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1.
Int J Mol Sci ; 22(7)2021 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-33804911

RESUMEN

BACKGROUND: Clinical management of ischemic events and prevention of vascular disease is based on antiplatelet drugs. Given the relevance of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) as a candidate target in thrombosis, the main goal of the present study was to identify novel antiplatelet agents within the existing inhibitors blocking PI3K isoforms. METHODS: We performed a biological evaluation of the pharmacological activity of PI3K inhibitors in platelets. The effect of the inhibitors was evaluated in intracellular calcium release and platelet functional assays, the latter including aggregation, adhesion, and viability assays. The in vivo drug antithrombotic potential was assessed in mice undergoing chemically induced arterial occlusion, and the associated hemorrhagic risk evaluated by measuring the tail bleeding time. RESULTS: We show that PI3K Class IA inhibitors potently block calcium mobilization in human platelets. The PI3K p110δ inhibitor Idelalisib inhibits platelet aggregation mediated by ITAM receptors GPVI and CLEC-2, preferentially by the former. Moreover, Idelalisib also inhibits platelet adhesion and aggregation under shear and adhesion to collagen. Interestingly, an antithrombotic effect was observed in mice treated with Idelalisib, with mild bleeding effects at high doses of the drug. CONCLUSION: Idelalisib may have antiplatelet effects with minor bleeding effects, which provides a rationale to evaluate its antithrombotic efficacy in humans.


Asunto(s)
Plaquetas/efectos de los fármacos , Fibrinolíticos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Purinas/farmacología , Quinazolinonas/farmacología , Trombosis/tratamiento farmacológico , Animales , Plaquetas/metabolismo , Plaquetas/fisiología , Calcio/metabolismo , Células Cultivadas , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Femenino , Fibrinolíticos/uso terapéutico , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Adhesividad Plaquetaria , Inhibidores de Proteínas Quinasas/uso terapéutico , Purinas/uso terapéutico , Quinazolinonas/uso terapéutico
3.
Rinsho Ketsueki ; 62(3): 180-185, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-33828011

RESUMEN

We report the case of a 26-year-old male patient with chronic myelogenous leukemia in the chronic phase with the e13a3 (b2a3) variant of BCR-ABL1 fusion. Despite the presence of Philadelphia chromosome and fluorescence in situ hybridization-detectable BCR-ABL1 fusion signals, quantitative measurement of BCR-ABL1 on the ABL1 using a reverse primer in exon 2 of ABL1 failed to detect the fusion transcripts. PCR direct sequencing analysis with a sense primer for exon 13 of BCR and an antisense primer for exon 3 of ABL1 revealed the e13a3 variant of BCR-ABL1 fusion. The variant fusion transcript level was successfully monitored by the TaqMan assay using a forward primer and probe both in exon 13 of BCR and a reverse primer in exon 3 of ABL1. The patient responded extremely well to imatinib treatment, similar to previously reported e13a3 cases. The patient achieved a molecular response (undetectable e13a3 transcripts) after 12 months of treatment.


Asunto(s)
Proteínas de Fusión bcr-abl , Leucemia Mielógena Crónica BCR-ABL Positiva , Adulto , Proteínas de Fusión bcr-abl/genética , Humanos , Mesilato de Imatinib/uso terapéutico , Hibridación Fluorescente in Situ , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Inhibidores de Proteínas Quinasas/uso terapéutico
4.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799513

