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PURPOSE OF REVIEW: This review seeks to identify and describe novel genetic and protein targets and their associated therapeutics currently being used or studied in the treatment of acute myeloid leukemia (AML). RECENT FINDINGS: Over the course of the last 5-6 years, several targeted therapies have been approved by the FDA, for the treatment of both newly diagnosed as well as relapsed/refractory AML. These novel therapeutics, as well as several others currently under investigation, have demonstrated activity in AML and have improved outcomes for many patients. Patient outcomes in AML have slowly improved over time, though for many patients, particularly elderly patients or those with relapsed/refractory disease, mortality remains very high. With the identification of several molecular/genetic drivers and protein targets and development of therapeutics which leverage those mechanisms to target leukemic cells, outcomes for patients with AML have improved and continue to improve significantly.
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Leucemia Mieloide Aguda , Humanos , Anciano , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genéticaRESUMEN
In recent years, immunotherapy strategies based on immune checkpoint inhibitors have yielded good efficacy in colorectal cancer (CRC)especially in colorectal cancer with microsatellite instability-high. However, microsatellite-stable (MSS) CRCs account for about 85% of CRCs and are resistant to immunotherapy. Previous studies have shown that compared with MSS CRC, high microsatellite instability CRC possesses a higher frequency of mutations and can generate more neoantigens. Therefore, improving the sensitivity of immunotherapy to MSS CRC is a hot topic which is crucial for the treatment of MSS CRC. This review aims to discuss the factors contributing to MSS CRC insensitivity to immunotherapy and explored potential solutions to overcome immunotherapy resistance.
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Neoplasias Colorrectales , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Inestabilidad de Microsatélites , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/inmunología , Inmunoterapia/métodos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Resistencia a Antineoplásicos/genética , MutaciónRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a notably poor prognosis, in urgent need of improved treatment strategies. The desmoplastic PDAC tumor microenvironment (TME), marked by a high concentration of cancer-associated-fibroblasts (CAFs), is a dynamic part of PDAC pathophysiology which occasions a variety of effects throughout the course of pancreatic tumorigenesis and disease evolution. A better understanding of the desmoplastic TME and CAF biology in particular, should provide new opportunities for improving therapeutics. That CAFs have a tumor-supportive role in oncogenesis is well known, yet research evidence has shown that CAFs also have tumor-repressive functions. In this review, we seek to clarify the intriguing heterogeneity and plasticity of CAFs and their ambivalent role in PDAC tumorigenesis and progression. Additionally, we provide recommendations to advance the implementation of CAF-directed PDAC care. An improved understanding of CAFs' origins, spatial location, functional diversity, and marker determination, as well as CAF behavior during the course of PDAC progression and metastasis will provide essential knowledge for the future improvement of therapeutic strategies for patients suffering from PDAC.
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Fibroblastos Asociados al Cáncer , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Fibroblastos Asociados al Cáncer/patología , Carcinogénesis/patología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Microambiente Tumoral/genética , Neoplasias PancreáticasRESUMEN
Modern medicine continues to evolve, and the treatment armamentarium for various diseases grows more individualized across a breadth of medical disciplines. Cure rates for infectious diseases that were previously pan-fatal approach 100% because of the identification of the specific pathogen(s) involved and the use of appropriate combinations of drugs, where needed, to completely extinguish infection and hence prevent emergence of resistant strains. Similarly, with the assistance of technologies such as next-generation sequencing and immunomic analysis as part of the contemporary oncology armory, therapies can be tailored to each tumor. Importantly, molecular interrogation has revealed that metastatic cancers are distinct from each other and complex. Therefore, it is conceivable that rational personalized drug combinations will be needed to eradicate cancers, and eradication will be necessary to mitigate clonal evolution and resistance.
