neoplasias/diagnóstico , Pirazóis , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Temozolomida/uso terapêutico , Adulto Jovem
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