RESUMEN

Squamous cell carcinomas of the lung, head and neck, esophagus, and cervix account for more than two million cases of cancer per year worldwide with very few targetable therapies available and minimal clinical improvement in the past three decades. Although these carcinomas are differentiated anatomically, their genetic landscape shares numerous common genetic alterations. Amplification of the third chromosome's distal portion (3q) is a distinguishing genetic alteration in most of these carcinomas and leads to copy-number gain and amplification of numerous oncogenic proteins. This area of the chromosome harbors known oncogenes involved in squamous cell fate decisions and differentiation, including TP63, SOX2, ECT2, and PIK3CA. Furthermore, novel targetable oncogenic kinases within this amplicon include PRKCI, PAK2, MAP3K13, and TNIK. TCGA analysis of these genes identified amplification in more than 20% of clinical squamous cell carcinoma samples, correlating with a significant decrease in overall patient survival. Alteration of these genes frequently co-occurs and is dependent on 3q-chromosome amplification. The dependency of cancer cells on these amplified kinases provides a route toward personalized medicine in squamous cell carcinoma patients through development of small-molecules targeting these kinases.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidad , Ensayos Clínicos como Asunto , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Neoplasias Esofágicas/enzimología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidad , Femenino , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello/enzimología , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Fosfatidilinositol 3-Quinasa/genética , Fosfatidilinositol 3-Quinasa/metabolismo , Medicina de Precisión/métodos , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/genética , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Análisis de Supervivencia , Neoplasias del Cuello Uterino/enzimología , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/mortalidad
5.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799514

RESUMEN

Treatment of patients with urothelial carcinoma (UC) of the bladder or renal cancer has changed significantly during recent years and efforts towards biomarker-directed therapy are being investigated. Immune checkpoint inhibition (ICI) or fibroblast growth factor receptor (FGFR) directed therapy are being evaluated for non-muscle invasive bladder cancer (NMIBC) patients, as well as muscle-invasive bladder cancer (MIBC) patients. Meanwhile, efforts to predict tumor response to neoadjuvant chemotherapy (NAC) are still ongoing, and genomic biomarkers are being evaluated in prospective clinical trials. Currently, patients with metastatic UC (mUC) are usually treated with second-line ICI, while cisplatin-ineligible patients with programmed death-ligand 1 (PD-L1) positive tumors can benefit from first-line ICI. Platinum-relapsed UC patients harboring FGFR2/3 mutations can be treated with erdafitinib, while enfortumab vedotin has emerged as a novel third-line treatment option for mUC. In metastatic (clear cell) renal cell carcinoma (RCC), ICI was first introduced as second-line treatment after vascular endothelial growth factor receptor-tyrosine kinase inhibition (VEGFR-TKI). Currently, ICIs have also been introduced as first-line treatment in metastatic RCC. Although there is no evidence up to now for beneficial adjuvant treatment after surgery with VEGFR-TKIs in high-risk non-metastatic RCC, several trials are underway investigating the potential beneficial effect of ICIs in this setting.


Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Biomarcadores de Tumor/inmunología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/patología , Cisplatino/uso terapéutico , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/genética , Neoplasias Renales/inmunología , Neoplasias Renales/patología , Metástasis Linfática , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Quinoxalinas/uso terapéutico , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/inmunología , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/inmunología , Recurrencia , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/patología
6.
Medicine (Baltimore) ; 100(15): e25576, 2021 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-33847688

RESUMEN

RATIONALE: Anaplastic lymphoma kinase (ALK) + anaplastic large cell lymphoma (ALCL) is considered as a good prognosis lymphoma. However, in an extremely rare subset of patients, ALK+ ALCL with leukemic presentations is known to be chemotherapy-resistant. Although several novel therapies have been tested, the standard therapy for relapsed/refractory ALK+ ALCL has not been established yet. PATIENT CONCERNS: An 18-year-old female patient who had conventional chemotherapy- and Brentuximab Vedotin (BV)-resistant ALK+ ALCL with leukemic presentation. She was successfully treated with an ALK inhibitor, crizotinib. Crizotinib induced complete remission (CR) and bridged to allogeneic bone marrow transplantation (BMT). DIAGNOSIS: However, her ALCL relapsed on day 60 after BMT and she developed high grade fever and lymphadenopathy. INTERVENTION: Although crizotinib was given to the patient immediately after relapse, she developed grade 3 nausea and could not continue to take it. Then, we gave alectinib to the patient, which promptly induced sustained CR without any further chemotherapy. The patient received second stem cell transplantation using umbilical cord blood with myeloablative regimen in 2nd CR. OUTCOMES: The patient has been in CR under maintenance therapy of alectinib for more than 16 months. LESSONS: Both ALK inhibitors demonstrated drastic efficacy for our patient who had chemotherapy- and BV-resistant ALK+ ALCL with leukemic presentation. Alectinib showed less gastro-intestinal toxicity than crizotinib and the patient was able to take it even at the relatively early phase of stem cell transplantation.


