RESUMO
Clear cell sarcoma of the kidney (CCSK) is the second most common malignant pediatric renal tumor. Two of the recurrent somatic alterations reported in CCSK are BCL-6 corepressor (BCOR) internal tandem duplication (ITD) and YWHAE-NUTM2B/E gene fusion. A minority of patients with CCSKs have other rare somatic alterations. We report two patients with CCSK showing BCOR-CCNB3 (where CCNB3 is cyclin B3) fusion, who had similar clinical presentation of a large renal mass with tumor thrombus extending through the inferior vena cava into the right atrium and a favorable response to chemotherapy. We recommend BCOR-CCNB3 fusion testing for all patients with CCSK who lack BCOR-ITD or YWHAE-NUTM2B/E gene fusions.
Assuntos
Ciclina B/genética , Neoplasias Renais/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Sarcoma de Células Claras/patologia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Terapia Combinada , Humanos , Neoplasias Renais/genética , Neoplasias Renais/terapia , Masculino , Nefrectomia , Prognóstico , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/terapiaRESUMO
BACKGROUND: Identification and development of young investigators (YI) is critical to the long-term success of research organizations. In 2004, the Children's Oncology Group (COG) created a mentorship program to foster the career development of YIs (faculty <10 years from initial appointment). This study sought to assess mentors' long-term assessment of this program. PROCEDURE: In 2018, 101 past or current mentors in the COG YI mentorship program completed an online survey. Statistical comparisons were made with the Kruskal-Walis test. RESULTS: The response rate was 74.2%. As some mentors had multiple mentees, we report on 138 total mentee-mentor pairs. Mentors were 57.4% male, and mentees were 39.1% male. Mentors rated being mentored as a YI as important with a median rating of 90 on a scale of 1-100, interquartile range (IQR) 80-100. Most mentors reported that being mentored themselves helped their own success within COG (78.2%) and with their overall career development (92.1%). Most mentors enjoyed serving in the program (72.3%) and the median success rating (on a scale of 1-100) across the mentor-mentee pairings was 75, IQR 39-90. Success ratings did not differ by mentor/mentee gender, but improved with increased frequency of mentor-mentee interactions (P < .001). Mentor-mentee pairs who set initial goals reported higher success ratings than those who did not (P < .001). Tangible successes included current mentee COG committee involvement (45.7%), ongoing mentor-mentee collaboration (53.6%), and co-authored manuscript publication (38.4%). CONCLUSION: These data indicate that mentorship is important for successful professional development. Long-term mentoring success improves when mentors and mentees set goals upfront and meet frequently.
Assuntos
Oncologia , Tutoria , Mentores , Feminino , Humanos , Masculino , Avaliação de Programas e Projetos de SaúdeRESUMO
BACKGROUND: Mentorship of junior faculty is an integral component of career development. The Children's Oncology Group (COG) Young Investigator (YI) Committee designed a mentorship program in 2004 whose purpose was to pair YIs (faculty ≤10 years of first academic appointment) with a senior mentor to assist with career development and involvement in COG research activities. This study reports on the committee's ability to achieve these goals. PROCEDURE: An online survey was sent to YIs who were registered with the program from 2004 to2015, assessing three major domains: (1) overall experience with the mentor pairing, (2) satisfaction with the program, and (3) academic accomplishments of the mentees. RESULTS: The response rate was 64% (110/171). Overall, YIs rated the success of their mentorship pairing as 7.2 out of 10 (median) (25th, 75th quartile 3.6, 9.6). The direct effects of the mentorship program included 70% YIs reporting a positive effect on their career, 40% reporting any grant or manuscript resulting from the pairing, 47% forming a new research collaboration, and 43% receiving appointment to a COG committee. Respondents reported success in COG with 38% authoring a manuscript on behalf of COG and 65% reporting a leadership position including seven current or past COG discipline chairs and 20 study chairs. Finally, 74% of respondents said they would consider serving as mentors in the program in the future. CONCLUSION: The COG YI mentorship program has been well received by the majority of the participants and has helped to identify and train many current leaders in COG.
