RESUMEN
Nilotinib has been used as a third-line drug for gastrointestinal stromal tumors (GISTs) after a failure of sunitinib. In this study, we aimed to evaluate the efficacy of nilotinib in different genomic subtypes of GISTs. We searched the English articles through EMBASE, Cochrane Library and PubMed Database regarding to the use of nilotinib on GISTs, which published up to February 15, 2019. Inclusion criteria were: GISTs patients received nilotinib in a clinical trial and had detailed genetic subtype records (such as KIT exon 9, KIT exon 11, or PDGFRA mutations, or wild-type). The clinical benefit rate was used to assess the efficacy of nilotinib. A total of 3 studies involving 218 GISTs were included in this meta-analysis. The overall OR (KIT group vs WT group) was 3.26 (95% CI: 1.14-9.28; Pâ¯=â¯0.027, Pheterogeneityâ¯=â¯0.613). The overall OR in KIT exon 11 group vs WT group was 5.30 (95% CI: 1.79-15.68; Pâ¯=â¯0.003, Pheterogeneityâ¯=â¯0.409). The overall OR in KIT exon 9 group vs WT group was 0.13 (95% CI: 0.02-0.86; Pâ¯=â¯0.035, Pheterogeneityâ¯=â¯0.229). The overall OR in KIT exon 11 group vs exon 9 group was 9.96 (95% CI: 0.39-254.66; P < 0.0001, Pheterogeneityâ¯=â¯0.024). Different genotypes of GISTs showed different responses to nilotinib, and KIT exon 11-mutant GISTs mostly benefited from nilotinib, followed by KIT exon 9-mutant or WT one.
Asunto(s)
Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/genética , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/genética , Pirimidinas/farmacología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/patología , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Proteínas Proto-Oncogénicas c-kit/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/efectos de los fármacos , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Resultado del Tratamiento , Adulto JovenRESUMEN
Rationale: Acute myeloid leukemia (AML) is a common type of haematological malignancy. Several studies have shown that neoplasia in AML is enhanced by tyrosine kinase pathways. Recently, given that aberrant activation of Fms-like tyrosine receptor kinase 3 (FLT3) acts as a critical survival signal for cancer cells in 20â30% patients with AML, inhibition of FLT3 may be a potential therapeutic strategy. Therefore, we identified LT-171-861, a novel kinase inhibitor with remarkable inhibitory activity against FLT3, in preclinical models of AML. Methods: We determined the inhibitory effects of LT-171-861 in vitro using AML cell lines and transformed BaF3 cells. Target engagement assays were used to verify the interaction between LT-171-861 and FLT3. Finally, a subcutaneous model and a bone marrow engrafted model were used to evaluate the antitumor effects of LT171861 in vivo. Results: Our data demonstrated that LT-171-861 had high affinity for FLT3 protein. We also showed that LT-171-861 had an inhibitory effect on FLT3 mutants in cellular assays. Moreover, LT-171-861 had a growth-inhibitory effect on human AML cell lines harboring FLT3 internal tandem duplications (FLT3-ITD) such as FLT3-D835Y, FLT3ITD-N676D, FLT3-ITD-D835Y, FLT3-ITD-F691L, FLT3-ITD-Y842C and AML blasts from patients with FLT3-ITD. Furthermore, LT-171-861 showed potent antileukemic efficacy against AML cells. We also show the efficacy of LT171-861 in a subcutaneous implantation model and a bone marrow engrafted model in vivo, where administration of LT-171-861 led to almost complete tumor regression and increased survival. Conclusions: Overall, this study not only identifies LT-171-861 as a potent FLT3 inhibitor, but also provides a rationale for the upcoming clinical trial of LT-171-861 in patients with AML and FLT3-ITD mutations.
Asunto(s)
Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Compuestos Heterocíclicos/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Purinas/farmacología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Animales , Proteína Tirosina Quinasa CSK/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Quinasas MAP Reguladas por Señal Extracelular/efectos de los fármacos , Femenino , Compuestos Heterocíclicos/uso terapéutico , Humanos , Concentración 50 Inhibidora , Quinasas Janus/efectos de los fármacos , Leucemia Mieloide Aguda/genética , Ratones , Ratones Desnudos , Ratones SCID , Trasplante de Neoplasias , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Purinas/uso terapéutico , Células THP-1 , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
OBJECTIVES: The 2019 Workshop of the Society for Hematopathology/European Association for Haematopathology received and reviewed cases covering the spectrum of mastocytosis and related diseases, including morphologic mimics, focusing on recent updates and relevant findings for pathologists. METHODS: The workshop panel reviewed 99 cases of cutaneous and systemic mastocytosis (SM) and SM and associated hematologic neoplasms (SM-AHN). RESULTS: Despite a common theme of KIT mutation (particularly D816V), mastocytosis is a heterogeneous neoplasm with a wide variety of presentations. This spectrum, including rare subtypes and extramedullary organ involvement, is discussed and illustrated by representative cases. CONCLUSIONS: In the age of targeted treatment aimed at KIT, the accurate diagnosis and classification of mastocytosis has major implications for therapy and further interventions. Understanding the clinical, pathologic, and genetic findings of mastocytosis is crucial for selecting the proper tests to perform and subsequent arrival at a correct diagnosis in this rare disease.
