RESUMEN
Ewing sarcoma (ES) is the second most common bone tumor in children and young adults. Unfortunately, there have been minimal recent advancements in improving patient outcomes, especially in metastatic and recurrent diseases. In this study, we investigated the biological role of p21-activated kinases (PAKs) in ES, and the ability to therapeutically target them in high-risk disease. Via informatics analysis, we established the inverse association of PAK1 and PAK4 expression with clinical stage and outcome in ES patients. Through expression knockdown and small-molecule inhibition of PAKs, utilizing FRAX-597, KPT-9274, and PF-3758309 in multiple ES cell lines and patient-derived xenograft models, we further explored the role of PAKs in ES tumor growth and metastatic capabilities. In vitro studies in several ES cell lines indicated that diminishing PAK1 and PAK4 expression reduces tumor cell viability, migratory, and invasive properties. In vivo studies using PAK4 inhibitors, KPT-9274 and PF-3758309 demonstrated significant inhibition of primary and metastatic tumor formation, while transcriptomic analysis of PAK4-inhibitor-treated tumors identified concomitant suppression of Notch, ß-catenin, and hypoxia-mediated signatures. In addition, the analysis showed enrichment of anti-tumor immune regulatory mechanisms, including interferon (IFN)-É£ and IFN-α responses. Altogether, our molecular and pre-clinical studies are the first to establish a critical role for PAKs in ES development and progression, and consequently as viable therapeutic targets for the treatment of high-risk ES in the near future.
Asunto(s)
Sarcoma de Ewing/tratamiento farmacológico , Quinasas p21 Activadas/genética , Acrilamidas/farmacología , Aminopiridinas/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Interferón-alfa/genética , Interferón gamma/genética , Pirazoles/farmacología , Pirroles/farmacología , Sarcoma de Ewing/genética , Sarcoma de Ewing/patología , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasas p21 Activadas/antagonistas & inhibidoresRESUMEN
Central giant cell granuloma (CGCG) is a benign but locally aggressive intraosseous lesion of the mandible. Historically, it is treated by curettage or resection. Medical therapy is indicated when surgery is associated with increased morbidity or in adjuvant setting to decrease recurrence. Treatment of CGCG with denosumab, a receptor activator of nuclear factor kappa-beta (RANK) ligand inhibitor, is not well studied, especially in children. Here, we describe our experience with the use of denosumab in the treatment of six children with CGCG. All patients had a favorable response with manageable side effects, which suggests that denosumab is an effective treatment option without increased morbidity.
Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Denosumab/uso terapéutico , Granuloma de Células Gigantes/tratamiento farmacológico , Niño , Preescolar , Femenino , Estudios de Seguimiento , Granuloma de Células Gigantes/patología , Humanos , Masculino , PronósticoRESUMEN
We discuss a child with severe thrombocytopenia and mild anemia admitted to the Hematology service who quickly deteriorated to a life-threatening state. However, once rickettsial disease was considered in the differential diagnosis and empiric doxycycline begun, she quickly and fully recovered. A diagnostic panel, including Rickettsia typhi serology, confirmed the diagnosis of murine typhus but this occurred weeks after she had recovered. Given the potential severity of rickettsial diseases and the ease of modern travel across geographic borders, hematology-oncology providers everywhere must consider rickettsial diseases in their differential diagnosis of critically ill children and begin empiric therapy with doxycycline promptly.