Assuntos
Tutoria/métodos , Oncologistas/educação , Pediatras/educação , Avaliação de Programas e Projetos de Saúde , Mobilidade Ocupacional , Feminino , Humanos , Masculino , Oncologia/educação , Mentores , Pediatria/educação , Satisfação Pessoal , Inquéritos e QuestionáriosRESUMO
PURPOSE AND OBJECTIVE: To determine the clinicopathologic and molecular features and outcome of children with mucoepidermoid carcinoma (MEC). METHODS: A retrospective analysis of clinical and histopathologic findings was performed in patients with MEC diagnosed at Texas Children's Cancer Center between 2000 and 2014. RESULTS: Ten female and four male patients with median age 12 years (range 7-19 years) were included in the study. Tumors involved major salivary glands, minor salivary glands of the palate, and the tracheobronchial tree. Nine of 11 patients with salivary MEC underwent more than one surgical resection at the time of initial diagnosis to achieve a gross total resection. Three patients with tracheobronchial tumors underwent pulmonary lobectomy. Three patients received postoperative radiation therapy. No patient was treated with chemotherapy. Histopathologic grades were classified as low (n = 2), intermediate (n = 9), and high (n = 3). All 12 patients with tumor tissue available for testing were positive for MECT1/MAML2 fusion transcripts. There were no deaths, metastases, or recurrences in this series, with a median follow-up of 24 months (range 5-96 months). CONCLUSIONS: Low to intermediate histopathologic grade MECs are more common than high grade MEC in children. In contrast to adults, MECT1/MAML2 fusion transcripts occur with a frequency of 100% in our pediatric MEC series. Complete excision is the treatment of choice and is associated with excellent outcome. The role of radiotherapy is unclear, but may be indicated in patients with high grade tumors with positive surgical margins.
Assuntos
Carcinoma Mucoepidermoide , Adolescente , Carcinoma Mucoepidermoide/genética , Carcinoma Mucoepidermoide/patologia , Carcinoma Mucoepidermoide/terapia , Criança , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Proteínas de Fusão Oncogênica/genética , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/patologia , Neoplasias das Glândulas Salivares/terapia , Resultado do Tratamento , Adulto JovemRESUMO
Tracheobronchial mucoepidermoid carcinomas (MEC) are rare in the pediatric population with literature limited primarily to case reports. Here we present our institutional experience treating MEC in three patients and review the literature of 142 pediatric cases previously published from 1968 to 2013. Although rare, tracheobronchial MEC should be included in the differential diagnosis in a child with recurrent respiratory symptoms. Conservative surgical management is often sufficient to achieve complete resection and good outcomes.
Assuntos
Neoplasias Brônquicas/diagnóstico , Carcinoma Mucoepidermoide/diagnóstico , Neoplasias da Traqueia/diagnóstico , Adolescente , Neoplasias Brônquicas/complicações , Neoplasias Brônquicas/cirurgia , Broncoscopia , Carcinoma Mucoepidermoide/complicações , Carcinoma Mucoepidermoide/cirurgia , Criança , Humanos , Masculino , Pneumonectomia , Pneumonia/etiologia , Tomografia Computadorizada por Raios X , Neoplasias da Traqueia/complicações , Neoplasias da Traqueia/cirurgiaRESUMO
BACKGROUND: EZN-2208 is a water-soluble PEGylated conjugate of the topoisomerase inhibitor SN38, the active metabolite of irinotecan. Compared to irinotecan, EZN-2208 has a prolonged half-life permitting extended exposure to SN38. EZN-2208 has demonstrated clinical tolerability and antitumor activity in adults with advanced solid tumors. This Phase 1 study evaluated the safety, pharmacokinetics, and preliminary antitumor activity of EZN-2208 in children with relapsed or refractory solid tumors. PROCEDURE: EZN-2208 was administered as a 1-hour intravenous infusion once every 21 days at five dose levels (12-30 mg/m(2) ). Filgrastim or pegfilgrastim was administered 24-48 hours after treatment with EZN-2208. The rolling-six design was used for dose determination. RESULTS: Thirty eligible patients (15 females; median [range] age 11.5 years [2-21 years]) were treated with EZN-2208. Dose-limiting diarrhea occurred in one patient receiving 16 mg/m(2) and dose-limiting dehydration was seen in one patient receiving 24 mg/m(2) . At dose levels above 16 mg/m(2) , Grade ≥3 myelosuppression was demonstrated in the majority of patients. Additional adverse events included nausea, vomiting, and fatigue. The maximum tolerated dose was identified as 24 mg/m(2) due to dose-limiting thrombocytopenia in two patients receiving 30 mg/m(2) . Two of nine patients with neuroblastoma who were evaluable for response had partial responses. Five patients (four with neuroblastoma) remained on study for ≥8 cycles. CONCLUSIONS: EZN-2208 was generally well-tolerated and was associated with clinical benefit in patients with neuroblastoma.
