RESUMEN
Immuno-oncology has gained momentum with the approval of antibodies with clinical activities in different indications. Unfortunately, for anti-PD (L)1 agents in monotherapy, only half of the treated population achieves a clinical response. For other agents, such as anti-CTLA4 antibodies, no biomarkers exist, and tolerability can limit administration. In this study, using publicly available genomic datasets, we evaluated the expression of the macrophage scavenger receptor-A (SR-A) (MSR1) and its association with a response to check-point inhibitors (CPI). MSR1 was associated with the presence of macrophages, dendritic cells (DCs) and neutrophils in most of the studied indications. The presence of MSR1 was associated with macrophages with a pro-tumoral phenotype and correlated with TIM3 expression. MSR1 predicted favorable overall survival in patients treated with anti-PD1 (HR: 0.56, FDR: 1%, p = 2.6 × 10-5), anti PD-L1 (HR: 0.66, FDR: 20%, p = 0.00098) and anti-CTLA4 (HR: 0.37, FDR: 1%, p = 4.8 × 10-5). When specifically studying skin cutaneous melanoma (SKCM), we observed similar effects for anti-PD1 (HR: 0.65, FDR: 50%, p = 0.0072) and anti-CTLA4 (HR: 0.35, FDR: 1%, p = 4.1 × 10-5). In a different dataset of SKCM patients, the expression of MSR1 predicted a clinical response to anti-CTLA4 (AUC: 0.61, p = 2.9 × 10-2). Here, we describe the expression of MSR1 in some solid tumors and its association with innate cells and M2 phenotype macrophages. Of note, the presence of MSR1 predicted a response to CPI and, particularly, anti-CTLA4 therapies in different cohorts of patients. Future studies should prospectively explore the association of MSR1 expression and the response to anti-CTLA4 strategies in solid tumors.
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Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Perfilación de la Expresión Génica , Transcriptoma , Oncología Médica , Receptores Depuradores de Clase ARESUMEN
The identification of targets that are expressed on the cell membrane is a main goal in cancer research. The Lymphocyte Antigen 6 Family Member G6D (LY6G6D) gene codes for a protein that is mainly present on the surface of colorectal cancer (CRC) cells. Therapeutic strategies against this protein like the development of T cell engagers (TCE) are currently in the early clinical stage. In the present work, we interrogated public genomic datasets including TCGA to evaluate the genomic and immunologic cell profile present in tumors with high expression of LY6G6D. We used data from TCGA, among others, and the Tumor Immune Estimation Resource (TIMER2.0) platform for immune cell estimations and Spearman correlation tests. LY6G6D expression was exclusively present in CRC, particularly in the microsatellite stable (MSS) subtype, and was associated with left-side tumors and the canonical genomic subgroup. Tumors with mutations of APC and p53 expressed elevated levels of LY6G6D. This protein was expressed in tumors with an inert immune microenvironment with an absence of immune cells and co-inhibitory molecules. In conclusion, we described clinical, genomic and immune-pathologic characteristics that can be used to optimize the clinical development of agents against this target. Future studies should be performed to confirm these findings and potentially explore the suggested clinical development options.
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Neoplasias Colorrectales , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Humanos , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Femenino , Masculino , Proteína de la Poliposis Adenomatosa del Colon/genética , Proteína de la Poliposis Adenomatosa del Colon/metabolismo , Regulación Neoplásica de la Expresión Génica , Mutación , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/genética , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Antígenos Ly/metabolismo , Antígenos Ly/genética , Antígenos B7/genética , Antígenos B7/metabolismoRESUMEN
The identification of surfaceome proteins is a main goal in cancer research to design antibody-based therapeutic strategies. T cell engagers based on KLK2, a kallikrein specifically expressed in prostate cancer (PRAD), are currently in early clinical development. Using genomic information from different sources, we evaluated the immune microenvironment and genomic profile of prostate tumors with high expression of KLK2. KLK2 was specifically expressed in PRAD but it was not significant associated with Gleason score. Additionally, KLK2 expression did not associate with the presence of any immune cell population and T cell activating markers. A mild correlation between the high expression of KLK2 and the deletion of TMPRSS2 was identified. KLK2 expression associated with high levels of surface proteins linked with a detrimental response to immune checkpoint inhibitors (ICIs) including CHRNA2, FAM174B, OR51E2, TSPAN1, PTPRN2, and the non-surface protein TRPM4. However, no association of these genes with an outcome in PRAD was observed. Finally, the expression of these genes in PRAD did not associate with an outcome in PRAD and any immune populations. We describe the immunologic microenvironment on PRAD tumors with a high expression of KLK2, including a gene signature linked with an inert immune microenvironment, that predicts the response to ICIs in other tumor types. Strategies targeting KLK2 with T cell engagers or antibody-drug conjugates will define whether T cell mobilization or antigen release and stimulation of immune cell death are sufficient effects to induce clinical activity.