Asunto(s)
Quinasa de Linfoma Anaplásico/metabolismo , Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Linfoma Anaplásico de Células Grandes/terapia , Recurrencia Local de Neoplasia/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Adolescente , Carbazoles/uso terapéutico , Crizotinib/uso terapéutico , Femenino , Humanos , Linfoma Anaplásico de Células Grandes/enzimología , Ilustración Médica , Recurrencia Local de Neoplasia/enzimología , Piperidinas/uso terapéutico , Trasplante Homólogo
7.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33802080

RESUMEN

Recent studies on cyclin-dependent kinase (CDK) inhibitors have revealed that small molecule drugs have become very attractive for the treatment of cancer and neurodegenerative disorders. Most CDK inhibitors have been developed to target the ATP binding pocket. However, CDK kinases possess a very similar catalytic domain and three-dimensional structure. These features make it difficult to achieve required selectivity. Therefore, inhibitors which bind outside the ATP binding site present a great interest in the biomedical field, both from the fundamental point of view and for the wide range of their potential applications. This review tries to explain whether the ATP competitive inhibitors are still an option for future research, and highlights alternative approaches to discover more selective and potent small molecule inhibitors.


Asunto(s)
Quinasas Ciclina-Dependientes , Proteínas de Neoplasias , Neoplasias , Enfermedades Neurodegenerativas , Inhibidores de Proteínas Quinasas , Sitios de Unión , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/química , Quinasas Ciclina-Dependientes/metabolismo , Humanos , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/enzimología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Relación Estructura-Actividad
8.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33807722

RESUMEN

The liver is one of the most important organs, playing critical roles in maintaining biochemical homeostasis. Accordingly, disease of the liver is often debilitating and responsible for untold human misery. As biochemical nexus, with kinases being master regulators of cellular biochemistry, targeting kinase enzymes is an obvious avenue for treating liver disease. Development of such therapy, however, is hampered by the technical difficulty of obtaining comprehensive insight into hepatic kinase activity, a problem further compounded by the often unique aspects of hepatic kinase activities, which makes extrapolations from other systems difficult. This consideration prompted us to review the current state of the art with respect to kinome profiling approaches towards the hepatic kinome. We observe that currently four different approaches are available, all showing significant promise. Hence we postulate that insight into the hepatic kinome will quickly increase, leading to rational kinase-targeted therapy for different liver diseases.


Asunto(s)
Descubrimiento de Drogas , Hepatopatías , Análisis por Matrices de Proteínas , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Quinasas/metabolismo , Proteómica , Humanos , Hepatopatías/tratamiento farmacológico , Hepatopatías/enzimología
9.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33802643

RESUMEN

Patients with advanced head and neck squamous cell carcinoma (HNSCC) usually show a dismal prognosis. It is this worthwhile to develop new, effective therapeutic regimens for these patients, such as molecular targeted therapy, which is promising as an alternative or combination treatment for HNSCC. The mammalian target of rapamycin (mTOR) pathway, which plays an important role in the carcinogenesis of HNSCC, is the most frequently activated, and is thus worthy of further investigation. In this study, two human HNSCC cell lines, FaDu and SAS, were evaluated for cell growth with trypan blue staining and tumor growth using an orthotopic xenograft model. The immunohistochemical expression of mTOR in the subcutaneous xenograft model and the inhibitory effects of docetaxel on the growth and state of activation of the PI3K/mTOR pathway were also evaluated and examined by colony formation and Western blot, respectively. Cell proliferation and migration were measured by water-soluble tetrazolium salt (WST-1) and OrisTM cell migration assay, respectively. Furthermore, the effects of rapamycin and BEZ235, a phosphatidylinositol 3-kinases (PI3K) and mTOR inhibitor in combination with docetaxel or CCL20 were evaluated in the FaDu and SAS cells. The results showed that the expression of mTOR was significantly higher in the SAS and FaDu xenograft models than in the control. Docetaxel treatment significantly suppressed HNSCC cell proliferation and migration in vitro via the PI3K/mTOR/CCL-20 signaling pathway. Additionally, when administered in a dose-dependent fashion, mTOR inhibitors inhibited the growth and migration of the HNSCC cells. This combination was synergistic with docetaxel, resulting in almost complete cell growth and migration arrest. In conclusion, docetaxel significantly inhibited HNSCC cell proliferation and migration in vitro via the PI3K/mTOR/CCL-20 signaling pathway. The synergistic and additive activity of mTOR inhibitors combined with docetaxel shows potential as a new treatment strategy for HNSCC.