Assuntos
Antineoplásicos/administração & dosagem , Camptotecina/análogos & derivados , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Adolescente , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinética , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Histone deacetylase (HDAC) inhibitors, such as vorinostat, decrease Aurora kinase activity by a variety of mechanisms. Vorinostat and MLN8237, a selective Aurora A kinase inhibitor, disrupt the spindle assembly and the mitotic checkpoint at different points, suggesting that the combination could have increased antitumor activity. The purpose of this study was to determine the cytotoxicity of vorinostat and MLN8237 in pediatric tumor cell lines. METHODS: Cell survival was measured after 72 h of drug treatment using a modified methyl tetrazolium assay. For drug combination experiments, cells were exposed to medium alone (controls), single drug alone, or to different concentrations of the combination of the two drugs, for a total of 36 concentration pairs per plate. The interaction of the drug combination was analyzed using the universal response surface approach. RESULTS: The cells express the target of MLN8237, Aurora A. For each cell line, the single agent IC(50) for MLN8237 and for vorinostat was in the clinically relevant range. Both drugs inhibited cell survival in a concentration-dependent fashion. At concentrations of MLN8237 exceeding approximately 1 µM, there was a paradoxical increase in viability signal in all three lines that may be explained by inhibition of Aurora B kinase. The combination of MLN8237 and vorinostat showed additive cytotoxicity in all three cell lines and nearly abrogated the paradoxical increase in survival noted at high single-agent MLN8237 concentrations. CONCLUSION: MLN8237 and vorinostat are active in vitro against cancer cell lines. These results provide important preclinical support for the development of future clinical studies of MLN8237and vorinostat.
Assuntos
Antineoplásicos/administração & dosagem , Azepinas/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Ácidos Hidroxâmicos/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/administração & dosagem , Aurora Quinase B , Aurora Quinases , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Interações Medicamentosas , Humanos , Leucemia/tratamento farmacológico , Leucemia/enzimologia , Meduloblastoma/tratamento farmacológico , Meduloblastoma/enzimologia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , VorinostatRESUMO
BACKGROUND: A pediatric Phase I trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of vorinostat and bortezomib, in patients with solid tumors. PROCEDURE: Oral vorinostat was administered on days 1-5 and 8-12 of a 21-day cycle (starting dose 180 mg/m(2) /day with dose escalations to 230 and 300 mg/m(2) /day). Bortezomib (1.3 mg/m(2) i.v.) was administered on days 1, 4, 8, and 11 of the same cycle. PK and correlative biology studies were performed during Cycle 1. RESULTS: Twenty-three eligible patients [17 male, median age 12 years (range: 1-20)] were enrolled of whom 17 were fully evaluable for toxicity. Cycle 1 DLTs that occurred in 2/6 patients at dose level 3 (vorinostat 300 mg/m(2) /day) were Grade 2 sensory neuropathy that progressed to Grade 4 (n = 1) and Grade 3 nausea and anorexia (n = 1). No objective responses were observed. There was wide interpatient variability in vorinostat PK parameters. Bortezomib disposition was best described by a three-compartment model that demonstrated rapid distribution followed by prolonged elimination. We did not observe a decrease in nuclear factor-κB activity or Grp78 induction after bortezomib treatment in peripheral blood mononuclear cells from solid tumor patients. CONCLUSION: The recommended Phase 2 dose and schedule is vorinostat (230 mg/m(2) /day PO on days 1-5 and 8-12) in combination with bortezomib (1.3 mg/m(2) /day i.v. on days 1, 4, 8, and 11 of a 21-day cycle) in children with recurrent or refractory solid tumors.