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Calicreínas , Neoplasias de la Próstata , Receptores Odorantes , Humanos , Masculino , Genómica , Calicreínas/genética , Calicreínas/inmunología , Calicreínas/metabolismo , Proteínas de Neoplasias , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/metabolismo , Tetraspaninas , Microambiente Tumoral/genéticaRESUMEN
The modular synthesis of the guanidine core by guanylation reactions using commercially available ZnEt2 as a catalyst has been exploited as a tool for the rapid development of antitumoral guanidine candidates. Therefore, a series of phenyl-guanidines were straightforwardly obtained in very high yields. From the in vitro assessment of the antitumoral activity of such structurally diverse guanidines, the guanidine termed ACB3 has been identified as the lead compound of the series. Several biological assays, an estimation of AMDE values, and an uptake study using Fluorescence Lifetime Imaging Microscopy were conducted to gain insight into the mechanism of action. Cell death apoptosis, induction of cell cycle arrest, and reduction in cell adhesion and colony formation have been demonstrated for the lead compound in the series. In this work, and as a proof of concept, we discuss the potential of the catalytic guanylation reactions for high-throughput testing and the rational design of guanidine-based cancer therapeutic agents.
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Guanidinas , Neoplasias , Humanos , Guanidina , Guanidinas/farmacología , Apoptosis , Muerte Celular , Neoplasias/tratamiento farmacológicoRESUMEN
Endocrine-resistant, hormone receptor-positive, and HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) is largely governed by acquired mutations in the estrogen receptor, which promote ligand-independent activation, and by truncal alterations in the PI3K signaling pathway, with a broader range of gene alterations occurring with less prevalence. Circulating tumor DNA (ctDNA)-based technologies are progressively permeating the clinical setting. However, their utility for serial monitoring has been hindered by their significant costs, inter-technique variability, and real-world patient heterogeneity. We interrogated a longitudinal collection of 180 plasma samples from 75 HR+/HER2- mBC patients who progressed or relapsed after exposure to aromatase inhibitors and were subsequently treated with endocrine therapy (ET) by means of highly sensitive and affordable digital PCR and SafeSEQ sequencing. Baseline PIK3CA and TP53 mutations were prognostic of a shorter progression-free survival in our population. Mutant PIK3CA was prognostic in the subset of patients receiving fulvestrant monotherapy after progression to a CDK4/6 inhibitor (CDK4/6i)-containing regimen, and its suppression was predictive in a case of long-term benefit with alpelisib. Mutant ESR1 was prognostic in patients who did not receive concurrent CDK4/6i, an impact influenced by the variant allele frequency, and its early suppression was strongly predictive of efficacy and associated with long-term benefit in the whole cohort. Mutations in ESR1, TP53, and KRAS emerged as putative drivers of acquired resistance. These findings collectively contribute to the characterization of longitudinal ctDNA in real-world cases of HR+/HER2- mBC previously exposed to aromatase inhibitors and support ongoing studies either targeting actionable alterations or leveraging the ultra-sensitive tracking of ctDNA.
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Inhibidores de la Aromatasa , Neoplasias de la Mama , Femenino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/sangre , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Fosfatidilinositol 3-Quinasa Clase I/genética , Biopsia Líquida , Fosfatidilinositol 3-Quinasas , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , MutaciónRESUMEN
Degradation of targeted proteins using proteolysis targeting chimeras (PROTACs) has gained momentum. A PROTAC is a bifunctional molecule that consists of three parts: a ligand that interacts with the protein to be degraded, another ligand that binds to an E3 ubiquitin ligase and a linker that connects both. Identification of the right proteins as targets to be degraded and a ligase that is highly expressed in tumors compare with normal tissue is mandatory, as can augment efficacy reducing toxicity. In this article we review the current development stage of PROTACs in cancer to categorize the best PROTAC construction. Targets including BCL2, CDK4 and MCL1 were highly expressed in all tumors; MCL1 was significantly increased in breast cancer and lung adenocarcinoma and CDK4 in colon adenocarcinoma. Degradation of CDK9, AURKA or PLK1, followed by BCL2, MCL1, PTPN11, BRD4, PTK2, showed a high dependency. Most ligases evaluated were not highly present in tumors except for MDM2 in breast, lung, prostate and gastric cancer. In non-transformed tissue MDM2 was the most abundant ligase, followed by cIAP and CRBN, and those with low expression included XIAP and VHL. MDM2 ligase coupled with inhibitors of the targets BCL2, BRD4, CDK9, PLK1 and MCL1 in stomach tumor, and MDM2 with PIK3C3 inhibitors in breast cancer, seems to be the best therapeutic strategy. Our results suggest potential options for the design of PROTACS in specific medical indications.