Asunto(s)
Mastocitosis , Adolescente , Adulto , Anciano , Antineoplásicos/uso terapéutico , Niño , Diagnóstico Diferencial , Femenino , Pruebas Genéticas , Humanos , Inmunohistoquímica , Lactante , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mielomonocítica Crónica/diagnóstico , Masculino , Mastocitos/patología , Mastocitosis/diagnóstico , Mastocitosis/tratamiento farmacológico , Mastocitosis/genética , Mastocitosis/patología , Mastocitosis Sistémica/tratamiento farmacológico , Mastocitosis Sistémica/patología , Persona de Mediana Edad , Mutación , Oncogenes , Pronóstico , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Proteínas Proto-Oncogénicas c-kit/genética , Triptasas/aislamiento & purificación , Adulto JovenRESUMEN
As the first clinical proteasome inhibitor, Bortezomib (BTZ) has been reported to improve the outcome of lymphoma. However, due to the unstable property, low bioavailability, and hydrophobic properties of BTZ, it is needed to develop effective drug delivery systems to deliver BTZ into targeted cells or organs. Here we developed a bortezomib (BTZ)-loaded HMSNs (BTZ@HMSNs) system, which can sustain the release of BTZ in targeted tissues. In vitro assays showed that BTZ@HMSNs limited cell proliferation and augmented apoptosis of lymphoma SNK-1 cells. Moreover, BTZ@HMSNs significantly diminished migration and invasion of SNK-1 cells as compared with BTZ. In contrast to the upregulation of SHP-1, BTZ@HMSNs decreased the mRNA levels of c-Kit, NF-κB, and JAK1, which elicit oncogenic role in lymphoma development. Importantly, lymphoma mice model showed that BTZ@HMSNs significantly activated p53 signaling and reduced tumor volume and weight compared with free BTZ. Our data thus demonstrate that BTZ@HMSNs manifests improved tumor-suppressing effect in vitro and in vivo compared to free BTZ. We believe that HMSNs is a promising strategy for delivering therapeutic agents for cancer treatment.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Bortezomib/administración & dosificación , Bortezomib/farmacología , Proliferación Celular/efectos de los fármacos , Linfoma/tratamiento farmacológico , Nanosferas , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Portadores de Fármacos , Humanos , Técnicas In Vitro , Janus Quinasa 1/efectos de los fármacos , Janus Quinasa 1/genética , Linfoma/genética , Linfoma/metabolismo , Ratones , Ratones Desnudos , FN-kappa B/efectos de los fármacos , FN-kappa B/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 6/efectos de los fármacos , Proteína Tirosina Fosfatasa no Receptora Tipo 6/genética , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Proteínas Proto-Oncogénicas c-kit/genética , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Dióxido de Silicio , Proteína p53 Supresora de Tumor/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Advanced systemic mastocytosis is a rare and still untreatable disease. Blocking antibodies against inhibitory receptors, also known as "immune checkpoints", have revolutionized anti-cancer treatment. Inhibitory receptors are expressed not only on normal immune cells, including mast cells but also on neoplastic cells. Whether activation of inhibitory receptors through monoclonal antibodies can lead to tumor growth inhibition remains mostly unknown. Here we show that the inhibitory receptor Siglec-7 is expressed by primary neoplastic mast cells in patients with systemic mastocytosis and by mast cell leukemia cell lines. Activation of Siglec-7 by anti-Siglec-7 monoclonal antibody caused phosphorylation of Src homology region 2 domain-containing phosphatase-1 (SHP-1), reduced phosphorylation of KIT and induced growth inhibition in mast cell lines. In SCID-beige mice injected with either the human mast cell line HMC-1.1 and HMC-1.2 or with Siglec-7 transduced B cell lymphoma cells, anti-Siglec-7 monoclonal antibody reduced tumor growth by a mechanism involving Siglec-7 cytoplasmic domains in "preventive" and "treatment" settings. These data demonstrate that activation of Siglec-7 on mast cell lines can inhibit their growth in vitro and in vivo. This might pave the way to additional treatment strategies for mastocytosis.