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/efeitos adversos , Ácidos Borônicos/farmacocinética , Bortezomib , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Chaperona BiP do Retículo Endoplasmático , Feminino , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/efeitos adversos , Ácidos Hidroxâmicos/farmacocinética , Lactente , Masculino , Dose Máxima Tolerável , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Pirazinas/farmacocinética , Vorinostat , Adulto JovemRESUMO
Olaratumab is a monoclonal antibody that specifically binds to platelet-derived growth factor receptor alpha (PDGFRα) and blocks receptor activation. We conducted a phase 1 trial to evaluate the safety of olaratumab and determine a recommended dose in combination with three different chemotherapy regimens in children. Patients <18 years with relapsed/refractory solid or central nervous system tumors were enrolled to two dose levels of olaratumab. Patients received olaratumab monotherapy at 15 mg/kg (Part A) or 20 mg/kg (Part B) on Days 1 and 8 of the first 21-day cycle, followed by olaratumab combined with standard fixed doses of chemotherapy with doxorubicin, vincristine/irinotecan, or high-dose ifosfamide by investigator choice for subsequent 21-day cycles. In Part C, patients received olaratumab 20 mg/kg plus assigned chemotherapy for all cycles. Parts A-C enrolled 68 patients across three chemotherapy treatment arms; olaratumab in combination with doxorubicin (N = 16), vincristine/irinotecan (N = 26), or ifosfamide (N = 26). Three dose-limiting toxicities (DLTs) occurred during olaratumab monotherapy (at 15 mg/kg, grade [G] 4 alanine aminotransferase [ALT]; at 20 mg/kg, G3 lung infection and G3 gamma-glutamyl transferase). One DLT occurred during vincristine/irinotecan with olaratumab 20 mg/kg therapy (G3 ALT). Treatment-emergent adverse events ≥G3 in >25% of patients included neutropenia, anemia, leukopenia, lymphopenia, and thrombocytopenia. Pharmacokinetic profiles of olaratumab with chemotherapy were within the projected range based on adult data. There was one complete response (rhabdomyosarcoma [Part B vincristine/irinotecan arm]) and three partial responses (two rhabdomyosarcoma [Part A doxorubicin arm and Part C doxorubicin arm]; one pineoblastoma [Part B vincristine/irinotecan arm]). Olaratumab was tolerable and safely administered in combination with chemotherapy regimens commonly used in children and adolescents.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Terapia de Salvação , Adolescente , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias do Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Ifosfamida/administração & dosagem , Irinotecano/administração & dosagem , Masculino , Dose Máxima Tolerável , Recidiva Local de Neoplasia/patologia , Neoplasias/patologia , Prognóstico , Distribuição Tecidual , Vincristina/administração & dosagemRESUMO
BACKGROUND: Aromatase inhibitors (AIs) are used for estrogen-modulated conditions. Some borderline ovarian tumors (BOT) express estrogen receptors. We present 2 cases of progression from mucinous cystadenoma to mucinous BOT (mBOT) after prior cystectomies in whom an AI was used with recurrence prevention. CASES: Two patients underwent laparoscopic ovarian cystectomy for mucinous cystadenoma. Serial imaging demonstrated recurrent ovarian cysts for which both underwent fertility sparing surgery (FSS) with ovarian cystectomy for mBOT. Both patients were initiated on an AI and have been without recurrence. SUMMARY AND CONCLUSION: BOT predominantly occur in reproductive aged females. FSS with cystectomy is an option, but recurrence occurs in 12-36% of cases. The use of AI in prevention of recurrent BOT shows promise, and more studies are needed to explore this treatment.