Asunto(s)
Quimiocina CCL20/metabolismo , Docetaxel/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/metabolismo , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Docetaxel/farmacología , Humanos , Ratones Desnudos , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33804174

RESUMEN

Systemic mastocytosis (SM) is a rare clonal hematologic neoplasm, driven, in almost all cases, by the activating KIT D816V mutation that leads to the growth and accumulation of neoplastic mast cells. While patients with advanced forms of SM have a poor prognosis, the introduction of KIT inhibitors (e.g., midostaurin, and avapritinib) has changed their outlook. Because of the heterogenous nature of advanced SM (advSM), successive iterations of response criteria have tried to capture different dimensions of the disease, including measures of mast cell burden (percentage of bone marrow mast cells and serum tryptase level), and mast cell-related organ damage (referred to as C findings). Historically, response criteria have been anchored to reversion of one or more organ damage finding(s) as a minimal criterion for response. This is a central principle of the Valent criteria, Mayo criteria, and International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria. Irrespective of the response criteria, an ever-present challenge is how to apply response criteria in patients with SM and an associated hematologic neoplasm, where the presence of both diseases complicates assignment of organ damage and adjudication of response. In the context of trials with the selective KIT D816V inhibitor avapritinib, pure pathologic response (PPR) criteria, which rely solely on measures of mast cell burden and exclude consideration of organ damage findings, are being explored as more robust surrogate of overall survival. In addition, the finding that avapritinib can elicit complete molecular responses of KIT D816V allele burden, establishes a new benchmark for advSM and motivates the inclusion of definitions for molecular response in future criteria. Herein, we also outline how the concept of PPR can inform a proposal for new response criteria which use a tiered evaluation of pathologic, molecular, and clinical responses.


Asunto(s)
Proliferación Celular/genética , Mastocitosis Sistémica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/genética , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Mastocitos/efectos de los fármacos , Mastocitos/patología , Mastocitosis Sistémica/genética , Mastocitosis Sistémica/patología , Pirazoles/uso terapéutico , Pirroles/uso terapéutico , Estaurosporina/análogos & derivados , Estaurosporina/uso terapéutico , Triazinas/uso terapéutico
11.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33805800

RESUMEN

Cyclin-dependent kinases (CDKs) are involved in many crucial processes, such as cell cycle and transcription, as well as communication, metabolism, and apoptosis. The kinases are organized in a pathway to ensure that, during cell division, each cell accurately replicates its DNA, and ensure its segregation equally between the two daughter cells. Deregulation of any of the stages of the cell cycle or transcription leads to apoptosis but, if uncorrected, can result in a series of diseases, such as cancer, neurodegenerative diseases (Alzheimer's or Parkinson's disease), and stroke. This review presents the current state of knowledge about the characteristics of cyclin-dependent kinases as potential pharmacological targets.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Ciclo Celular/genética , Quinasas Ciclina-Dependientes/genética , Neoplasias/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/enzimología , Cardiomegalia/genética , Cardiomegalia/patología , Fármacos Cardiovasculares/uso terapéutico , Ciclo Celular/efectos de los fármacos , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/metabolismo , Ciclinas/genética , Ciclinas/metabolismo , Regulación de la Expresión Génica , Humanos , Neoplasias/enzimología , Neoplasias/genética , Neoplasias/patología , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/enzimología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/enzimología , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/patología
12.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33807608