Asunto(s)
Lectinas/agonistas , Leucemia de Mastocitos/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Animales , Anticuerpos Monoclonales/uso terapéutico , Antígenos de Diferenciación Mielomonocítica , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Genes src/efectos de los fármacos , Humanos , Leucemia de Mastocitos/patología , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/patología , Masculino , Mastocitosis/tratamiento farmacológico , Ratones , Ratones SCID , Persona de Mediana Edad , Fosforilación , Proteína Tirosina Fosfatasa no Receptora Tipo 6/efectos de los fármacos , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Mutations in two type-3 receptor tyrosine kinases (RTKs), KIT and FLT3, are common in both acute myeloid leukaemia (AML) and systemic mastocytosis (SM) and lead to hyperactivation of key signalling pathways. A large number of tyrosine kinase inhibitors (TKIs) have been developed that target either FLT3 or KIT and significant clinical benefit has been demonstrated in multiple clinical trials. Given the structural similarity of FLT3 and KIT, it is not surprising that some of these TKIs inhibit both of these receptors. This is typified by midostaurin, which has been approved by the US Food and Drug Administration for mutant FLT3-positive AML and for KIT D816V-positive SM. Here, we compare the in vitro activities of the clinically available FLT3 and KIT inhibitors with those of midostaurin against a panel of cells expressing a variety of oncogenic FLT3 or KIT receptors, including wild-type (wt) FLT3, FLT3-internal tandem duplication (ITD), FLT3 D835Y, the resistance mutant FLT3-ITD+ F691L, KIT D816V, and KIT N822K. We also examined the effects of these inhibitors in vitro and in vivo on cells expressing mutations in c-CBL found in AML that result in hypersensitization of RTKs, such as FLT3 and KIT. The results show a wide spectrum of activity of these various mutations to these clinically available TKIs.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Hematológicas/tratamiento farmacológico , Proteínas Mutantes/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Antineoplásicos/uso terapéutico , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Benzotiazoles/farmacología , Benzotiazoles/uso terapéutico , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Neoplasias Hematológicas/genética , Humanos , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Piperidinas/farmacología , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-cbl/efectos de los fármacos , Proteínas Proto-Oncogénicas c-cbl/genética , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Proteínas Proto-Oncogénicas c-kit/genética , Pirazinas/farmacología , Pirazinas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Pirroles/farmacología , Pirroles/uso terapéutico , Sorafenib/farmacología , Sorafenib/uso terapéutico , Estaurosporina/análogos & derivados , Estaurosporina/farmacología , Estaurosporina/uso terapéutico , Triazinas/farmacología , Triazinas/uso terapéutico , Tirosina Quinasa 3 Similar a fms/efectos de los fármacos , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
RATIONALE: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract and is characterized by KIT mutations. Patientsresistant to 1st-line imatinib therapy are usually given sunitinib assecond-line treatment, which provides a median progression-free survival of 8 to 12 months. We report the 1st case of metastatic jejunum GIST with a KIT exon 11 deletion that showed complete response (CR) to sunitinib for more than 3 years. PATIENT CONCERNS: A 34-year-old man with advanced jejunum GIST was surgically treated upon initial diagnosis, and was histologically found to carry a high recurrence risk. Genetic testing revealed a KIT exon 11 deletion, and adjuvant therapy with imatinib was administered. The imatinib dose was escalated following recurrence in the abdomen, but the mass continued to grow. DIAGNOSIS: He was diagnosed with abdominal recurrence of GIST based on his medical history and histopathological results. INTERVENTION: Second-line sunitinib therapy was given. OUTCOMES: The mass disappeared, and CR was seen following 7 months of sunitinib therapy; this CR was sustained for more than 45 months. LESSONS: In cases of metastatic jejunum GIST with a KIT exon 11 deletion, sunitinib as second-line therapy can be used to achieve CR for more than 3 years.
Asunto(s)
Antineoplásicos/administración & dosificación , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Neoplasias del Yeyuno/tratamiento farmacológico , Sunitinib/administración & dosificación , Adulto , Esquema de Medicación , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Exones , Tumores del Estroma Gastrointestinal/genética , Humanos , Quimioterapia de Inducción , Neoplasias del Yeyuno/genética , Masculino , Mutación , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Proteínas Proto-Oncogénicas c-kit/genética , Factores de Tiempo , Resultado del TratamientoRESUMEN
RATIONALE: Gastrointestinal stromal tumor (GIST) is the most common tumor of mesenchymal origin in gastrointestinal tract. Immunohistochemical (IHC) staining combined with a typical morphology is used for the diagnosis of GIST. Typically, IHC staining for v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene (KIT) and discovered on GIST-1(DOG1) is positive in almost all GISTs. However, imatinib mesylate, a specific inhibitor of KIT tyrosine kinase, frequently involves changes in the morphology and IHC staining of GIST, impeding the diagnosis. Recently, in situ hybridization (ISH) for E26 transformation-specific sequence variant 1 (ETV1) mRNA was introduced as a useful marker to diagnose GIST. PATIENT CONCERNS: We report 2 cases of gastric GIST, which expressed unusual phenotypes after imatinib therapy. DIAGNOSES: The first patient was found to have a gastric subepithelial tumor in gastroduodenoscopy done for regular checkup. In biopsy of the tumor, it showed homogenous spindle cells that were positive to standard IHC markers for GIST. The second patient visited our hospital because of a palpable mass in the abdomen. In abdominal computed tomography (CT), a tumor arising from the stomach was found. A needle biopsy was done and the patient was diagnosed of gastric GIST because the biopsy showed spindle cells positive to typical IHC markers for GIST. After imatinib treatment, in both patients, the resected tumors were composed of heterogeneous spindle cells negative to KIT, DOG1, and CD34 IHC staining, which was unusual for GIST. However, ISH for ETV1 mRNA done for both biopsied and resected tumors was positive, even after imatinib treatment. A molecular analysis found a mutation in exon 11 of KIT gene before and after imatinib therapy in both patients, confirming the diagnosis of GIST. INTERVENTIONS: Both patients took neoadjuvant imatinib treatment, and afterwards, underwent a surgical resection. OUTCOMES: The patients remain on imatinib treatment and no progression or recurrence has been detected to date. LESSONS: ISH for ETV1 mRNA is a useful technique in diagnosing GIST when IHC with KIT, DOG1, or CD34 fail to stain positive after imatinib therapy.