Assuntos
Inibidores da Aromatase/uso terapêutico , Cistadenoma Mucinoso/tratamento farmacológico , Preservação da Fertilidade/métodos , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias Ovarianas/tratamento farmacológico , Criança , Cistadenoma Mucinoso/patologia , Feminino , Humanos , Neoplasias Ovarianas/patologia , Estudos RetrospectivosRESUMO
Pediatric germ cell tumors (GCTs) are neoplasms that originate from primordial germ cells and, according to their site of presentation, are classified as gonadal or extragonadal. The most common site of extragonadal GCTs in children is the sacrococcygeal region, and the standard management is multimodal with a focus on chemotherapy. In selected instances, sacrococcygeal resection is performed. Herein, the authors report on 2 patients who presented with presacral yolk sac tumors managed with multimodal treatment. Both patients underwent salvage sacrococcygeal resection for oncological control and surgical removal of the sacral vertebral elements: a 27-month-old girl with a recurrent sacrococcygeal yolk sac tumor following chemotherapy and initial resection and a 24-month-old boy in whom a primary sacrococcygeal yolk sac tumor was resected following chemotherapy. These 2 cases illustrate the complexity in the management of these unusual tumors and will help neurosurgeons with the understanding of yolk sac tumors in the sacrococcygeal region.
RESUMO
STUDY OBJECTIVE: To determine the diagnosis, management, and outcome for children and adolescents with borderline ovarian tumor (BOT), and to provide a review of the literature on BOT in children and adolescents. DESIGN: A retrospective cohort study of female adolescents younger than age 21 years diagnosed with BOT between January 2001 and May 2016. SETTING: Texas Children's Hospital, Houston, Texas. PARTICIPANTS: Fourteen patients (ages 12 to 18 years) diagnosed with BOT. MAIN OUTCOME MEASURES: Clinical presentation, preoperative characteristics, surgical technique, cancer stage, histology, treatment, and recurrence. RESULTS: Median age at diagnosis was 15.5 years, with most postmenarchal. Abdominal mass/pain were the most common presenting symptoms. Median tumor size was 16.6 cm (range, 4-32 cm). Preoperative cancer antigen 125 (CA 125) was elevated in 54% (7/13) of cases. All patients had fertility-preserving surgery, either cystectomy (CY) or unilateral salpingo-oophorectomy (USO): 5 via laparoscopy (LSC) and 9 via laparotomy. Most were stage I with 5 serous and 9 mucinous BOT histology. No one received adjuvant chemotherapy. Two patients had recurrence. One had ipsilateral recurrence 2 months after LSC CY for FIGO stage IC1 mucinous BOT. The second had contralateral recurrence 15 months after laparotomy, right USO for FIGO stage IIIC serous BOT treated with LSC CY, then a second recurrence treated with USO after oocyte cryopreservation for fertility preservation. All patients were alive at last follow-up, 1 with disease. CONCLUSIONS: BOT in children and adolescents can be treated conservatively with fertility-preserving techniques and surveillance with good outcome. The role of adjuvant therapy is not known.