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Hydra , Neoplasias , Animales , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Oncología MédicaRESUMEN
PURPOSE OF REVIEW: The AXL signaling pathway is associated with tumor growth as well as poor prognosis in cancer. Here, we highlight recent strategies for targeting AXL in the treatment of solid and hematological malignancies. RECENT FINDINGS: AXL is a key player in survival, metastasis, and therapeutic resistance in many cancers. A range of AXL-targeted therapies, including tyrosine kinase inhibitors, monoclonal antibodies, antibody-drug conjugates, and soluble receptors, have entered clinical development. Notably, AXL inhibitors in combination with immune checkpoint inhibitors demonstrate early promise; however, further understanding of predictive biomarkers and treatment sequencing is necessary. Based on its role in tumor growth and drug resistance, AXL represents a promising therapeutic target in oncology. Results from ongoing clinical trials will provide valuable insights into the role of AXL inhibitors, both as single agents and in combination with other therapies.
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Tirosina Quinasa del Receptor Axl , Neoplasias , Humanos , Proteínas Tirosina Quinasas Receptoras , Proteínas Proto-Oncogénicas/uso terapéutico , Transducción de Señal , Neoplasias/tratamiento farmacológicoRESUMEN
OPINION STATEMENT: In 2023, breast cancer brain metastases (BCBrM) remain a major clinical challenge gaining well-deserved attention. Historically managed with local therapies alone, systemic therapies including small molecule inhibitors and antibody-drug conjugates (ADCs) have shown unprecedented activity in recent trials including patients with brain metastases. These advancements stem from efforts to include patients with stable and active BCBrM in early- and late-phase trial design. Tucatinib added to trastuzumab and capecitabine improves intracranial and extracranial progression-free survival and overall survival in stable and active human epidermal growth factor receptor 2 (HER2+)-positive brain metastases. Trastuzumab deruxtecan (T-DXd) has both shown impressive intracranial activity in stable and active HER2+ BCBrMs challenging historical thinking of ADCs' inability to penetrate the central nervous system (CNS). T-DXd has shown potent activity in HER2-low (immunohistochemistry scores of 1+ or 2+, non-amplified by fluorescence in situ hybridization) metastatic breast cancer and will be studied in HER2-low BCBrM as well. Novel endocrine therapies including oral selective estrogen downregulators (SERDs) and complete estrogen receptor antagonists (CERANs) are being studied in hormone receptor-positive BCBrM clinical trials due to robust intracranial activity in preclinical models. Triple-negative breast cancer (TNBC) brain metastases continue to portend the worst prognosis of all subtypes. Clinical trials leading to the approval of immune checkpoint inhibitors have enrolled few BCBrM patients leading to a lack of understanding of immunotherapies contribution in this subgroup. Data surrounding the use of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in patients with germline BRCA mutation carriers with CNS disease is hopeful. ADCs including those targeting low-level HER2 expression and TROP2 are under active investigation in triple-negative BCBrMs.
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Neoplasias Encefálicas , Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Neoplasias de la Mama/patología , Hibridación Fluorescente in Situ , Trastuzumab , Receptor ErbB-2 , Neoplasias Encefálicas/tratamiento farmacológico , Capecitabina , Pronóstico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
Lysophosphatidic acid receptors (LPARs) are six G-protein-coupled receptors that mediate LPA signaling to promote tumorigenesis and therapy resistance in many cancer subtypes, including breast cancer. Individual-receptor-targeted monotherapies are under investigation, but receptor agonism or antagonism effects within the tumor microenvironment following treatment are minimally understood. In this study, we used three large, independent breast cancer patient cohorts (TCGA, METABRIC, and GSE96058) and single-cell RNA-sequencing data to show that increased tumor LPAR1, LPAR4, and LPAR6 expression correlated with a less aggressive phenotype, while high LPAR2 expression was particularly associated with increased tumor grade and mutational burden and decreased survival. Through gene set enrichment analysis, it was determined that cell cycling pathways were enriched in tumors with low LPAR1, LPAR4, and LPAR6 expression and high LPAR2 expression. LPAR levels were lower in tumors over normal breast tissue for LPAR1, LPAR3, LPAR4, and LPAR6, while the opposite was observed for LPAR2 and LPAR5. LPAR1 and LPAR4 were highest in cancer-associated fibroblasts, while LPAR6 was highest in endothelial cells, and LPAR2 was highest in cancer epithelial cells. Tumors high in LPAR5 and LPAR6 had the highest cytolytic activity scores, indicating decreased immune system evasion. Overall, our findings suggest that potential compensatory signaling via competing receptors must be considered in LPAR inhibitor therapy.
