RESUMEN
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that has been implicated in numerous oncogenic processes. GSK-3 inhibitor elraglusib (9-ING-41) has shown promising preclinical and clinical antitumor activity across multiple tumor types. Despite promising early-phase clinical trial results, there have been limited efforts to characterize the potential immunomodulatory properties of elraglusib. We report that elraglusib promotes immune cell-mediated tumor cell killing of microsatellite stable colorectal cancer (CRC) cells. Mechanistically, elraglusib sensitized CRC cells to immune-mediated cytotoxicity and enhanced immune cell effector function. Using western blots, we found that elraglusib decreased CRC cell expression of NF-κB p65 and several survival proteins. Using microarrays, we discovered that elraglusib upregulated the expression of proapoptotic and antiproliferative genes and downregulated the expression of cell proliferation, cell cycle progression, metastasis, TGFß signaling, and anti-apoptotic genes in CRC cells. Elraglusib reduced CRC cell production of immunosuppressive molecules such as VEGF, GDF-15, and sPD-L1. Elraglusib increased immune cell IFN-γ secretion, which upregulated CRC cell gasdermin B expression to potentially enhance pyroptosis. Elraglusib enhanced immune effector function resulting in augmented granzyme B, IFN-γ, TNF-α, and TRAIL production. Using a syngeneic, immunocompetent murine model of microsatellite stable CRC, we evaluated elraglusib as a single agent or combined with immune checkpoint blockade (anti-PD-1/L1) and observed improved survival in the elraglusib and anti-PD-L1 group. Murine responders had increased tumor-infiltrating T cells, augmented granzyme B expression, and fewer regulatory T cells. Murine responders had reduced immunosuppressive (VEGF, VEGFR2) and elevated immunostimulatory (GM-CSF, IL-12p70) cytokine plasma concentrations. To determine the clinical significance, we then utilized elraglusib-treated patient plasma samples and found that reduced VEGF and BAFF and elevated IL-1 beta, CCL22, and CCL4 concentrations correlated with improved survival. Using paired tumor biopsies, we found that tumor-infiltrating immune cells had a reduced expression of inhibitory immune checkpoints (VISTA, PD-1, PD-L2) and an elevated expression of T-cell activation markers (CTLA-4, OX40L) after elraglusib treatment. These results address a significant gap in knowledge concerning the immunomodulatory mechanisms of GSK-3 inhibitor elraglusib, provide a rationale for the clinical evaluation of elraglusib in combination with immune checkpoint blockade, and are expected to have an impact on additional tumor types, besides CRC.
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Neoplasias Colorrectales , Glucógeno Sintasa Quinasa 3 , Humanos , Animales , Ratones , Glucógeno Sintasa Quinasa 3/metabolismo , Granzimas/genética , Granzimas/metabolismo , Modelos Animales de Enfermedad , Inhibidores de Puntos de Control Inmunológico/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Neoplasias Colorrectales/metabolismo , Linfocitos Infiltrantes de Tumor , Biopsia , Línea Celular Tumoral , Antígeno B7-H1RESUMEN
BACKGROUND: Tissue tumor mutational burden (TMB) has emerged as a potential biomarker predicting response to anti-programmed cell death-1 protein receptor (PD-1)/programmed cell death-1 protein ligand (PD-L1) therapy, but few studies have explored using circulating tumor DNA (ctDNA) TMB in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A total of 136 patients with NSCLC with ctDNA testing were retrospectively evaluated from a single institution, along with a validation cohort from a second institution. ctDNA TMB was derived using the number of detected mutations over the DNA sequencing length. RESULTS: Higher ctDNA TMB was significantly correlated with smoking history (p < .05, chi-squared test). Among patients treated with immune checkpoint inhibitors (n = 20), higher ctDNA TMB was significantly correlated with shorter progressive free survival (PFS) and overall survival (OS; 45 vs. 355 days; hazard ratio [HR], 5.6; 95% confidence interval [CI], 1.3-24.6; p < .01, and OS 106 days vs. not reached; HR, 6.0; 95% CI, 1.3-27.1; p < .01, respectively). In a small independent validation cohort (n = 12), there was a nonsignificant numerical difference for higher ctDNA TMB predicting shorter OS but not PFS. ctDNA TMB was not correlated with RECIST tumor burden estimation in the subset of patients treated with immune checkpoint blockade. CONCLUSION: The findings indicate that higher ctDNA TMB, at the current commercial sequencing length, reflects worse clinical outcomes. IMPLICATIONS FOR PRACTICE: Biomarkers to identify patients who will respond to immune checkpoint blockade are critical. Tissue tumor mutational burden (TMB) has emerged as a viable biomarker to predict response to anti-PD-1/PD-L1 therapy, but few studies have explored the meaning and potential clinical significance of noninvasive, blood-based TMB. Here, we investigated circulating tumor DNA (ctDNA) TMB and present data demonstrating that current ctDNA TMB may reflect tumor burden and that ctDNA panels with a greater number of mutations may be necessary to more accurately reflect tissue TMB.