Assuntos
Preservação da Fertilidade/métodos , Neoplasias Ovarianas/patologia , Adolescente , Criança , Estudos de Coortes , Terapia Combinada , Feminino , Humanos , Laparoscopia/métodos , Laparotomia/métodos , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Neoplasias Ovarianas/cirurgia , Estudos Retrospectivos , TexasRESUMO
Purpose: Pediatric glioblastoma multiforme (pGBM) is a highly aggressive tumor in need of novel therapies. Our objective was to demonstrate the therapeutic efficacy of MLN8237 (alisertib), an orally available selective inhibitor of Aurora A kinase (AURKA), and to evaluate which in vitro model system (monolayer or neurosphere) can predict therapeutic efficacy in vivoExperimental Design: AURKA mRNA expressions were screened with qRT-PCR. In vitro antitumor effects were examined in three matching pairs of monolayer and neurosphere lines established from patient-derived orthotopic xenograft (PDOX) models of the untreated (IC-4687GBM), recurrent (IC-3752GBM), and terminal (IC-R0315GBM) tumors, and in vivo therapeutic efficacy through log rank analysis of survival times in two models (IC-4687GBM and IC-R0315GBM) following MLN8237 treatment (30 mg/kg/day, orally, 12 days). Drug concentrations in vivo and mechanism of action and resistance were also investigated.Results: AURKA mRNA overexpression was detected in 14 pGBM tumors, 10 PDOX models, and 6 cultured pGBM lines as compared with 11 low-grade gliomas and normal brains. MLN8237 penetrated into pGBM xenografts in mouse brains. Significant extension of survival times were achieved in IC-4687GBM of which both neurosphere and monolayer were inhibited in vitro, but not in IC-R0315GBM of which only neurosphere cells responded (similar to IC-3752GBM). Apoptosis-mediated MLN8237 induced cell death, and the presence of AURKA-negative and CD133+ cells appears to have contributed to in vivo therapy resistance.Conclusions: MLN8237 successfully targeted AURKA in a subset of pGBMs. Our data suggest that combination therapy should aim at AURKA-negative and/or CD133+ pGBM cells to prevent tumor recurrence. Clin Cancer Res; 24(9); 2159-70. ©2018 AACR.
Assuntos
Antineoplásicos/farmacologia , Aurora Quinase A/antagonistas & inibidores , Azepinas/farmacologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Biomarcadores , Biomarcadores Tumorais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Linhagem Celular Tumoral , Criança , Pré-Escolar , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Glioblastoma/tratamento farmacológico , Glioblastoma/mortalidade , Humanos , Imuno-Histoquímica , Imunofenotipagem , Masculino , Gradação de Tumores , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Aberrant activation of the non-receptor tyrosine kinases Src and c-Abl contributes to the progression of NB. Thus, targeting these kinases could be a promising strategy for NB therapy. In this paper, we report that the potent dual Src/Abl inhibitor bosutinib exerts anti-tumor effects on NB. Bosutinib inhibited NB cell proliferation in a dose-dependent manner and suppressed colony formation ability of NB cells. Mechanistically, bosutinib effectively decreased the activity of Src/Abl and PI3K/AKT/mTOR, MAPK/ERK, and JAK/STAT3 signaling pathways. In addition, bosutinib enhanced doxorubicin (Dox)- and etoposide (VP-16)-induced cytotoxicity in NB cells. Furthermore, bosutinib demonstrated anti-tumor efficacy in an orthotopic xenograft NB mouse model in a similar mechanism as of that in vitro. In summary, our results reveal that Src and c-Abl are potential therapeutic targets in NB and that the novel Src/Abl inhibitor bosutinib alone or in combination with other chemotherapeutic agents may be a valuable therapeutic option for NB patients.
