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1.
JCO Precis Oncol ; 8: e2400258, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39298693

RESUMO

PURPOSE: Patients age 1-21 years with relapsed or refractory solid and CNS tumors were assigned to phase II studies of molecularly targeted therapies on the National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial. Patients whose tumors harbored predefined genetic alterations in the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway and lacked mitogen-activated protein kinase pathway activating alterations were treated with the PI3K/mTOR inhibitor samotolisib. METHODS: Patients received samotolisib twice daily in 28-day cycles until disease progression or unacceptable toxicity. A rolling 6 limited dose escalation was performed as, to our knowledge, this was the first pediatric study of samotolisib. The primary end point was the objective response rate; secondary end points included progression-free survival (PFS) and the recommended phase II dose and toxicity of samotolisib in children. RESULTS: A total of 3.4% (41/1,206) of centrally tested patients were matched to this arm. Seventeen patients were treated. Among treated patients, the most common diagnoses included osteosarcoma (n = 6) and high-grade glioma (n = 5) harboring alterations in phosphatase and tensin homolog (n = 6), PIK3CA (n = 5), and tuberous sclerosis complex 2 (n = 3). No objective responses or prolonged stable disease were observed. Three-month PFS was 12% (95% CI, 2 to 31). Two patients experienced dose-limiting toxicities (mucositis and pneumonitis). Dose level 2 (115 mg/m2/dose twice daily) was determined to be the recommended phase II dose of samotolisib in children. CONCLUSION: This nationwide study was successful at identifying patients and evaluating the efficacy of molecularly targeted therapy for rare molecular subgroups of patients in a histology-agnostic fashion. Unfortunately, there was no activity of samotolisib against tumors with PI3K/mTOR pathway alterations. Prospective trials such as the NCI-COG Pediatric MATCH are necessary to evaluate the efficacy of molecularly targeted therapies given their increasing use in clinical practice.


Assuntos
Serina-Treonina Quinases TOR , Humanos , Criança , Adolescente , Feminino , Masculino , Adulto Jovem , Pré-Escolar , Lactente , Neoplasias/tratamento farmacológico , Neoplasias/genética , Inibidores de MTOR/uso terapêutico , Fosfatidilinositol 3-Quinases/genética , Pirimidinas , Compostos Bicíclicos Heterocíclicos com Pontes
2.
Leuk Res Rep ; 21: 100410, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38273970

RESUMO

B/T mixed phenotype acute leukemia (MPAL) is a rare aggressive leukemia. Three cases of B/T MPAL were identified with comprehensive immunophenotypic, cytogenetic, and molecular studies. T-lineage predominant B/T MPAL shares a genetic signature with T-ALL whereas B/T lineage co-dominant B/T MPAL lacks such a T-ALL signature. All three patients were treated with lineage-matched-ALL therapy and alive at the last follow-up. Our study is the first to demonstrate molecular heterogeneity within B/T MPAL in a context of an immunophenotype of T-lineage versus B-lineage predominance. The implication of such a phenotype-genotype association on diagnostic classification is briefly discussed.

4.
CA Cancer J Clin ; 71(4): 315-332, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33793968

RESUMO

Although significant improvements have been made in the outcomes of children with cancer, the pace of improvement has slowed in recent years as the limits of therapy intensification may have been reached for many pediatric cancers. Furthermore, with increasing numbers of pediatric cancer survivors, the long-term side effects of treatment have become increasingly apparent. Therefore, attention has shifted to the use of molecularly targeted agents and immunotherapies to improve the outcomes of children who are not cured by traditional cytotoxic chemotherapies and to decrease exposure to cytotoxic chemotherapy and reduce late effects. This review describes the recent progress in the treatment of children with cancer, focusing in particular on diseases in which targeted and immunotherapeutic agents have made an impact.