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Antineoplásicos Inmunológicos/uso terapéutico , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , ADN Tumoral Circulante/genética , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , ADN Tumoral Circulante/sangre , Resistencia a Antineoplásicos/genética , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Tasa de Mutación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Supervivencia sin Progresión , Criterios de Evaluación de Respuesta en Tumores Sólidos , Estudios Retrospectivos , Carga TumoralRESUMEN
The emergence of immunotherapy has revolutionized cancer treatment in recent years. Inhibitors of immune checkpoints, including antibodies against cytotoxic T-lymphocyte-associated protein 4, programmed cell death protein 1, and programmed death ligand 1, have demonstrated notable efficacy in certain advanced cancers. Unfortunately, many patients do not benefit from these therapies and either exhibit primary resistance to treatment or develop acquired mechanisms of resistance after initially responding to therapy. Here, we review the genomic and immune traits that may promote resistance to T-cell-mediated immunotherapy, with a focus on identifying potential biomarkers that could eventually be used in the clinical setting to guide treatment selection. We summarize the clinical evidence for these markers and discuss how current understanding of resistance mechanisms can inform future studies and aid clinical decision-making in order to derive maximum benefit from immunotherapy. IMPLICATIONS FOR PRACTICE: Immunotherapy has rapidly progressed as a treatment modality for multiple cancers, but it is still unclear which patients are likely to benefit from these therapies. Studies of resistance mechanisms have only recently started to identify biomarkers that can help predict patient outcomes. This review summarizes the available clinical data in regard to immunotherapy resistance, with a focus on molecular biomarkers that may be useful in guiding clinical decision-making. It discusses possible applications of these biomarkers and highlights opportunities for further clinical discovery.
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Antineoplásicos Inmunológicos/uso terapéutico , Biomarcadores , Resistencia a Antineoplásicos , Inmunoterapia , Neoplasias/terapia , Linfocitos T/inmunología , Antineoplásicos Inmunológicos/farmacología , Biomarcadores/metabolismo , Resistencia a Antineoplásicos/genética , Humanos , Neoplasias/inmunología , Transducción de Señal , Escape del Tumor , Microambiente TumoralRESUMEN
Mitogen-activated protein kinase interacting protein kinases (Mnks) play important roles in the development and progression of acute myeloid leukemia (AML) by regulating eukaryotic translation initiation factor 4E (eIF4E) activation. Inhibiting Mnk1/2-induced phosphorylation of eIF4E may represent a unique approach for the treatment of AML. We provide evidence for antileukemic effects of merestinib, an orally bioavailable multikinase inhibitor with suppressive effects on Mnk activity. Our studies show that merestinib effectively blocks eIF4E phosphorylation in AML cells and suppresses primitive leukemic progenitors from AML patients in vitro and in an AML xenograft model in vivo. Our findings provide evidence for potent preclinical antileukemic properties of merestinib and support its clinical development for the treatment of patients with AML.