Assuntos
Compostos de Anilina/farmacologia , Neuroblastoma/tratamento farmacológico , Nitrilas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-abl/metabolismo , Quinolinas/farmacologia , Quinases da Família src/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Criança , Humanos , Camundongos , Camundongos Nus , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Quinases da Família src/antagonistas & inibidoresRESUMO
Activating germline mutations of anaplastic lymphoma kinase (ALK) occur in most cases of hereditary neuroblastoma (NB) and the constitutively active kinase activity of ALK promotes cell proliferation and survival in NB. Therefore, ALK kinase is a potential therapeutic target for NB. In this study, we show that the novel ALK inhibitor alectinib effectively suppressed cell proliferation and induces apoptosis in NB cell lines with either wild-type ALK or mutated ALK (F1174L and D1091N) by blocking ALK-mediated PI3K/Akt/mTOR signaling. In addition, alectinib enhanced doxorubicin-induced cytotoxicity and apoptosis in NB cells. Furthermore, alectinib induced apoptosis in an orthotopic xenograft NB mouse model. Also, in the TH-MYCN transgenic mouse model, alectinib resulted in decreased tumor growth and prolonged survival time. These results indicate that alectinib may be a promising therapeutic agent for the treatment of NB.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carbazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/tratamento farmacológico , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Carga Tumoral/efeitos dos fármacos , Quinase do Linfoma Anaplásico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Feminino , Predisposição Genética para Doença , Humanos , Concentração Inibidora 50 , Camundongos Nus , Camundongos Transgênicos , Mutação , Neuroblastoma/enzimologia , Neuroblastoma/genética , Neuroblastoma/patologia , Fenótipo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fatores de Tempo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Neuroblastoma (NB), the most common extracranial pediatric solid tumor, continues to cause significant cancer-related morbidity and mortality in children. Dysregulation of oncogenic receptor tyrosine kinases (RTKs) has been shown to contribute to tumorigenesis in various human cancers and targeting these RTKs has had therapeutic benefit. RET is an RTK which is commonly expressed in NB, and high expression of RET correlates with poor outcomes in patients with NB. Herein we report that RET is required for NB cell proliferation and that the small molecule inhibitor regorafenib (BAY 73-4506) blocks glial cell derived neurotrophic factor (GDNF)-induced RET signaling in NB cells and inhibits NB growth both in vitro and in vivo. We found that regorafenib significantly inhibited cell proliferation and colony formation ability of NB cells. Moreover, regorafenib suppressed tumor growth in both an orthotopic xenograft NB mouse model and a TH-MYCN transgenic NB mouse model. Finally, regorafenib markedly improved the overall survival of TH-MYCN transgenic tumor-bearing mice. In summary, our study suggests that RET is a potential therapeutic target in NB, and that using a novel RET inhibitor, like regorafenib, should be investigated as a therapeutic treatment option for children with NB.
RESUMO
ALK receptor tyrosine kinase has been shown to be a therapeutic target in neuroblastoma. Germline ALK activating mutations are responsible for the majority of hereditary neuroblastoma and somatic ALK activating mutations are also frequently observed in sporadic cases of advanced NB. Crizotinib, a first-line therapy in the treatment of advanced non-small cell lung cancer (NSCLC) harboring ALK rearrangements, demonstrates striking efficacy against ALK-rearranged NB. However, crizotinib fails to effectively inhibit the activity of ALK when activating mutations are present within its kinase domain, as with the F1174L mutation. Here we show that a new ALK inhibitor AZD3463 effectively suppressed the proliferation of NB cell lines with wild type ALK (WT) as well as ALK activating mutations (F1174L and D1091N) by blocking the ALK-mediated PI3K/AKT/mTOR pathway and ultimately induced apoptosis and autophagy. In addition, AZD3463 enhanced the cytotoxic effects of doxorubicin on NB cells. AZD3463 also exhibited significant therapeutic efficacy on the growth of the NB tumors with WT and F1174L activating mutation ALK in orthotopic xenograft mouse models. These results indicate that AZD3463 is a promising therapeutic agent in the treatment of NB.
Assuntos
Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Neuroblastoma/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Quinase do Linfoma Anaplásico , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Crizotinibe , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Camundongos , Mutação , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Imetelstat is a covalently-lipidated 13-mer thiophosphoramidate oligonucleotide that acts as a potent specific inhibitor of telomerase. It binds with high affinity to the template region of the RNA component of human telomerase (hTERC) and is a competitive inhibitor of telomerase enzymatic activity. The purpose of this study was to determine the recommended phase II dose of imetelstat in children with recurrent or refractory solid tumors. EXPERIMENTAL DESIGN: Imetelstat was administered intravenously more than two hours on days 1 and 8, every 21 days. Dose levels of 225, 285, and 360 mg/m(2) were evaluated, using the rolling-six design. Imetelstat pharmacokinetic and correlative biology studies were also performed during the first cycle. RESULTS: Twenty subjects were enrolled (median age, 14 years; range, 3-21). Seventeen were evaluable for toxicity. The most common toxicities were neutropenia, thrombocytopenia, and lymphopenia, with dose-limiting myelosuppression in 2 of 6 patients at 360 mg/m(2). Pharmacokinetics is dose dependent with a lower clearance at the highest dose level. Telomerase inhibition was observed in peripheral blood mononuclear cells at 285 and 360 mg/m(2). Two confirmed partial responses, osteosarcoma (n = 1) and Ewing sarcoma (n = 1), were observed. CONCLUSIONS: The recommended phase II dose of imetelstat given on days 1 and 8 of a 21-day cycle is 285 mg/m(2).