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Adenocarcinoma , Neoplasias de la Mama , Neoplasias del Colon , Femenino , Humanos , Proteínas de Ciclo Celular/metabolismo , Ligandos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteínas Nucleares/metabolismo , Proteolisis , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Cyclin-dependent kinases (CDKs) are a broad family of proteins involved in the cell cycle and transcriptional regulation. In this article, we explore the antitumoral activity of a novel proteolysis-targeting chimera (PROTAC) compound against CDK9. Breast cancer cell lines from different subtypes were used. Transcriptomic mapping of CDKs in breast cancer demonstrated that the expression of CDK9 predicted a detrimental outcome in basal-like tumors (HR = 1.51, CI = 1.08-2.11, p = 0.015) and, particularly, in the luminal B subtype with HER2+ expression (HR = 1.82, CI = 1.17-2.82, p = 0.0069). The novel CDK9 PROTAC, THAL-SNS-032, displayed a profound inhibitory activity in MCF7, T47D, and BT474 cells, with less effect in SKBR3, HCC1569, HCC1954, MDA-MB-231, HS578T, and BT549 cells. The three cell lines with HER2 overexpression and no presence of ER, SKBR3, HCC1569, and HCC1954 displayed an EC50 three times higher compared to ER-positive and dual ER/HER2-positive cell lines. BT474-derived trastuzumab-resistant cell lines displayed a particular sensitivity to THAL-SNS-032. Western blot analyses showed that THAL-SNS-032 caused a decrease in CDK9 levels in BT474, BT474-RH, and BT474-TDM1R cells, and a significant increase in apoptosis. Experiments in animals demonstrated an inverse therapeutic index of THAL-SNS-032, with doses in the nontherapeutic and toxic range. The identified toxicity was mainly due to an on-target off-tumor effect of the compound in the gastrointestinal epithelium. In summary, the potent and efficient antitumoral properties of the CDK9 PROTAC THAL-SNS-032 opens the possibility of using this type of compound in breast cancer only if specifically delivered to cancer cells, particularly in ER/HER2-positive and HER2-resistant tumors.
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Neoplasias de la Mama , Animales , Femenino , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Quinasa 9 Dependiente de la Ciclina/genética , Quinasa 9 Dependiente de la Ciclina/metabolismo , Proteolisis , Receptor ErbB-2/metabolismoRESUMEN
BACKGROUND: Sarcomas comprise a group of aggressive malignancies with very little treatment options beyond standard chemotherapy. Reposition of approved drugs represents an attractive approach to identify effective therapeutic compounds. One example is mithramycin (MTM), a natural antibiotic which has demonstrated a strong antitumour activity in several tumour types, including sarcomas. However, its widespread use in the clinic was limited by its poor toxicity profile. RESULTS: In order to improve the therapeutic index of MTM, we have loaded MTM into newly developed nanocarrier formulations. First, polylactide (PLA) polymeric nanoparticles (NPs) were generated by nanoprecipitation. Also, liposomes (LIP) were prepared by ethanol injection and evaporation solvent method. Finally, MTM-loaded hydrogels (HG) were obtained by passive loading using a urea derivative non-peptidic hydrogelator. MTM-loaded NPs and LIP display optimal hydrodynamic radii between 80 and 105 nm with a very low polydispersity index (PdI) and encapsulation efficiencies (EE) of 92 and 30%, respectively. All formulations show a high stability and different release rates ranging from a fast release in HG (100% after 30 min) to more sustained release from NPs (100% after 24 h) and LIP (40% after 48 h). In vitro assays confirmed that all assayed MTM formulations retain the cytotoxic, anti-invasive and anti-stemness potential of free MTM in models of myxoid liposarcoma, undifferentiated pleomorphic sarcoma and chondrosarcoma. In addition, whole genome transcriptomic analysis evidenced the ability of MTM, both free and encapsulated, to act as a multi-repressor of several tumour-promoting pathways at once. Importantly, the treatment of mice bearing sarcoma xenografts showed that encapsulated MTM exhibited enhanced therapeutic effects and was better tolerated than free MTM. CONCLUSIONS: Overall, these novel formulations may represent an efficient and safer MTM-delivering alternative for sarcoma treatment.