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Neoplasias de la Mama , Receptores del Ácido Lisofosfatídico , Humanos , Femenino , Receptores del Ácido Lisofosfatídico/genética , Receptores del Ácido Lisofosfatídico/metabolismo , Neoplasias de la Mama/genética , Microambiente Tumoral/genética , Células Endoteliales/metabolismo , Transducción de Señal , Lisofosfolípidos/metabolismoRESUMEN
Heart diseases and related complications constitute a leading cause of death and socioeconomic threat worldwide. Despite intense efforts and research on the pathogenetic mechanisms of these diseases, the underlying cellular and molecular mechanisms are yet to be completely understood. Several lines of evidence indicate a critical role of inflammatory and oxidative stress responses in the development and progression of heart diseases. Nevertheless, the molecular machinery that drives cardiac inflammation and oxidative stress is not completely known. Recent data suggest an important role of cardiac bitter taste receptors (TAS2Rs) in the pathogenetic mechanism of heart diseases. Independent groups of researchers have demonstrated a central role of TAS2Rs in mediating inflammatory, oxidative stress responses, autophagy, impulse generation/propagation and contractile activities in the heart, suggesting that dysfunctional TAS2R signalling may predispose to cardiac inflammatory and oxidative stress disorders, characterised by contractile dysfunction and arrhythmia. Moreover, cardiac TAS2Rs act as gateway surveillance units that monitor and detect toxigenic or pathogenic molecules, including microbial components, and initiate responses that ultimately culminate in protection of the host against the aggression. Unfortunately, however, the molecular mechanisms that link TAS2R sensing of the cardiac milieu to inflammatory and oxidative stress responses are not clearly known. Therefore, we sought to review the possible role of TAS2R signalling in the pathophysiology of cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction in heart diseases. Potential therapeutic significance of targeting TAS2R or its downstream signalling molecules in cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction is also discussed.
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Cardiopatías , Gusto , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Estrés Oxidativo , Arritmias Cardíacas , InflamaciónRESUMEN
HIV-1 maturation inhibitors (MIs) offer a novel mechanism of action and potential for use in HIV-1 treatment. Prior MIs displayed clinical efficacy but were associated with the emergence of resistance and some gastrointestinal tolerability events. Treatment with the potentially safer next-generation MI GSK3640254 (GSK'254) resulted in up to a 2-log10 viral load reduction in a phase IIa proof-of-concept study. In vitro experiments have defined the antiviral and resistance profiles for GSK'254. The compound displayed strong antiviral activity against a library of subtype B and C chimeric viruses containing Gag polymorphisms and site-directed mutants previously shown to affect potency of earlier-generation MIs, with a mean protein-binding adjusted 90% effective concentration (EC90) of 33 nM. Furthermore, GSK'254 exhibited robust antiviral activity against a panel of HIV-1 clinical isolates, with a mean EC50 of 9 nM. Mechanistic studies established that bound GSK'254 dissociated on average 7.1-fold more slowly from wild-type Gag virus-like particles (VLPs) than a previous-generation MI. In resistance studies, the previously identified A364V Gag region mutation was selected under MI pressure in cell culture and during the phase IIa clinical study. As expected, GSK'254 inhibited cleavage of p25 in a range of polymorphic HIV-1 Gag VLPs. Virus-like particles containing the A364V mutation exhibited a p25 cleavage rate 9.3 times higher than wild-type particles, providing a possible mechanism for MI resistance. The findings demonstrate that GSK'254 potently inhibits a broad range of HIV-1 strains expressing Gag polymorphisms.