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Adenosina Trifosfatasas/antagonistas & inhibidores , Proteínas de Transporte de Catión/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteínas de Neoplasias/antagonistas & inhibidores , Adenosina Trifosfatasas/metabolismo , Animales , Proteínas de Transporte de Catión/metabolismo , Línea Celular Tumoral , ATPasas Transportadoras de Cobre , Factor 4E Eucariótico de Iniciación/metabolismo , Humanos , Leucemia Mieloide Aguda/enzimología , Ratones , Proteínas de Neoplasias/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Lung cancer is the leading cause of cancer death worldwide. In up to 57% of patients, it is diagnosed at an advanced stage and the 5-year survival rate ranges between 10%-16%. There has been a significant amount of research using machine learning to generate tools using patient data to improve outcomes. METHODS: This narrative review is based on research material obtained from PubMed up to Nov 2017. The search terms include "artificial intelligence," "machine learning," "lung cancer," "Nonsmall Cell Lung Cancer (NSCLC)," "diagnosis" and "treatment." RESULTS: Recent studies support the use of computer-aided systems and the use of radiomic features to help diagnose lung cancer earlier. Other studies have looked at machine learning (ML) methods that offer prognostic tools to doctors and help them in choosing personalized treatment options for their patients based on molecular, genetics and histological features. Combining artificial intelligence approaches into health care may serve as a beneficial tool for patients with NSCLC, and this review outlines these benefits and current shortcomings throughout the continuum of care. CONCLUSION: We present a review of the various applications of ML methods in NSCLC as it relates to improving diagnosis, treatment and outcomes.
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Inteligencia Artificial , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Predicción , Genoma Humano , Humanos , Inmunoterapia/métodos , Neoplasias Pulmonares/diagnóstico , Aprendizaje Automático , Medicina de Precisión/métodosRESUMEN
Advanced stage neuroblastoma is a very aggressive pediatric cancer with limited treatment options and a high mortality rate. Glycogen synthase kinase-3ß (GSK-3ß) is a potential therapeutic target in neuroblastoma. Using immunohistochemical staining, we observed positive GSK-3ß expression in 67% of human neuroblastomas (34 of 51 cases). Chemically distinct GSK-3 inhibitors (AR-A014418, TDZD-8, and 9-ING-41) suppressed the growth of neuroblastoma cells, whereas 9-ING-41, a clinically relevant small-molecule GSK-3ß inhibitor with broad-spectrum preclinical antitumor activity, being the most potent. Inhibition of GSK-3 resulted in a decreased expression of the antiapoptotic molecule XIAP and an increase in neuroblastoma cell apoptosis. Mouse xenograft studies showed that the combination of clinically relevant doses of CPT-11 and 9-ING-41 led to greater antitumor effect than was observed with either agent alone. These data support the inclusion of patients with advanced neuroblastoma in clinical studies of 9-ING-41, especially in combination with CPT-11.
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Inhibidores Enzimáticos/farmacología , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Indoles/farmacología , Maleimidas/farmacología , Neuroblastoma/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Sinergismo Farmacológico , Femenino , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Indoles/administración & dosificación , Irinotecán/administración & dosificación , Irinotecán/farmacología , Maleimidas/administración & dosificación , Ratones , Ratones Desnudos , Neuroblastoma/enzimología , Neuroblastoma/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Major technologic advances in genomics have made possible the identification of critical genetic alterations in cancer, which has led to a rapid paradigm shift in what is now considered personalized cancer treatment. This exponential growth in the understanding of cancer genomics is reshaping the drug development process, from drug discovery to novel designs of clinical trials. It is also exposing the critical importance of rigorous validation of molecular diagnostics platforms, such as the use of whole-exome sequencing and patient-derived xenografts, which may eventually be utilized to guide treatment decisions and may ultimately enable the true practice of personalized oncology. This review describes the achievements in therapeutic and molecular diagnostics, details evolving molecular platforms, and highlights the challenges for the translation of these developments to daily clinical practice.
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Neoplasias/genética , Medicina de Precisión , Biología Computacional , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias/diagnóstico , Neoplasias/terapia , Microambiente TumoralRESUMEN
Harbored as relics of ancient germline infections, human endogenous retroviruses (HERVs) now constitute up to 8% of our genome. A proportion of this sequence has been co-opted for molecular and cellular processes, beneficial to human physiology, such as the fusogenic activity of the envelope protein, a vital component of placentogenesis. However, the discovery of high levels of HERV-K mRNA and protein and even virions in a wide array of cancers has revealed that HERV-K may be playing a more sinister role-a role as an etiological agent in cancer itself. Whether the presence of this retroviral material is simply an epiphenomenon, or an actual causative factor, is a hotly debated topic. This review will summarize the current state of knowledge regarding HERV-K and cancer and attempt to outline the potential mechanisms by which HERV-K could be involved in the onset and promotion of carcinogenesis.