Asunto(s)
Antineoplásicos/farmacología , Proteínas de Unión al ADN/genética , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Mesilato de Imatinib/farmacología , ARN Mensajero/sangre , Neoplasias Gástricas/tratamiento farmacológico , Factores de Transcripción/genética , Anciano , Biomarcadores de Tumor/genética , Exones/genética , Femenino , Tumores del Estroma Gastrointestinal/diagnóstico , Tumores del Estroma Gastrointestinal/genética , Humanos , Hibridación in Situ/métodos , Masculino , Mutación , Fenotipo , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genéticaRESUMEN
OBJECTIVE: Currently, medical and surgical treatment options for endometriosis are limited due to suboptimal efficacy, and also safety and tolerance issues. Long-term use of gonadotrophin-releasing hormone analogs, androgenes, and the danazol, which are widely used drugs for endometriosis, is usually not possible due to their suboptimal safety and tolerance profile. The lack of an effective, tolerable and safe treatment option for endometriosis makes animal models of experimental endometriosis necessary to study candidate drugs. The aim of this study was to investigate the efficacy of imatinib on the experimental endometriosis in a rat model. STUDY DESIGN: Endometriosis was induced by autotransplantation of uterine tissue into the peritoneal cavity. Twenty-four rats, which had visually confirmed endometriotic implants on subsequent laparotomy, were randomized into three groups to receive imatinib (25mg/kg/day, p.o.), anastrozole (0.004 mg/day, p.o.), or normal saline (0.1 mL, i.p.) for 14 days. After removal of endometriotic tissue and H & E staining, endometriosis score was determined according to a semiquantitative histological classification. Also, immunostaining with primary antibodies including VEGF, CD117, and Bax were used for immunohistochemical (IHC) examination. RESULTS: Both anastrozole and imatinib suppressed the growth of endometriotic tissue and reduced the number of ovarian follicles. Although the difference was not statistically significant, imatinib was less effective than anastrozole for treatment of endometriosis. CONCLUSION: Imatinib effectively treats experimental endometriosis by its inhibitor effects on angiogenesis and cell proliferation.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Aromatasa/farmacología , Proliferación Celular/efectos de los fármacos , Endometriosis , Endometrio/efectos de los fármacos , Mesilato de Imatinib/farmacología , Nitrilos/farmacología , Enfermedades Peritoneales , Peritoneo/efectos de los fármacos , Triazoles/farmacología , Anastrozol , Animales , Modelos Animales de Enfermedad , Endometriosis/metabolismo , Endometrio/metabolismo , Endometrio/trasplante , Femenino , Folículo Ovárico/efectos de los fármacos , Enfermedades Peritoneales/metabolismo , Peritoneo/metabolismo , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Proteínas Proto-Oncogénicas c-kit/metabolismo , Ratas , Trasplante Autólogo , Factor A de Crecimiento Endotelial Vascular/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteína X Asociada a bcl-2/efectos de los fármacos , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Although stem cell factor receptor (c-KIT) kinase is responsible for various malignant human cancers, the presence of constitutively active gain-of-function mutants has made it difficult to discover new anticancer agents using c-KIT as the target protein. To identify the common inhibitors of wild-type c-KIT and the most abundant gain-of-function mutant (D816V), the virtual screening of natural products was performed for the two target proteins in parallel with the scoring function improved by implementing a sophisticated solvation free energy term. As a result, four common inhibitors of natural origin are found with biochemical potencies ranging from low micromolar to submicromolar levels. The results of extensive docking simulations show that although the natural-product inhibitors establish weaker hydrophobic interactions with the D816V mutant than with the wild type, they exhibit a little higher inhibitory activity for the former than the latter by strengthening the hydrogen-bond interactions to a sufficient extent. Of the four natural-product inhibitors, (Z)-6-hydroxy-2-(4-methoxybenzylidene)benzofuran-3(2H)-one (3) is anticipated to serve as a new molecular core for the structure-activity relationship studies to optimize the biochemical potencies because it exhibits good inhibitory activity against both the wild type and D816V mutant despite its low molecular weight (268.3 amu).