RESUMEN

Oncogenic kinases contribute to immunosuppression and modulate the tumor microenvironment in solid tumors. Increasing evidence supports the fundamental role of oncogenic kinase signaling networks in coordinating immunosuppressive tumor microenvironments. This has led to numerous studies examining the efficacy of kinase inhibitors in inducing anti-tumor immune responses by increasing tumor immunogenicity. Kinase inhibitors are the second most common FDA-approved group of drugs that are deployed for cancer treatment. With few exceptions, they inevitably lead to intrinsic and/or acquired resistance, particularly in patients with metastatic disease when used as a monotherapy. On the other hand, cancer immunotherapies, including immune checkpoint inhibitors, have revolutionized cancer treatment for malignancies such as melanoma and lung cancer. However, key hurdles remain to successfully incorporate such therapies in the treatment of other solid cancers. Here, we review the recent literature on oncogenic kinases that regulate tumor immunogenicity, immune suppression, and anti-tumor immunity. Furthermore, we discuss current efforts in clinical trials that combine kinase inhibitors and immune checkpoint inhibitors to treat breast cancer and other solid tumors.


Asunto(s)
/farmacología , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Humanos , Inmunoterapia/métodos , Neoplasias/inmunología , Neoplasias/terapia , Oncogenes/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos
13.
Zhonghua Xue Ye Xue Za Zhi ; 42(2): 101-108, 2021 Feb 14.
Artículo en Chino | MEDLINE | ID: mdl-33858039

RESUMEN

Objective: To explore the clinical characteristics, treatment patterns, and outcomes in newly diagnosed patients with chronic myeloid leukemia in the chronic phase (CML-CP) by age. Methods: Clinical data of consecutive ≥14 years old newly diagnosed CML-CP patients were retrospectively analyzed. Results: This study included 957 patients. Of the patients, 597 (62.4%) were male. The median age was 40 years (range, 14-83 years) . The patients were stratified into three age groups: <40 years (n=470; 49.1%) , 40-59 years (n=371; 38.8%) , and ≥60 years (n=116; 12.1%) . The proportions of the patients who had splenomegaly (P<0.001) , WBC ≥100 × 10(9)/L (P<0.001) , anemia (P<0.001) , PLT<450 × 10(9)/L (P=0.022) , more blasts in the blood (P=0.010) , and clonal chromosome abnormalities in Philadelphia chromosome-positive cells (P=0.006) at diagnosis significantly decreased with age. However, the proportions of those with comorbidities (P<0.001) , intermediate or high Sokal risk (P<0.001) , and receiving imatinib as front-line therapy (P<0.001) significantly increased with age. No significant differences in gender and the EUTOS Long-Term Survival risks were noted across the three age groups. The multivariate analysis showed that ≥60 years was an adverse predictor for overall survival. However, age was not significantly associated with tyrosine kinase inhibitor (TKI) therapy responses and other outcomes. The incidences of nonhematological toxicity were significantly increased with age during TKI therapy (P<0.001) . However, those of hematological toxicity was similar across the three age groups. The proportions of the patients maintaining imatinib therapy (P=0.026) and receiving low-dose TKI therapy (P<0.001) significantly increased with age at the end of follow-up. Conclusions: Significant differences exist in clinical characteristics, TKI response, overall survival rates, and nonhematological toxicity among newly diagnosed CML-CP patients of different ages.


Asunto(s)
Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Adolescente , Adulto , Antineoplásicos/uso terapéutico , Humanos , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos , Resultado del Tratamiento
14.
Zhonghua Zhong Liu Za Zhi ; 43(4): 405-413, 2021 Apr 23.
Artículo en Chino | MEDLINE | ID: mdl-33902203

RESUMEN

The introduction of cyclin-dependent kinase (CDK) 4/6 inhibitors has revolutionized the clinical management paradigm of hormone receptor (HR) positive/human epidermal growth factor receptor (HER) 2 negative breast cancer. As of today, CDK 4/6 inhibitors including Palbociclib, Ribociclib, and Abemaciclib have been widely approved by regulatory agencies. Randomized clinical trials demonstrated that CDK 4/6 inhibitors in combination with an aromatase inhibitor (AI) or fulvestrant in the first-, second- or later-line setting for HR positive/HER2 negative locally advanced or metastatic breast cancer led to substantial reduction in the risk of disease progression or death. Adverse effects of treatment were manageable and as or better than expected in terms of patient satisfaction. Considering CDK4/6 inhibitors in combination with endocrine therapy being a novel approach in China clinical practice, the panel developed the consensus comprehensively describing the pharmacology properties, monitoring strategy during treatment and adverse events management, to facilitate greater understanding in Chinese oncologists of a whole new therapeutic class of drug, promote accuracy of clinical decision and help reach the ultimate goal of improving survival and quality of life of the target patient population.