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Carcinogénesis/genética , Neoplasias/genética , Neoplasias/virología , Retroviridae/genética , Animales , Humanos , Neoplasias/etiología , ARN Mensajero/genética , ARN Viral/genéticaRESUMEN
This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m(2) , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed.
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Ciclopentanos , Inhibidores Enzimáticos , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Pirimidinas , Enzimas Activadoras de Ubiquitina/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Ciclopentanos/administración & dosificación , Ciclopentanos/efectos adversos , Ciclopentanos/farmacocinética , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Femenino , Humanos , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Insuficiencia Multiorgánica/sangre , Insuficiencia Multiorgánica/inducido químicamente , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/tratamiento farmacológico , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Pirimidinas/farmacocinéticaRESUMEN
BACKGROUND: Acute lymphoblastic leukemia (ALL) is a potentially fatal disease that involves clonal expansion of early lymphoid progenitor cells. Much of drug development for ALL treatment involves targeting antigens of the clonal cell surface. Blinatumomab belongs to an emerging class of anti-cancer therapeutics referred to as bispecific T-cell engaging antibodies. The Food and Drug Administration approved its use in relapsed or refractory adult Philadelphia chromosome-negative B-cell precursor ALL in December of 2014. MECHANISM OF ACTION AND PHARMACODYNAMICS: Blinatumomab contains both an anti-CD3 and anti-CD19 arm, allowing for the juxtaposition of CD3+ T-cells to malignant CD19+ B-cells, thereby resulting in granzyme- and perforin-mediated B-cell apoptosis. PRECLINICAL PHARMACOLOGY: Preclinical studies suggest that blinatumomab's efficacy is related to the effector-to-target ratio and to the difference between its affinity for CD19 and CD3. PHARMACOKINETICS AND METABOLISM: Preclinical and early phase clinical studies have allowed for the characterization of the pharmacokinetics of blinatumomab, including the determination of its short half-life. The metabolic pathway has not been fully characterized but is thought to be similar to that of other antibodies. CLINICAL STUDIES: Phase I and II studies led to the identification of an ideal stepwise dose, involving long-term continuous intravenous infusion (CIVI), to optimize its efficacy and reduce the risk of certain toxicities. A high remission rate and duration were noted among a relapsed/refractory population of patients. SAFETY: The results of clinical trials have identified cytokine release syndrome and neurotoxicity, among others, as serious drug-related toxicities, leading to the institution of a Risk Evaluation and Mitigation Strategy. DISCUSSION AND CONCLUSIONS: Blinatumomab represents a significant addition to the treatment options for ALL, but it is not without its limitations, of which are its short-half life, necessitating long-term CIVI, and the eventual emergence of CD19-negative clones. Continual development of the agent involves assessing its role in the frontline setting and in combination with chemotherapy.
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Anticuerpos Biespecíficos/uso terapéutico , Antineoplásicos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Animales , Ensayos Clínicos como Asunto/métodos , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologíaRESUMEN
High-density lipoproteins (HDL) are diverse natural nanoparticles that carry cholesterol and are best known for the role that they play in cardiovascular disease. However, due to their unique targeting capabilities, diverse molecular cargo, and natural functions beyond cholesterol transport, it is becoming increasingly appreciated that HDLs are critical to cancer development and progression. Accordingly, this chapter highlights ongoing research focused on the connections between HDL and cancer in order to design new drugs and targeted drug delivery vehicles. Research is focused on synthesizing biomimetic HDL-like nanoparticles (NP) that can be loaded with diverse therapeutic cargo (e.g., chemotherapies, nucleic acids, proteins) and specifically targeted to cancer cells. Beyond drug delivery, new data is emerging that HDL-like NPs may be therapeutically active in certain tumor types, for example, B cell lymphoma. Overall, HDL-like NPs are becoming increasingly appreciated as targeted, biocompatible, and efficient therapies for cancer, and may soon become indispensable agents in the cancer therapeutic armamentarium.