Asunto(s)
Antineoplásicos/farmacología , Benzofuranos/farmacología , Productos Biológicos/farmacología , Proteínas Proto-Oncogénicas c-kit/metabolismo , Algoritmos , Antineoplásicos/química , Benzofuranos/química , Productos Biológicos/química , Células HEK293 , Humanos , Estructura Molecular , Mutación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Proteínas Proto-Oncogénicas c-kit/genética , Relación Estructura-ActividadRESUMEN
PURPOSE: This retrospective cohort study aimed to determine the predictive relevance of clinical characteristics, additional cytogenetic aberrations, and cKIT and RAS mutations, as well as to evaluate whether specific treatment elements were associated with outcomes in pediatric t(8;21)-positive patients with acute myeloid leukemia (AML). PATIENTS AND METHODS: Karyotypes of 916 pediatric patients with t(8;21)-AML were reviewed for the presence of additional cytogenetic aberrations, and 228 samples were screened for presence of cKIT and RAS mutations. Multivariable regression models were used to assess the relevance of anthracyclines, cytarabine, and etoposide during induction and overall treatment. End points were the probability of achieving complete remission, cumulative incidence of relapse (CIR), probability of event-free survival, and probability of overall survival. RESULTS: Of 838 patients included in final analyses, 92% achieved complete remission. The 5-year overall survival, event-free survival, and CIR were 74%, 58%, and 26%, respectively. cKIT mutations and RAS mutations were not significantly associated with outcome. Patients with deletions of chromosome arm 9q [del(9q); n = 104] had a lower probability of complete remission (P = .01). Gain of chromosome 4 (+4; n = 21) was associated with inferior CIR and survival (P < .01). Anthracycline doses greater than 150 mg/m(2) and etoposide doses greater than 500 mg/m(2) in the first induction course and high-dose cytarabine 3 g/m(2) during induction were associated with better outcomes on various end points. Cumulative doses of cytarabine greater than 30 g/m(2) and etoposide greater than 1,500 mg/m(2) were associated with lower CIR rates and better probability of event-free survival. CONCLUSION: Pediatric patients with t(8;21)-AML and additional del(9q) or additional +4 might not be considered at good risk. Patients with t(8;21)-AML likely benefit from protocols that have high doses of anthracyclines, etoposide, and cytarabine during induction, as well as from protocols comprising cumulative high doses of cytarabine and etoposide.
Asunto(s)
Antineoplásicos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Terapia Molecular Dirigida , Mutación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-kit/genética , Translocación Genética/efectos de los fármacos , Proteínas ras/genética , Adolescente , Antraciclinas/administración & dosificación , Antraciclinas/efectos adversos , Niño , Preescolar , Aberraciones Cromosómicas/efectos de los fármacos , Cromosomas Humanos Par 21 , Cromosomas Humanos Par 8 , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Etopósido/administración & dosificación , Femenino , Alemania , Trasplante de Células Madre Hematopoyéticas , Humanos , Incidencia , Quimioterapia de Inducción , Cooperación Internacional , Estimación de Kaplan-Meier , Cariotipo , Leucemia Mieloide Aguda/mortalidad , Masculino , Terapia Molecular Dirigida/métodos , Valor Predictivo de las Pruebas , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Estudios Retrospectivos , Trasplante Homólogo , Resultado del Tratamiento , Proteínas ras/efectos de los fármacosRESUMEN
Prospermatogonia transition to type A spermatogonia, which provide the source for the spermatogonial stem cell (SSC) pool. A percentage of these type A spermatogonia then differentiate to enter meiosis as spermatocytes by â¼P10. It is currently unclear as to when these distinct populations are initially formed in the neonatal testis, and when the expression of markers both characteristic of and required for the adult undifferentiated and differentiating states is established. In this study, we compared expression of known spermatogonial cell fate markers during normal development and in response to the differentiation signal provided by retinoic acid (RA). We found that some markers for the undifferentiated state (ZBTB16/PLZF and CDH1) were expressed in nearly all spermatogonia from P1 through P7. In contrast, differentiation markers (STRA8 and KIT) appeared in a subset of spermatogonia at P4, coincident with the onset of RA signaling. GFRA1, which was present in nearly all prospermatogonia at P1, was only retained in STRA8/KIT- spermatogonia. From P4 through P10, there was a great deal of heterogeneity in the male germ cell population in terms of expression of markers, as markers characteristic of the undifferentiated (except GFRA1) and differentiating states were co-expressed through this interval. After P10, these fate markers diverged to mark distinct populations of undifferentiated and differentiating spermatogonia, and this pattern was maintained in juvenile (P18) and adult (P>60) testes. Taken together, these results reveal that the spermatogonia population is heterogeneous during the first wave of spermatogenesis, and indicate that neonatal spermatogonia may not serve as an ideal substitute for studying the function of adult spermatogonia.