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VIH-1 , Triterpenos , Farmacorresistencia Viral/genética , Succinatos/farmacología , Triterpenos/farmacología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/metabolismoRESUMEN
Enterococcus faecalis, a leading cause of health care-associated infections, forms biofilms and is resistant to many antimicrobial agents. Planktonic-phase E. faecalis is resistant to high concentrations of the enzyme lysozyme, which catalyzes the hydrolysis of N-acetylmuramic acid and N-acetylglucosamine linkages in peptidoglycan and is also a cationic antimicrobial peptide (CAMP). E. faecalis lysozyme resistance in planktonic cells is stimulated upon activation of the extracytoplasmic function sigma factor SigV via cleavage of the anti-sigma factor RsiV by the transmembrane protease Eep. Planktonically grown E. faecalis lacking eep is more sensitive than wild-type strains to growth inhibition by lysozyme. This study was initiated to determine whether E. faecalis OG1RFΔeep biofilms would be protected from lysozyme. Serendipitously, we discovered that exposure of both E. faecalis OG1RF and OG1RFΔeep biofilms to chicken egg white lysozyme resulted in decreases in biofilm cell viability of 3.7 and 3.8 log10 CFU/mL, respectively. Treatment of biofilms of both strains with recombinant purified human lysozyme was associated with reductions in cell viability of >99.9% for both strains. Lysozyme-treated OG1RF and OG1RFΔeep biofilms contained a higher percentage of dead cells by Live/Dead staining and were associated with more extracellular DNA. Heat-inactivated human lysozyme, which was devoid of muramidase activity, as well as the lysozyme-derived CAMP LP9 and the CAMP polymyxin B, decreased biofilm cell viability. These results are consistent with a model in which the CAMP activity, rather than the muramidase activity, of lysozyme causes lysis of E. faecalis biofilm cells despite them having an intact lysozyme resistance-inducing signaling pathway. Finally, lysozyme was also effective in reducing viable biofilm cells of several other E. faecalis strains, including the vancomycin-resistant strain V583 and multidrug-resistant strain MMH594. This study demonstrates the potential for lysozyme to be developed as a novel antibiofilm therapeutic.
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Enterococcus faecalis , Muramidasa , Antibacterianos/metabolismo , Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Péptidos Antimicrobianos , Biopelículas , Muramidasa/metabolismo , Muramidasa/farmacología , PlanctonRESUMEN
Candida auris is an emerging, multi drug resistant fungal pathogen that has caused infectious outbreaks in over 45 countries since its first isolation over a decade ago, leading to in-hospital crude mortality rates as high as 72%. The fungus is also acclimated to disinfection procedures and persists for weeks in nosocomial ecosystems. Alarmingly, the outbreaks of C. auris infections in Coronavirus Disease-2019 (COVID-19) patients have also been reported. The pathogenicity, drug resistance and global spread of C. auris have led to an urgent exploration of novel, candidate antifungal agents for C. auris therapeutics. This narrative review codifies the emerging data on the following new/emerging antifungal compounds and strategies: antimicrobial peptides, combinational therapy, immunotherapy, metals and nano particles, natural compounds, and repurposed drugs. Encouragingly, a vast majority of these exhibit excellent anti- C. auris properties, with promising drugs now in the pipeline in various stages of development. Nevertheless, further research on the modes of action, toxicity, and the dosage of the new formulations are warranted. Studies are needed with representation from all five C. auris clades, so as to produce data of grater relevance, and broader significance and validity. LAY SUMMARY: Elimination of Candida auris that causes deadly infections to susceptible individuals is extremely challenging due to the lack of effective treatment options. Promising, new antifungal agents and strategies are being developed and further refinement will facilitate their clinical use in the near future.
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COVID-19 , Candida , Animales , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , COVID-19/veterinaria , Candida auris , Ecosistema , Pruebas de Sensibilidad Microbiana/veterinariaRESUMEN
PURPOSE OF REVIEW: Antibody-drug conjugates (ADCs) are a class of therapeutics that combine target-specific monoclonal antibodies with cytotoxic chemotherapy. Here, we describe the components of ADCs and review their promising activity, safety, and applicability in non-small cell lung cancer (NSCLC). RECENT FINDINGS: Technological advancements have reinvigorated ADCs as a viable treatment strategy in advanced solid tumors. Several target-specific ADCs have shown promise in treatment-refractory NSCLC, including agents targeting HER2, HER3, TROP2, CEACAM5, and MET, among others, with multiple confirmatory phase 3 trials ongoing. Critically, ADCs have demonstrated efficacy signals in both driver mutation-positive and mutation-negative advanced NSCLC, reinforcing their potential as an efficacious treatment strategy that transcends diverse tumor biology in advanced NSCLC. ADCs are a promising class of anti-cancer therapeutics that have significant potential in advanced NSCLC. Beyond confirmatory phase 3 trials, several questions remain including optimal agent sequencing, combinatorial methods, and unique toxicity management.