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Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Lipoproteínas HDL/uso terapéutico , Nanoconjugados/uso terapéutico , Nanomedicina/métodos , Neoplasias/tratamiento farmacológico , Animales , Humanos , Lipoproteínas HDL/químicaRESUMEN
PURPOSE OF REVIEW: Although frontline treatment of acute myeloid leukemia (AML) achieves high remission rates, approximately 75-80% of patients will either not respond to or relapse after initial therapy. Some patients, generally those who are younger, can be successfully salvaged with second-line chemotherapy followed by allogeneic stem cell transplantation. There is a great need for novel therapies in AML. RECENT FINDINGS: Advances in molecular technology recently identified recurrent mutations including mutations of DNMT3A, IDH1/2, and TET2. These mutations represent a major advance in the understanding of leukemogenesis and prognosis, and have enabled the development of targeted therapies. SUMMARY: Improved knowledge of the molecular pathogenesis of AML has allowed development of therapies targeting epigenetic modulation, intracellular signaling pathways, prosurvival proteins, and the tumor microenvironment.
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Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Epigénesis Genética/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Recurrencia Local de Neoplasia , Transducción de Señal/efectos de los fármacos , Investigación Biomédica Traslacional , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genéticaRESUMEN
Aberrant expression of subgroup k human endogenous retroviruses (HERV-K) has been observed in prostate cancer. This subgroup is unique because it encodes sequences in the human genome containing open reading frames for near intact retroviruses. We hypothesized that HERV-K reactivation could serve as a non-invasive early disease detection marker for prostate cancer. We evaluated HERV-K gag messenger RNA (mRNA) expression in blood samples of African-American and European-American men using a case-control design via quantitative real-time PCR. Additionally, we examined HERV-K envelope protein expression in prostate tumors by immunohistochemistry. HERV-K envelope protein was commonly upregulated in prostate tumors, but more so in tumors of African-American than European-American patients (61% versus 40%, P < 0.01). Examining HERV-K gag expression in peripheral blood mononuclear cells (PBMC) from 294 cases and 135 healthy men, we found that the abundance of HERV-K gag message was significantly higher in cases than controls and was associated with increased plasma interferon-γ. Men with gag expression in the highest quartile had >12-fold increased odds {odds ratio = 12.87 [95% confidence interval 6.3-26.25]} of being diagnosed with prostate cancer than those in the lowest quartile. Moreover, our results showed that HERV-K expression may perform better as a disease biomarker in older than younger men (whereas the sensitivity of prostate-specific antigen (PSA) testing decreases with age) and in men with a smoking history compared with never smokers. Combining non-invasive HERV-K testing with PSA testing may improve the efficacy of prostate cancer detection specifically among older men and smokers who tend to develop a more aggressive disease.
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Adenocarcinoma/sangre , Productos del Gen gag/sangre , Leucocitos Mononucleares/metabolismo , Neoplasias de la Próstata/sangre , Fumar/sangre , Adenocarcinoma/diagnóstico , Adenocarcinoma/virología , Quimiocina CXCL10/sangre , Retrovirus Endógenos/enzimología , Expresión Génica , Humanos , Interferón gamma/sangre , Leucocitos Mononucleares/virología , Masculino , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/virología , ARN Mensajero/sangre , ARN Mensajero/genética , Factores de RiesgoRESUMEN
Anisomycin was identified in a screen of clinical compounds as a drug that kills breast cancer cells (MDA16 cells, derived from the triple negative breast cancer cell line, MDA-MB-468) that express high levels of an efflux pump, ABCB1. We show the MDA16 cells died by a caspase-independent mechanism, while MDA-MB-468 cells died by apoptosis. There was no correlation between cell death and either protein synthesis or JNK activation, which had previously been implicated in anisomycin-induced cell death. In addition, anisomycin analogues that did not inhibit protein synthesis or activate JNK retained the ability to induce cell death. These data suggest that either a ribosome-ANS complex is a death signal in the absence of JNK activation or ANS kills cells by binding to an as yet unidentified target.
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Anisomicina/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , MAP Quinasa Quinasa 4/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/farmacología , Anisomicina/análogos & derivados , Línea Celular Tumoral , Activación Enzimática/efectos de los fármacos , HumanosRESUMEN
Acute leukaemias are a group of malignancies characterised by the invasion of the bone marrow by immature haematopoietic precursors and differentiation arrest at various maturation steps. Multiplicity of intrinsic and extrinsic factors influences the transformation and progression of leukaemia. The intrinsic factors encompass genetic alterations of cellular pathways leading to the activation of, among others, inflammatory pathways (such as nuclear factor kappa B). The extrinsic components include, among others, the inflammatory pathways activated by the bone marrow microenvironment and include chemokines, cytokines and adhesion molecules. In this chapter, we review the role of inflammatory processes in the transformation, survival and proliferation of leukaemias, particularly the role of nuclear factor kappa B and its downstream signalling in leukaemias and the novel therapeutic strategies that exploit potentially unique properties of inflammatory signalling that offer interesting options for future therapeutic interventions.