Asunto(s)
Biomarcadores/metabolismo , Diferenciación Celular/fisiología , Espermatogénesis/fisiología , Espermatogonias/citología , Testículo/citología , Animales , Animales Recién Nacidos , Antineoplásicos/farmacología , Proteínas Cdh1/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Técnicas para Inmunoenzimas , Factores de Transcripción de Tipo Kruppel/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Espermatogénesis/efectos de los fármacos , Espermatogonias/efectos de los fármacos , Espermatogonias/metabolismo , Testículo/efectos de los fármacos , Testículo/metabolismo , Tretinoina/farmacologíaRESUMEN
Gastrointestinal stromal tumour (GIST), while relatively rare, is the most common mesenchymal tumour of the gastrointestinal tract. These tumours are largely resistant to cytotoxic chemotherapy and, in the past, were typically managed surgically. However, as a result of the identification of activating mutations in the proto-oncogene KIT and the development of compounds that inhibit the KIT receptor tyrosine kinase, GISTs have, in the last 14 years, become the archetype of a targeted agent-responsive tumour. Due to the almost continual emergence of new data from clinical trials and other studies on GIST diagnosis and treatment, the management of this disease requires regular review. The 2013 ArcheoloGIST summit was convened in Prague, Czech Republic. Interaction between attending physicians and the expert faculty was a core component of the summit. The current article is based on discussions held during two interactive sessions at ArcheoloGIST 2013 in which the authors aimed to: (1) reach a consensus on the current management of GIST and (2) provide a vision for the future diagnosis and treatment of this disease.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Oncología Médica/tendencias , Terapia Molecular Dirigida/métodos , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-kit/genética , Antineoplásicos/farmacología , Benzamidas/uso terapéutico , Quimioterapia Adyuvante , Ensayos Clínicos como Asunto , Congresos como Asunto , Consenso , Esquema de Medicación , Resistencia a Antineoplásicos , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/patología , Neoplasias Gastrointestinales/cirugía , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/patología , Tumores del Estroma Gastrointestinal/cirugía , Humanos , Mesilato de Imatinib , Mutación/efectos de los fármacos , Piperazinas/uso terapéutico , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Pirimidinas/uso terapéutico , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Resultado del TratamientoRESUMEN
Receptor tyrosine kinase KIT controls many signal transduction pathways and represents a typical allosterically regulated protein. The mutation-induced deregulation of KIT activity impairs cellular physiological functions and causes serious human diseases. The impact of hotspots mutations (D816H/Y/N/V and V560G/D) localized in crucial regulatory segments, the juxtamembrane region (JMR) and the activation (A-) loop, on KIT internal dynamics was systematically studied by molecular dynamics simulations. The mutational outcomes predicted in silico were correlated with in vitro and in vivo activation rates and drug sensitivities of KIT mutants. The allosteric regulation of KIT in the native and mutated forms is described in terms of communication between the two remote segments, JMR and A-loop. A strong correlation between the communication profile and the structural and dynamical features of KIT in the native and mutated forms was established. Our results provide new insight on the determinants of receptor KIT constitutive activation by mutations and resistance of KIT mutants to inhibitors. Depiction of an intra-molecular component of the communication network constitutes a first step towards an integrated description of vast communication pathways established by KIT in physiopathological contexts.
Asunto(s)
Mutación/genética , Proteínas Proto-Oncogénicas c-kit/química , Proteínas Proto-Oncogénicas c-kit/genética , Regulación Alostérica/genética , Antineoplásicos/farmacología , Citoplasma/química , Citoplasma/metabolismo , Humanos , Enlace de Hidrógeno , Simulación de Dinámica Molecular , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Proteínas Proto-Oncogénicas c-kit/metabolismo , Transducción de SeñalRESUMEN
RATIONALE: Sorafenib is an effective treatment for renal cell carcinoma, but recent clinical reports have documented its cardiotoxicity through an unknown mechanism. OBJECTIVE: Determining the mechanism of sorafenib-mediated cardiotoxicity. METHODS AND RESULTS: Mice treated with sorafenib or vehicle for 3 weeks underwent induced myocardial infarction (MI) after 1 week of treatment. Sorafenib markedly decreased 2-week survival relative to vehicle-treated controls, but echocardiography at 1 and 2 weeks post MI detected no differences in cardiac function. Sorafenib-treated hearts had significantly smaller diastolic and systolic volumes and reduced heart weights. High doses of sorafenib induced necrotic death of isolated myocytes in vitro, but lower doses did not induce myocyte death or affect inotropy. Histological analysis documented increased myocyte cross-sectional area despite smaller heart sizes after sorafenib treatment, further suggesting myocyte loss. Sorafenib caused apoptotic cell death of cardiac- and bone-derived c-kit+ stem cells in vitro and decreased the number of BrdU+ (5-bromo-2'-deoxyuridine+) myocytes detected at the infarct border zone in fixed tissues. Sorafenib had no effect on infarct size, fibrosis, or post-MI neovascularization. When sorafenib-treated animals received metoprolol treatment post MI, the sorafenib-induced increase in post-MI mortality was eliminated, cardiac function was improved, and myocyte loss was ameliorated. CONCLUSIONS: Sorafenib cardiotoxicity results from myocyte necrosis rather than from any direct effect on myocyte function. Surviving myocytes undergo pathological hypertrophy. Inhibition of c-kit+ stem cell proliferation by inducing apoptosis exacerbates damage by decreasing endogenous cardiac repair. In the setting of MI, which also causes large-scale cell loss, sorafenib cardiotoxicity dramatically increases mortality.