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Indóis/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Niacinamida/análogos & derivados , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Antineoplásicos/farmacocinética , Área Sob a Curva , Criança , Pré-Escolar , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Indóis/farmacocinética , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/enzimologia , Masculino , Niacinamida/administração & dosagem , Niacinamida/farmacocinética , Oligonucleotídeos , Telomerase/antagonistas & inibidores , Telomerase/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Thalidomide, originally developed as a sedative, was subsequently identified to have antiangiogenic properties. Lenalidomide is an antiangiogenic and immunomodulatory agent that has been utilized in the treatment of patients with brain tumors. We studied the pharmacokinetics and cerebrospinal fluid (CSF) penetration of thalidomide and lenalidomide in a nonhuman primate model. METHODS: A dose of 50 mg of thalidomide or 20 mg of lenalidomide was administered once orally to each of three rhesus monkeys. Plasma and CSF samples were obtained at specified intervals, and the thalidomide or lenalidomide concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods. CSF penetration was calculated as area under the concentration-time curve (AUC) CSF/AUC plasma. RESULTS: For thalidomide, the median apparent clearance (Cl/F) was 2.9 mL/min/kg, the median plasma AUC was 80 µM h, and the median terminal half-life (t(½)) was 13.3 h. For lenalidomide, the median Cl/F was 8.7 mL/min/kg, the median AUC was 9 µM h, and the median t(½) was 5.6 h. Thalidomide was detected in the CSF of all animals, with a median penetration of 42%. Lenalidomide was detected in the CSF of 2 of 3 animals, with a CSF penetration of 11% in each. CONCLUSION: Thalidomide and lenalidomide penetrate into the CSF after oral administration of clinically relevant doses. Plasma exposure to lenalidomide was similar in our model to that observed in studies involving children who have brain tumors. These results support further development of lenalidomide for the treatment of central nervous system malignancies.
Assuntos
Talidomida/análogos & derivados , Talidomida/sangue , Talidomida/líquido cefalorraquidiano , Animais , Antineoplásicos/sangue , Antineoplásicos/líquido cefalorraquidiano , Antineoplásicos/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Lenalidomida , Macaca mulatta , Masculino , Talidomida/farmacocinéticaRESUMO
PURPOSE: ABT-888 inhibits poly(ADP-ribose) polymerase (PARP) and may enhance the efficacy of chemotherapy and radiation in CNS tumors. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of ABT-888 in a non-human primate (NHP) model that is highly predictive of human CSF penetration. METHODS: ABT-888, 5 mg/kg, was administered orally to three NHPs. Serial blood and CSF samples were obtained. Plasma and CSF concentrations of ABT-888 were measured using LC/MS/MS, and the resulting concentration versus time data were evaluated using non-compartmental and compartmental PK methods. RESULTS: The CSF penetration of ABT-888 was 57+/-7% (mean+/-SD). The peak ABT-888 concentration in the plasma was 0.62+/-0.18 microM. Plasma and CSF AUC0-infinity were 3.7+/-1.7 and 2.1+/-0.8 microM h. PARP inhibition in peripheral blood mononuclear cells was evident 2 h after ABT-888 administration. CONCLUSION: The CSF penetration of ABT-888 after oral administration was 57%. Plasma and CSF concentrations were in the range that has been shown to inhibit PARP activity in vivo in humans.