Assuntos
Oncologia/tendências , Neoplasias/terapia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Criança , Ensaios Clínicos como Assunto , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/genética
5.
Pediatrics ; 143(3)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30792255

RESUMO

Giant congenital nevi are melanocytic proliferations of the skin that may be complicated by melanoma, neurocutaneous melanocytosis, pain, pruritus, and disfigurement. Current treatment options include surgical resection and medical management of associated symptoms. There is limited efficacy in these modalities. No effective pharmacologic treatments are available for the treatment of these lesions. We present the case of a 7-year-old girl with a giant congenital melanocytic nevus that had an AKAP9-BRAF fusion and was treated with trametinib, which resulted in rapid resolution of the patient's lifelong, intractable pain and pruritus as well as dramatic improvement in the extent of her nevus.


Assuntos
Antineoplásicos/uso terapêutico , Nevo Pigmentado/diagnóstico por imagem , Nevo Pigmentado/tratamento farmacológico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/tratamento farmacológico , Criança , Feminino , Humanos , Nevo Pigmentado/cirurgia , Neoplasias Cutâneas/cirurgia , Resultado do Tratamento
6.
Cancer Res ; 78(1): 246-255, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29180468

RESUMO

Activation of the receptor tyrosine kinase Axl is associated with poor outcomes in pancreatic cancer (PDAC), where it coordinately mediates immune evasion and drug resistance. Here, we demonstrate that the selective Axl kinase inhibitor BGB324 targets the tumor-immune interface to blunt the aggressive traits of PDAC cells in vitro and enhance gemcitibine efficacy in vivo Axl signaling stimulates the TBK1-NFκB pathway and innate immune suppression in the tumor microenvironment. In tumor cells, BGB324 treatment drove epithelial differentiation, expression of nucleoside transporters affecting gemcitabine response, and an immune stimulatory microenvironment. Our results establish a preclinical mechanistic rationale for the clinical development of Axl inhibitors to improve the treatment of PDAC patients.Significance: These results establish a preclinical mechanistic rationale for the clinical development of AXL inhibitors to improve the treatment of PDAC patients. Cancer Res; 78(1); 246-55. ©2017 AACR.


Assuntos
Benzocicloeptenos/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Triazóis/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzocicloeptenos/administração & dosagem , Carcinoma Ductal Pancreático/imunologia , Linhagem Celular Tumoral , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Terapia de Alvo Molecular , Neoplasias Pancreáticas/imunologia , Triazóis/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina , Receptor Tirosina Quinase Axl
7.
Cancer Res ; 75(18): 3699-705, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26206560

RESUMO

Repurposing "old" drugs can facilitate rapid clinical translation but necessitates novel mechanistic insight. Warfarin, a vitamin K "antagonist" used clinically for the prevention of thrombosis for more than 50 years, has been shown to have anticancer effects. We hypothesized that the molecular mechanism underlying its antitumor activity is unrelated to its effect on coagulation, but is due to inhibition of the Axl receptor tyrosine kinase on tumor cells. Activation of Axl by its ligand Gas6, a vitamin K-dependent protein, is inhibited at doses of warfarin that do not affect coagulation. Here, we show that inhibiting Gas6-dependent Axl activation with low-dose warfarin, or with other tumor-specific Axl-targeting agents, blocks the progression and spread of pancreatic cancer. Warfarin also inhibited Axl-dependent tumor cell migration, invasiveness, and proliferation while increasing apoptosis and sensitivity to chemotherapy. We conclude that Gas6-induced Axl signaling is a critical driver of pancreatic cancer progression and its inhibition with low-dose warfarin or other Axl-targeting agents may improve outcome in patients with Axl-expressing tumors.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Proteínas de Neoplasias/fisiologia , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas/fisiologia , Receptores Proteína Tirosina Quinases/fisiologia , Varfarina/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Progressão da Doença , Sinergismo Farmacológico , Feminino , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , Metástase Neoplásica , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Organismos Livres de Patógenos Específicos , Varfarina/administração & dosagem , Varfarina/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina , Receptor Tirosina Quinase Axl
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