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Antineoplásicos Inmunológicos , Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Inmunoconjugados , Neoplasias Pulmonares , Humanos , Inmunoconjugados/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Antineoplásicos Inmunológicos/uso terapéuticoRESUMEN
De-regulated cellular energetics is an emerging hallmark of cancer with alterations to glycolysis, oxidative phosphorylation, the pentose phosphate pathway, lipid oxidation and synthesis and amino acid metabolism. Understanding and targeting of metabolic reprogramming in cancers may yield new treatment options, but metabolic heterogeneity and plasticity complicate this strategy. One highly heterogeneous cancer for which current treatments ultimately fail is the deadly brain tumor glioblastoma. Therapeutic resistance, within glioblastoma and other solid tumors, is thought to be linked to subsets of tumor initiating cells, also known as cancer stem cells. Recent profiling of glioblastoma and brain tumor initiating cells reveals changes in metabolism, as compiled here, that may be more broadly applicable. We will summarize the profound role for metabolism in tumor progression and therapeutic resistance and discuss current approaches to target glioma metabolism to improve standard of care.
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Neoplasias Encefálicas/metabolismo , Transformación Celular Neoplásica/metabolismo , Metabolismo Energético , Glioblastoma/metabolismo , Células Madre Neoplásicas/metabolismo , Aminoácidos/metabolismo , Animales , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Resistencia a Antineoplásicos , Metabolismo Energético/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/patología , Glucosa/metabolismo , Humanos , Metabolismo de los Lípidos , Terapia Molecular Dirigida , Invasividad Neoplásica , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Microambiente TumoralRESUMEN
Vasomotor symptoms (hot flushes, flashes, night sweats) occur in the majority of menopausal women, and are reported as being of the highest symptom priority as they often persist over many years and can be highly disruptive. Hormone therapy is the most effective available treatment but is not without risk if taken long term, and is sometimes contraindicated; for example, in women with a personal or family history of breast cancer, which is the most common female cancer worldwide. Other treatment alternatives are not as efficacious, can cause side effects, and/or are not widely available. A new, effective, targeted treatment could therefore benefit millions of women worldwide. This became possible to investigate after accumulated evidence from both animal and human models implicated heightened signaling of a hypothalamic neuropeptide together with its receptor (neurokinin B/NK3R) in the etiology of sex-steroid-deficient vasomotor symptoms. Four clinical trials of three chemically distinct oral NK3R antagonists for the treatment of menopausal flushes have since completed and published, which consistently demonstrate efficacy and tolerability of these agents. These suggest great promise to change practice in the future if ongoing further larger-scale studies of longer duration confirm the same; as, estrogen exposure will no longer be required to effectively and safely treat vasomotor symptoms.
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Sofocos/tratamiento farmacológico , Menopausia , Receptores de Neuroquinina-3/antagonistas & inhibidores , Femenino , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
High-risk, relapsed and refractory neuroblastoma are associated with poor 5-years survival rates, demonstrating the need for investigational therapeutic agents to treat this disease. Taurolidine is derived from the aminosulfoacid taurine and has known anti-microbial and anti-inflammatory properties. Taurolidine has also demonstrated anti-neoplastic effects in a range of cancers, providing the rationale to investigate the activity of taurolidine against neuroblastoma in preclinical studies. We investigated the in vitro activity of taurolidine against neuroblastoma using the alamar blue cytotoxicity assay, phase-contrast light microscopy, western blotting and analysis of global gene expression by RNA-Seq. In vivo activity of taurolidine was evaluated using mouse xenograft models. In vitro pre-clinical data show that taurolidine is cytotoxic to neuroblastoma cell lines, inducing cell death by apoptosis. Analysis of global gene expression and determination of signaling pathway activation scores using the in silico Pathway Activation Network Decomposition Analysis (iPANDA) platform indicates that taurolidine has an effect on the Notch, mitogen-activated protein kinase (MAPK) and interleukin-10 (IL-10) signaling pathways. In vivo experiments in xenograft mouse models show that taurolidine decreases tumor growth and improves survival. These results provide supportive pre-clinical data on the activity of taurolidine against neuroblastoma. The findings support the rationale for further evaluation of taurolidine for the treatment of relapsed/refractory neuroblastoma patients in an early phase clinical trial.