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Inflamación/complicaciones , Leucemia/etiología , Animales , Antiinflamatorios/uso terapéutico , Citocinas/fisiología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/inmunología , Mediadores de Inflamación/fisiología , Leucemia/patología , Leucemia/terapia , Macrófagos/patología , Macrófagos/fisiología , Transducción de Señal/fisiologíaRESUMEN
In the phase 4 BYOND trial, patients with pretreated chronic myeloid leukemia (CML) received bosutinib (starting dose: 500 mg/day). Efficacy and safety after ≥3 years of follow-up in 156 patients with Philadelphia chromosome-positive chronic phase CML by age and Charlson Comorbidity Index scores (without the age component; mCCI) is reported. Cumulative major molecular response rates at any time on treatment were 73.6%, 64.5%, and 74.1% in patients <65, 65-74, and ≥75 years of age, and 77.9%, 63.0%, and 59.3% in patients with mCCI scores 2, 3, and ≥4, respectively. Patients <65, 65-74, and ≥75 years of age experienced grade 3/4 treatment-emergent adverse events (TEAEs) at rates of 74.7%, 78.8%, and 96.4% and permanent discontinuations due to AEs at rates of 22.1%, 39.4%, and 46.4%, respectively. In patients with mCCI 2, 3, and ≥4, respective rates of grade 3/4 TEAEs were 77.8%, 77.8%, and 86.7%, and permanent discontinuations due to AEs were 25.3%, 33.3%, and 43.3%. In conclusion, a substantial proportion of patients maintained/achieved cytogenetic and molecular responses across age groups and mCCI scores. Older patients (≥75 years) and those with high comorbidity burden (mCCI ≥4) may require more careful monitoring due to the increased risk of TEAEs. Clinicaltrials.gov: NCT02228382.
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Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide de Fase Crónica , Quinolinas , Humanos , Anciano , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Nitrilos/efectos adversos , Quinolinas/efectos adversos , Comorbilidad , Antineoplásicos/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Resultado del TratamientoRESUMEN
PURPOSE: The safety, pharmacokinetics, and efficacy of elraglusib, a glycogen synthase kinase-3ß (GSK-3ß) small-molecule inhibitor, as monotherapy or combined with chemotherapy, in patients with relapsed or refractory solid tumors or hematologic malignancies was studied. PATIENTS AND METHODS: Elraglusib (intravenously twice weekly in 3-week cycles) monotherapy dose escalation was followed by dose escalation with eight chemotherapy regimens (gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, gemcitabine/nab-paclitaxel, paclitaxel/carboplatin, and pemetrexed/carboplatin) in patients previously exposed to the same chemotherapy. RESULTS: Patients received monotherapy (n = 67) or combination therapy (n = 171) elraglusib doses 1 to 15 mg/kg twice weekly. The initial recommended phase II dose (RP2D) of elraglusib was 15 mg/kg twice weekly and was defined, without dose-limiting toxicity observation, due to fluid volumes necessary for drug administration. The RP2D was subsequently reduced to 9.3 mg/kg once weekly to reduce elraglusib-associated central/peripheral vascular access catheter blockages. Other common elraglusib-related adverse events (AE) included transient visual changes and fatigue. Grade ≥3 treatment-emergent AEs occurred in 55.2% and 71.3% of patients on monotherapy and combination therapy, respectively. Part 1 monotherapy (n = 62) and part 2 combination (n = 138) patients were evaluable for response. In part 1, a patient with melanoma had a complete response, and a patient with acute T-cell leukemia/lymphoma had a partial response (PR). In part 2, seven PRs were observed, and the median progression-free survival and overall survival were 2.1 [95% confidence interval (CI), 2-2.6] and 6.9 (95% CI, 5.7-8.4) months, respectively. CONCLUSIONS: Elraglusib had a favorable toxicity profile as monotherapy and combined with chemotherapy and was associated with clinical benefit supporting further clinical evaluation in combination with chemotherapy.