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Plicamicina/análogos & derivados , Plicamicina/farmacología , Plicamicina/uso terapéutico , Sarcoma/patología , Animales , Antibacterianos/uso terapéutico , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Condrosarcoma/tratamiento farmacológico , Composición de Medicamentos , Femenino , Humanos , Hidrogeles/química , Hidrogeles/uso terapéutico , Liposomas , Ratones , Ratones Desnudos , Nanopartículas/química , Nanopartículas/uso terapéutico , Poliésteres/química , Poliésteres/uso terapéutico , Sarcoma/tratamiento farmacológicoRESUMEN
Targeting the innate immune system has attracted attention with the development of anti- CD47 antibodies. Anti-CD47 antibodies block the inhibition of the phagocytic activity of macrophages caused by the up-regulation of CD47 on tumor cells. In this study, public genomic data was used to identify genes highly expressed in breast tumors with elevated CD47 expression and analyzed the association between the presence of tumor immune infiltrates and the expression of the selected genes. We found that 142 genes positively correlated with CD47, of which 83 predicted favorable and 32 detrimental relapse-free survival (RFS). From those associated with favorable RFS, we selected the genes with immunologic biological functions and defined a CD47-immune signature composed of PTPRC, HLA-E, TGFBR2, PTGER4, ETS1, and OPTN. In the basal-like and HER2+ breast cancer subtypes, the expression of the CD47-immune signature predicted favorable outcome, correlated with the presence of tumor immune infiltrates, and with gene expression signatures of T cell activation. Moreover, CD47 up-regulated genes associated with favorable survival correlated with pro-tumoral macrophages. In summary, we described a CD47-immune gene signature composed of 6 genes associated with favorable prognosis, T cell activation, and pro-tumoral macrophages in breast cancer tumors expressing high levels of CD47.
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Neoplasias de la Mama/etiología , Neoplasias de la Mama/mortalidad , Antígeno CD47/genética , Inmunomodulación/genética , Transcriptoma , Biomarcadores de Tumor , Neoplasias de la Mama/patología , Femenino , Expresión Génica , Perfilación de la Expresión Génica/métodos , Humanos , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Estimación de Kaplan-Meier , Leucocitos/inmunología , Leucocitos/metabolismo , Leucocitos/patología , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Pronóstico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Identification of druggable vulnerabilities is a main objective in triple-negative breast cancer (TNBC), where no curative therapies exist. Gene set enrichment analyses (GSEA) and a pharmacological evaluation using a library of compounds were used to select potential druggable combinations. MTT and studies with semi-solid media were performed to explore the activity of the combinations. TNBC cell lines (MDAMB-231, BT549, HS-578T and HCC3153) and an additional panel of 16 cell lines were used to assess the activity of the two compounds. Flow cytometry experiments and biochemical studies were also performed to explore the mechanism of action. GSEA were performed using several data sets (GSE21422, GSE26910, GSE3744, GSE65194 and GSE42568), and more than 35 compounds against the identified functions were evaluated to discover druggable opportunities. Analyses done with the Chou and Talalay algorithm confirmed the synergy of dasatinib and olaparib. The combination of both agents significantly induced apoptosis in a caspase-dependent manner and revealed a pleotropic effect on cell cycle: Dasatinib arrested cells in G0/G1 and olaparib in G2/M. Dasatinib inhibited pChk1 and induced DNA damage measured by pH2AX, and olaparib increased pH3. Finally, the effect of the combination was also evaluated in a panel of 18 cell lines representative of the most frequent solid tumours, observing a particularly synergism in ovarian cancer. Breast cancer, triple negative, dasatinib, olaparib, screening.