Asunto(s)
Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Corazón/efectos de los fármacos , Infarto del Miocardio/mortalidad , Niacinamida/análogos & derivados , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/farmacología , Animales , Apoptosis/efectos de los fármacos , Gatos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Técnicas In Vitro , Masculino , Metoprolol/farmacología , Ratones , Ratones Endogámicos C57BL , Infarto del Miocardio/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Niacinamida/efectos adversos , Niacinamida/farmacología , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Proteínas Proto-Oncogénicas c-kit/metabolismo , SorafenibRESUMEN
BACKGROUND: Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue sarcoma, marked by NR4A3 rearrangement. Herein we report on the activity of sunitinib in a series of 10 patients, strengthening what initially observed in two cases. PATIENTS AND METHODS: From July 2011, 10 patients with progressive metastatic translocated EMC have been consecutively treated with sunitinib 37.5mg/day, on a named-use basis. In an attempt to interpret the activity of sunitinib in EMC, genotype/phenotype correlations were carried out by fluorescence in situ hybridization (FISH) analyses. Moreover, transcriptome, immunohistochemical and biochemical analyses of a limited set of samples were performed focusing on some putative targets of sunitinib. RESULTS: Eight of 10 patients are still on therapy. Six patients had a Response Evaluation Criteria in Solid Tumours (RECIST) partial response (PR), two were stable, two progressed. Positron emission tomography (PET) was consistent in 6/6 evaluable cases. One patient underwent surgery after sunitinib, with evidence of a pathologic response. At a median follow-up of 8.5 months (range 2-28), no secondary resistance was detected. Median progression free survival (PFS) has not been reached. Interestingly, all responsive cases turned out to express the typical EWSR1-NR4A3 fusion, while refractory cases carried the alternative TAF15-NR4A3 fusion. Among putative sunitinib targets, only RET was expressed and activated in analysed samples. CONCLUSIONS: This report confirms the therapeutic activity of sunitinib in EMC. Genotype/phenotype analyses support a correlation between response and EWSR1-NR4A3 fusion. Involvement of RET deserves further investigation.
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Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Óseas , Condrosarcoma/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias de los Tejidos Conjuntivo y Blando/tratamiento farmacológico , Pirroles/uso terapéutico , Adulto , Anciano , Proteínas de Unión a Calmodulina/genética , Condrosarcoma/genética , Condrosarcoma/secundario , Proteínas de Unión al ADN/genética , Resistencia a Antineoplásicos/genética , Femenino , Reordenamiento Génico/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de los Tejidos Conjuntivo y Blando/genética , Neoplasias de los Tejidos Conjuntivo y Blando/secundario , Fenotipo , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Proteínas Proto-Oncogénicas c-ret/efectos de los fármacos , Proteína EWS de Unión a ARN , Proteínas de Unión al ARN/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/efectos de los fármacos , Receptores de Esteroides/genética , Receptores de Hormona Tiroidea/genética , Sunitinib , Factores Asociados con la Proteína de Unión a TATA/genética , Resultado del Tratamiento , Receptor 2 de Factores de Crecimiento Endotelial Vascular/efectos de los fármacos , Tirosina Quinasa 3 Similar a fms/efectos de los fármacosRESUMEN
BACKGROUND: To investigate the effects of the c-kit blocker imatinib mesylate (Glivec) on the bladders of animals with suprasacral cord injury (SSCI) and sacral cord injury (SCI). MATERIALS AND METHODS: We randomized 60 female Sprague-Dawley rats into control, sham, SSCI (T8/9 transection), and SCI (S1-3 transection) groups. Six weeks later, we evaluated the effects of stepwise Glivec administrations on urinary bladder contraction using cystometry and the detrusor strip stretch-test. We investigated spontaneous calcium transients of kit-positive interstitial cells of Cajal (ICCs) with the preloaded Ca(2+) indicator fluo-3AM. The expression levels of c-kit and the number of ICCs in those bladders were determined using Western blot and fluorescence staining analyses, respectively. RESULTS: Bladder capacity and compliance were decreased in SSCI bladders and increased in SCI bladders (P<0.05). The amplitude and frequency of spontaneous contractions of detrusor strips, the frequency and relative fluorescence intensity of the spontaneous Ca(2+) waves, and c-kit expression in the bladder were significantly increased in the SSCI group and decreased in the SCI group compared with the control and sham groups (P<0.05). The dose-dependent effects of Glivec also confirmed consistent functional variations in bladder activity. CONCLUSIONS: The expressions and effects of Glivec were enhanced in SSCI bladders and inhibited in SCI bladders, which may indicate potential roles of ICCs for the c-kit signaling pathway in the pathogenesis of SSCI and SCI bladder.