Asunto(s)
Linfoma , Neoplasias , Humanos , Gemcitabina , Carboplatino , Glucógeno Sintasa Quinasa 3 beta , Neoplasias/patología , Linfoma/tratamiento farmacológico , Paclitaxel , Inhibidores de Proteínas Quinasas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Nitric oxide (NO) is a short-lived, pleiotropic molecule that affects numerous critical functions in the body. Presently, there are markedly conflicting findings in the literature regarding NO and its role in carcinogenesis and tumor progression. NO has been shown to have dichotomous effects on cellular proliferation, apoptosis, migration, invasion, angiogenesis and many other important processes in cancer biology. It has been shown to be both pro- and antitumorigenic, depending on the concentration and the tumor microenvironment in question. NO is generated by three isoforms of NO synthase (NOS) that are widely expressed and sometimes upregulated in human tumors. Due to its vast array of physiological functions, it presents a huge challenge to researchers to discover its true potential in cancer biology and consequently, its use in anticancer therapies. In this study, we review the current knowledge in this area, with an emphasis placed on NO modulation as an anticancer therapy, focusing on NO-donating drugs and NOS inhibitors.
Asunto(s)
Neoplasias/metabolismo , Óxido Nítrico/fisiología , Animales , Apoptosis , Proliferación Celular , Progresión de la Enfermedad , Epigénesis Genética , Transición Epitelial-Mesenquimal , Humanos , Terapia Molecular Dirigida , Neoplasias/patología , Neoplasias/terapia , Neovascularización Patológica/metabolismo , Óxido Nítrico Sintasa/metabolismo , Tolerancia a RadiaciónRESUMEN
Nilotinib has significant efficacy in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) and in patients with CML-CP or CML in accelerated phase (CML-AP) after imatinib failure. We investigated the occurrence of cross-intolerance to nilotinib in imatinib-intolerant patients with CML. Only 1/75 (1%) patients with nonhematologic imatinib intolerance experienced a similar grade 3/4 adverse event (AE), and 3/75 (4%) experienced a similar persistent grade 2 nonhematologic AE on nilotinib. Only 7/40 (18%) patients with hematologic imatinib intolerance discontinued nilotinib, all because of grade 3/4 thrombocytopenia. Ninety percent of imatinib-intolerant patients with CML-CP who did not have complete hematologic response (CHR) at baseline (n = 52) achieved CHR on nilotinib. Nilotinib induced a major cytogenetic response in 66% and 41% of patients with imatinib-intolerant CML-CP and CML-AP (complete cytogenetic response in 51% and 30%), respectively. Minimal cross-intolerance was confirmed in patients with imatinib-intolerant CML. The favorable tolerability of nilotinib in patients with imatinib intolerance leads to alleviation of AE-related symptoms and significant and durable responses. In addition to its established clinical benefit in patients with newly diagnosed CML and those resistant to imatinib, nilotinib is effective and well-tolerated for long-term use in patients with imatinib intolerance. This study is registered at http://www.clinicaltrials.gov as NCT00471497.
Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Mieloide de Fase Acelerada/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Piperazinas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Benzamidas , Femenino , Humanos , Mesilato de Imatinib , Leucemia Mieloide de Fase Acelerada/patología , Leucemia Mieloide de Fase Crónica/patología , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Nilotinib is a potent selective inhibitor of the BCR-ABL tyrosine kinase approved for use in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP), and in CML-CP and CML-accelerated phase after imatinib failure. Nilotinib (400 mg twice daily) was approved on the basis of the initial results of this phase 2 open-label study. The primary study endpoint was the proportion of patients achieving major cytogenetic response (CyR). All patients were followed for ≥ 24 months or discontinued early. Of 321 patients, 124 (39%) continue on nilotinib treatment. Overall, 59% of patients achieved major CyR; this was complete CyR (CCyR) in 44%. Of patients achieving CCyR, 56% achieved major molecular response. CyRs were durable, with 84% of patients who achieved CCyR maintaining response at 24 months. The overall survival at 24 months was 87%. Adverse events were mostly mild to moderate, generally transient, and easily managed. This study indicates that nilotinib is effective, with a manageable safety profile, and can provide favorable long-term benefits for patients with CML-CP after imatinib failure.