Asunto(s)
Neoplasias de la Mama , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , China , Consenso , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Calidad de Vida , Receptor ErbB-2
15.
Zhonghua Zhong Liu Za Zhi ; 43(4): 431-442, 2021 Apr 23.
Artículo en Chino | MEDLINE | ID: mdl-33902205

RESUMEN

With the progress of tumor molecular biology research, the clinical treatment concept of advanced breast cancer gradually tends to be accurate. Hormone receptor (HR) positive and human epidermal growth factor receptor 2 (HER-2) negative breast cancer accounts for more than 70% of all breast cancers, and it is of great significance to explore new treatment strategies to break through the bottleneck of traditional treatment faced by the patient population. Targeted therapy for this type of breast cancer started relatively late. After the first cyclin-dependent kinase (CDK) 4/6 inhibitor Palbociclib entered the clinical application for HR positive and HER-2 negative advanced breast cancer patients in 2015, the clinical treatment pattern of HR positive and HER-2 negative advanced breast cancer has been changed significantly, with a consequent breakthrough improvement in patients' survival prognosis. Based on the basic pharmacological mechanism, the author analyzes the existing research data and puts forward opinions on how to achieve precise medication in clinical practice and wider application prospects in the future.


Asunto(s)
Neoplasias de la Mama , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Hormonas/uso terapéutico , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor ErbB-2
16.
Int J Mol Sci ; 22(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669671

RESUMEN

Triple-negative breast cancer (TNBC) has a poor prognosis as the therapy has several limitations, most importantly, treatment resistance. In this study we examined the different responses of triple-negative breast cancer line MDA-MB-231 and hormone receptor-positive breast cancer line MCF7 to a combined treatment including olaparib, a poly-(ADP ribose) polymerase (PARP) inhibitor, oxaliplatin, a third-generation platinum compound and LY294002, an Akt pathway inhibitor. We applied the drugs in a single, therapeutically relevant concentration individually and in all possible combinations, and we assessed the viability, type of cell death, reactive oxygen species production, cell-cycle phases, colony formation and invasive growth. In agreement with the literature, the MDA-MB-231 cells were more treatment resistant than the MCF7 cells. However, and in contrast with the findings of others, we detected no synergistic effect between olaparib and oxaliplatin, and we found that the Akt pathway inhibitor augmented the cytostatic properties of the platinum compound and/or prevented the cytoprotective effects of PARP inhibition. Our results suggest that, at therapeutically relevant concentrations, the cytotoxicity of the platinum compound dominated over that of the PARP inhibitor and the PI3K inhibitor, even though a regression-based model could have indicated an overall synergy at lower and/or higher concentrations.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cromonas/uso terapéutico , Morfolinas/uso terapéutico , Oxaliplatino/uso terapéutico , Ftalazinas/uso terapéutico , Piperazinas/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Invasividad Neoplásica , Oxaliplatino/farmacología , Ftalazinas/farmacología , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Ensayo de Tumor de Célula Madre
17.
Nat Commun ; 12(1): 1780, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741979

RESUMEN

Advanced non-small-cell lung cancer (NSCLC) patients with EGFR T790M-positive tumours benefit from osimertinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). Here we show that the size of the EGFR T790M-positive clone impacts response to osimertinib. T790M subclonality, as assessed by a retrospective NGS analysis of 289 baseline plasma ctDNA samples from T790M-positive advanced NSCLC patients from the AURA3 phase III trial, is associated with shorter progression-free survival (PFS), both in the osimertinib and the chemotherapy-treated patients. Both baseline and longitudinal ctDNA profiling indicate that the T790M subclonal tumours are enriched for PIK3CA alterations, which we demonstrate to confer resistance to osimertinib in vitro that can be partially reversed by PI3K pathway inhibitors. Overall, our results elucidate the impact of tumour heterogeneity on response to osimertinib in advanced stage NSCLC patients and could help define appropriate combination therapies in these patients.