Asunto(s)
Benzamidas/farmacología , Benzamidas/uso terapéutico , Piperazinas/farmacología , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-kit/metabolismo , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Traumatismos de la Médula Espinal/tratamiento farmacológico , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/fisiopatología , Animales , Calcio/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Mesilato de Imatinib , Células Intersticiales de Cajal/metabolismo , Células Intersticiales de Cajal/patología , Modelos Animales , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Sacro , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/fisiopatología , Vejiga Urinaria/patologíaRESUMEN
Correctly predicting off-targets for a given molecular structure, which would have the ability to bind a large range of ligands, is both particularly difficult and important if they share no significant sequence or fold similarity with the respective molecular target ("distant off-targets"). A novel approach for identification of off-targets by direct superposition of protein binding pocket surfaces is presented and applied to a set of well-studied and highly relevant drug targets, including representative kinases and nuclear hormone receptors. The entire Protein Data Bank is searched for similar binding pockets and convincing distant off-target candidates were identified that share no significant sequence or fold similarity with the respective target structure. These putative target off-target pairs are further supported by the existence of compounds that bind strongly to both with high topological similarity, and in some cases, literature examples of individual compounds that bind to both. Also, our results clearly show that it is possible for binding pockets to exhibit a striking surface similarity, while the respective off-target shares neither significant sequence nor significant fold similarity with the respective molecular target ("distant off-target").
Asunto(s)
Diseño de Fármacos , Sitios de Unión , Quinasa de la Caseína II/química , Quinasa de la Caseína II/efectos de los fármacos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/efectos de los fármacos , Bases de Datos de Proteínas , Receptor beta de Estrógeno/química , Receptor beta de Estrógeno/efectos de los fármacos , Humanos , Ligandos , Modelos Moleculares , Unión Proteica , Conformación Proteica , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/efectos de los fármacos , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/efectos de los fármacos , Proteínas/química , Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-kit/química , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Receptores de Glucocorticoides/química , Receptores de Glucocorticoides/efectos de los fármacos , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/efectos de los fármacosRESUMEN
Melanoma is one of the most common cancers in Western countries but has defied the trend of reductions in age-adjusted mortality observed in most other cancers in recent years. Biologically, melanoma is characterized by a high propensity to metastasize at low tumor volumes necessitating the need for effective drug therapies to support efforts in prevention and early detection for reducing mortality. Efforts to study the clinical biology of melanoma have led to a new understanding of the disease, with genomic studies identifying several targetable oncogenes, in particular the protein kinases BRAF and KIT. Biologic studies have also identified a variety of immunologic targets, including the programmed death 1 (PD-1) and cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4) inhibitory molecules expressed on T lymphocytes. After several decades of clinical trials that failed to demonstrate improvement in overall survival in patients with advanced melanoma, small molecule inhibitors of BRAF or MEK and inhibition of CTLA-4 can improve survival in patients with advanced disease. These early clinical studies have provided a great opportunity to improve mortality in melanoma with the significant potential of combinations of signaling inhibitors or signaling inhibitors combined with immunologic agents, particularly when used in the adjuvant setting, and to transform the care of patients with this most challenging of cancers.
Asunto(s)
Antineoplásicos/farmacología , Inmunoterapia/métodos , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/metabolismo , Traslado Adoptivo , Antineoplásicos/uso terapéutico , Antígeno CTLA-4/efectos de los fármacos , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/inmunología , Melanoma/enzimología , Melanoma/genética , Melanoma/inmunología , Melanoma/mortalidad , Melanoma/patología , Quinasas de Proteína Quinasa Activadas por Mitógenos/efectos de los fármacos , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-kit/efectos de los fármacos , Proteínas Proto-Oncogénicas c-kit/metabolismo , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patologíaRESUMEN
AIM: To clarify the biological role of stem cell factor (SCF)-mediated wild-type KIT receptor activation in gastrointestinal stromal tumor (GIST) growth. METHODS: The co-expression of wild-type KIT receptor and SCF was evaluated in 51 GIST samples using mutation analysis and immunohistochemistry, and the results were correlated with clinicopathological parameters, including the mitotic count, proliferative index (Ki-67 immunohistochemical staining), mitotic index (phospho-histone H3 immunohistochemical staining) and apoptotic index (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling). Using primary cultured GIST cells, the effect of SCF-mediated wild-type KIT receptor activation was determined by western blotting, methyl thiazolyl tetrazolium (MTT), and apoptosis assays. RESULTS: We found that wild-type KIT receptor and SCF protein were expressed in 100% and 76.5% of the 51 GIST samples, respectively, and the co-expression of wild-type KIT receptor and SCF was associated with known indicators of poor prognosis, including larger tumor size (P = 0.0118), higher mitotic count (P = 0.0058), higher proliferative index (P = 0.0012), higher mitotic index (P = 0.0282), lower apoptosis index (P = 0.0484), and increased National Institutes of Health risk level (P = 0.0012). We also found that the introduction of exogenous SCF potently increased KIT kinase activity, stimulated cell proliferation (P < 0.01) and inhibited apoptosis (P < 0.01) induced by serum starvation, while a KIT immunoblocking antibody suppressed proliferation (P = 0.01) and promoted apoptosis (P < 0.01) in cultured GIST cells. CONCLUSION: SCF-mediated wild-type KIT receptor activation plays an important role in GIST cell growth. The inhibition of SCF-mediated wild-type KIT receptor activation may prove to be particularly important for GIST therapy.