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Antiinfecciosos/farmacología , Antineoplásicos/farmacología , Neuroblastoma/tratamiento farmacológico , Taurina/análogos & derivados , Tiadiazinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Expresión Génica/efectos de los fármacos , Xenoinjertos/efectos de los fármacos , Xenoinjertos/metabolismo , Humanos , Ratones , Ratones SCID , Neuroblastoma/metabolismo , Transducción de Señal/efectos de los fármacos , Taurina/farmacologíaRESUMEN
INTRODUCTION: Currently, there are no proven drugs that are FDA approved for the treatment of dermatomyositis (DM), even though multiple clinical trials are ongoing to evaluate safety and efficacy of novel therapeutics in DM. The purpose of this review is to highlight the biological plausibility, existing clinical evidence as well as completed and ongoing clinical trials for various drugs in pipeline for development for use in dermatomyositis. AREAS COVERED: The drugs with the strongest evidence have been included in this review with a focus on the mechanism of their action pertaining to the disease process, clinical studies including completed and ongoing trials. With better understanding of the underlying pathophysiologic process, there are new molecular targets that have been identified that can be targeted by these novel drugs, predominantly biologic drugs. EXPERT OPINION: There are various drugs being evaluated in phase II/III clinical trials that hold promise in DM. At the forefront of these are immunoglobulin, Lenabasum, and Abatacept for which phase III clinical trials are ongoing. In addition, promising clinical studies are ongoing or reported for KZR-616, anti-B cell therapy, anti-interferon drugs, and Repository Corticotrophin Injection (RCI).
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Productos Biológicos/farmacología , Dermatomiositis/tratamiento farmacológico , Desarrollo de Medicamentos , Animales , Productos Biológicos/administración & dosificación , Dermatomiositis/fisiopatología , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/farmacología , Terapia Molecular DirigidaRESUMEN
Autoimmune diseases of the skin occur when the immune system attacks normal skin. The immune system can be broadly divided into an effector arm responsible for fighting infections and cancer and a regulatory arm that reduces autoreactivity and maintains immune homeostasis. Cutaneous autoimmunity develops when the equilibrium between the effector arm and regulatory arm of the immune system is disrupted. Recent insights into the inflammatory pathways that are overactive in some cutaneous autoimmune diseases have led to therapies targeting the effector arm of the immune system with greater treatment efficacy than previously used broad immunosuppressants. The current paradigm of inhibiting excessive immune activation for treating cutaneous autoimmunity will be discussed including cytokine blockade, cellular depletion, intracellular signaling blockade and costimulatory blockade. Despite the success of this approach many cutaneous autoimmune diseases lack a clearly delineated pathway to target and therefore new strategies are needed. An emerging therapeutic strategy targeting the regulatory arm of the immune system to induce tolerance and disease remission provides new hope for treating cutaneous autoimmunity. Such an approach includes cellular therapy with regulatory T cells and chimeric autoantibody receptor T cells, cytokine therapy with low-dose interleukin-2, immune checkpoint stimulation, tolerogenic vaccines and microbiome biotherapy. This mini-review will discuss the current and emerging therapeutic strategies for cutaneous autoimmune diseases and provide an organizational framework for understanding distinct mechanisms of action.
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Enfermedades Autoinmunes , Terapia Molecular Dirigida , Enfermedades de la Piel , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inmunología , Humanos , Sistema Inmunológico/efectos de los fármacos , Sistema Inmunológico/inmunología , Inmunoterapia/métodos , Terapia Molecular Dirigida/métodos , Terapia Molecular Dirigida/tendencias , Transducción de Señal/efectos de los fármacos , Enfermedades de la Piel/tratamiento farmacológico , Enfermedades de la Piel/inmunologíaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive neoplasm, predicted to become the second leading cause of cancer-related deaths before 2030. This dismal trend is mainly due to lack of effective treatments against its metastatic behavior. Therefore, a better understanding of the key mechanisms underlying metastasis should provide new opportunities for therapeutic purposes. Genomic analyses revealed that aberrations that fuel PDAC tumorigenesis and progression, such as SMAD4 loss, are also implicated in metastasis. Recently, microRNAs have been shown to play a regulatory role in the metastatic behavior of many tumors, including PDAC. In particular, miR-10 and miR-21 have appeared as master regulators of the metastatic program, while members of the miR-200 family are involved in the epithelial-to-mesenchymal switch, favoring cell migration and invasiveness. Several studies have also found a close relationship between cancer stem cells (CSCs) and biological features of metastasis, and the CSC markers ALDH1, ABCG2 and c-Met are expressed at high levels in metastatic PDAC cells. Emerging evidence reveals that exosomes are involved in the modulation of the tumor microenvironment and can initiate PDAC pre-metastatic niche formation in the liver and lungs. In this review, we provide an overview of the role of all these pivotal factors in the metastatic behavior of PDAC, and discuss their potential exploitation in the clinic to improve current therapeutics and identify new drug targets.