Asunto(s)
Acrilamidas/uso terapéutico , Compuestos de Anilina/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Mutación Missense , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , ADN Tumoral Circulante/análisis , ADN Tumoral Circulante/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Receptores ErbB/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos
18.
Medicine (Baltimore) ; 100(8): e24917, 2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33663128

RESUMEN

RATIONALE: Patients with lung adenocarcinoma harboring EML4-ALK rearrangements respond well to multiple ALK tyrosine kinase inhibitors (TKIs). However, the tumor will invariably progress due to acquired resistance. Comprehensive genomic profiling appears to be a promising strategy to reveal the underlying molecular mechanisms of ALK-TKIs resistance. PATIENT CONCERNS: A patient with right lung adenocarcinoma harboring an ALK rearrangement received targeted therapy with multiple ALK-TKIs. He sought for follow-up treatment after his disease progressed again. DIAGNOSIS: The patient had a tumor diagnosed with stage I (T1bN0M0) lung adenocarcinoma. INTERVENTIONS: Due to the surgical contraindication, the patient did not undergo surgical resection. Instead, he received crizotinib as the first-line therapy with the progression-free survival of 20 months. Then he switched to alectinib treatment, however the disease rapidly progressed again. OUTCOMES: Next-generation sequencing was performed and revealed that 7 somatic mutations were identified. Among them, 2 mutations, ALK I1171T and BRAF V600E, may be responsible for the resistance of this patient to ALK-TKIs. BRAF V600E mutation may explain the patient's resistance to lorlatinib. LESSONS: We present a case of ALK-rearranged lung adenocarcinoma with acquired resistance to ALK inhibition, in which the BRAF V600E mutation is a novel resistance mechanism. This provides evidence that BRAF V600E mutation is one mechanism of ALK-TKI resistance.


Asunto(s)
Adenocarcinoma del Pulmón/genética , Neoplasias Óseas/secundario , Neoplasias Pulmonares/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Quinasa de Linfoma Anaplásico/efectos de los fármacos , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/genética , Proteínas de Ciclo Celular , Crizotinib/farmacología , Crizotinib/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Resultado Fatal , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Proteínas Asociadas a Microtúbulos , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Serina Endopeptidasas
19.
Crit Rev Oncol Hematol ; 160: 103300, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33744362

RESUMEN

Since their discovery, relevant efforts have been made to optimize the detection approaches to EGFR mutations as well as the clinical management of EGFR-mutated NSCLC. The recent shift from single gene testing to novel comprehensive detection platforms along with the development of new generation tyrosine kinase inhibitors, targeting both common and uncommon EGFR-mutations, is leading to a progressive increase in the number of patients who may benefit from targeted approaches, with subsequent impact on their long-term survival and quality of life. However, a prompt and adequate implementation of the most recent diagnostic and treatment advances in the routine practice often remains critical to be specifically addressed. In this review we provide a complete and updated overview of the different detection platforms and therapeutic options currently available for the clinical management of advanced EGFR-positive NSCLC, summarizing scientific evidence and describing molecular testing as well as treatment practice in the real-word scenario.


Asunto(s)
Neoplasias Pulmonares , Calidad de Vida , Receptores ErbB/genética , Humanos , Italia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico
20.
Am J Nurs ; 121(4): 23-24, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33755621

RESUMEN

A new adjuvant treatment, osimertinib (Tagrisso), has been approved for patients with non-small cell lung cancer whose tumors have certain mutations.The most common adverse effects of treatment are leukopenia, lymphopenia, thrombocytopenia, diarrhea, anemia, rash, musculoskeletal pain, nail toxicity, neutropenia, dry skin, stomatitis, fatigue, and cough.


Asunto(s)
Acrilamidas/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad
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