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Adenocarcinoma/genética , Carcinogénesis/genética , Células Madre Neoplásicas , Neoplasias Pancreáticas/genética , Adenocarcinoma/patología , Biomarcadores de Tumor/genética , Movimiento Celular/genética , Proliferación Celular , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Metástasis de la Neoplasia , Neoplasias Pancreáticas/patología , Neoplasias PancreáticasRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease of increasing prevalence marked by poor prognosis and limited treatment options. Ca2+-activated KCa3.1 potassium channels have been shown to play a key role in the aberrant activation and responses to injury in both epithelial cells and fibroblasts, both considered key drivers in the fibrotic process of IPF. Pharmacological inhibition of IPF-derived fibroblasts is able to somewhat prevent TGF-ß- and basic fibroblast growth factor-dependent profibrotic responses. In the current study, we investigated whether blockade of the KCa3.1 ion channel in vivo with a selective inhibitor, Senicapoc, was able to attenuate both histological and physiological outcomes of early fibrosis in our large animal (sheep) model for pulmonary fibrosis. We also determined whether treatment was targeting the profibrotic activity of sheep lung fibroblasts. Senicapoc was administered in established fibrosis, at 2 weeks after bleomycin instillation, and drug efficacy was assessed 4 weeks after treatment. Treatment with Senicapoc improved pre-established bleomycin-induced changes compared with vehicle control, leading to improved lung compliance, reduced extracellular matrix and collagen deposition, and a reduction in both α-smooth muscle actin expression and proliferating cells, both in vivo and in vitro. These studies show that inhibiting the KCa3.1 ion channel is able to attenuate the early fibrogenic phase of bleomycin-dependent fibrosis and inhibits profibrotic behavior of primary sheep lung fibroblasts. This supports the previous research conducted in human IPF-derived fibroblasts and suggests that inhibiting KCa3.1 signaling may provide a novel therapeutic approach for IPF.
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Canales de Potasio de Conductancia Intermedia Activados por el Calcio/antagonistas & inhibidores , Fibrosis Pulmonar/metabolismo , Acetamidas/farmacología , Animales , Bleomicina , Adaptabilidad , Modelos Animales de Enfermedad , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Técnica del Anticuerpo Fluorescente , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Pulmón/fisiopatología , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/fisiopatología , Pruebas de Función Respiratoria , Ovinos , Compuestos de Tritilo/farmacologíaRESUMEN
Leukemia is a cancer of the white blood cells, with over 54,000 new cases per year diagnosed worldwide and a 5-year survival rate below 60%. This highlights a need for research into the mechanisms behind its etiology and causes of therapy failure. The bone marrow microenvironment, in which adult stem cells are maintained in healthy individuals, has been implicated as a source of chemoresistance and disease relapse. Here the various ways that the microenvironment can contribute to the resistance and persistence of leukemia are discussed. The targeting of the microenvironment by leukemia cells to create an environment more suitable for cancer progression is described. The role of soluble factors, drug transporters, microvesicles, as well as the importance of direct cell-cell contact, in addition to the effects of inflammation and immune surveillance in microenvironment-mediated drug resistance are discussed. An overview of the clinical potential of translating research findings to patients is also provided. Understanding of and further research into the role of the bone marrow microenvironment in leukemia progression and relapse are crucial towards developing more effective treatments and reduction in patient morbidity. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.