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Dasatinib/farmacología , Ftalazinas/farmacología , Piperazinas/farmacología , Transcriptoma/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Femenino , Humanos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
BACKGROUND: There has been substantial interest in HER2 intratumoral heterogeneity as an explanation for the development of resistance to anti-HER2 therapies in breast cancer, particularly to trastuzumab emtansine (T-DM1). METHODS: Through a literature-based approach, we discuss mechanisms of resistance to HER2-targeting antibody-drug conjugates (ADCs) in breast cancer. RESULTS: We describe results from clinical studies reporting the effect of anti-HER2 strategies particularly ADCs and their mechanistic effect. We review biological findings underlying HER2 heterogeneity and its implication in the development of novel anti-HER2 drugs including new ADCs in clinical development like trastuzumab deruxtecan (DS-8201). CONCLUSIONS: We suggest potential mechanisms to optimize these compounds and their future clinical implementation.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Evolución Clonal , Resistencia a Antineoplásicos , Inmunoconjugados/uso terapéutico , Receptor ErbB-2/metabolismo , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Receptor ErbB-2/antagonistas & inhibidoresRESUMEN
Breast cancer is the most common invasive tumor in women and the second leading cause of cancer-related death. Nanomedicine raises high expectations for millions of patients as it can provide better, more efficient, and affordable healthcare, and it has the potential to develop novel therapeutics for the treatment of solid tumors. In this regard, targeted therapies can be encapsulated into nanocarriers, and these nanovehicles are guided to the tumors through conjugation with antibodies-the so-called antibody-conjugated nanoparticles (ACNPs). ACNPs can preserve the chemical structure of drugs, deliver them in a controlled manner, and reduce toxicity. As certain breast cancer subtypes and indications have limited therapeutic options, this field provides hope for the future treatment of patients with difficult to treat breast cancers. In this review, we discuss the application of ACNPs for the treatment of this disease. Given the fact that ACNPs have shown clinical activity in this clinical setting, special emphasis on the role of the nanovehicles and their translation to the clinic is placed on the revision.
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Antineoplásicos Inmunológicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Inmunoconjugados/farmacología , Nanopartículas/química , Animales , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/química , Neoplasias de la Mama/inmunología , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Femenino , Humanos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/química , Liposomas/administración & dosificación , Liposomas/química , Liposomas/inmunología , Nanopartículas/administración & dosificación , Polímeros/químicaRESUMEN
Basal-like breast cancer is an incurable disease with limited therapeutic options, mainly due to the frequent development of anti-cancer drug resistance. Therefore, identification of druggable targets to improve current therapies and overcome these resistances is a major goal. Targeting DNA repair mechanisms has reached the clinical setting and several strategies, like the inhibition of the CHK1 kinase, are currently in clinical development. Here, using a panel of basal-like cancer cell lines, we explored the synergistic interactions of CHK1 inhibitors (rabusertib and SAR020106) with approved therapies in breast cancer and evaluated their potential to overcome resistance. We identified a synergistic action of these inhibitors with agents that produce DNA damage, like platinum compounds, gemcitabine, and the PARP inhibitor olaparib. Our results demonstrated that the combination of rabusertib with these chemotherapies also has a synergistic impact on tumor initiation, invasion capabilities, and apoptosis in vitro. We also revealed a biochemical effect on DNA damage and caspase-dependent apoptosis pathways through the phosphorylation of H2AX, the degradation of full-length PARP, and the increase of caspases 3 and 8 activity. This agent also demonstrated synergistic activity in a platinum-resistant cell line, inducing an increase in cell death in response to cisplatin only when combined with rabusertib, while no toxic effect was found on non-tumorigenic breast tissue-derived cell lines. Lastly, the combination of CHK1 inhibitor with cisplatin and gemcitabine resulted in more activity than single or double combinations, leading to a higher apoptotic effect. In conclusion, in our study we identify therapeutic options for the clinical development of CHK1 inhibitors, and confirm that the inhibition of this kinase can overcome acquired resistance to cisplatin.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/enzimología , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Daño del ADN , Resistencia a Antineoplásicos/efectos de los fármacos , Platino (Metal)/uso terapéutico , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Carboplatino/farmacología , Carboplatino/uso terapéutico , Caspasas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Cisplatino/farmacología , Cisplatino/uso terapéutico , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Sinergismo Farmacológico , Femenino , Humanos , Invasividad Neoplásica , Platino (Metal)/farmacología , GemcitabinaRESUMEN
BACKGROUND: An important proportion of HER2-positive metastatic breast cancer patients do not respond to trastuzumab. The combination of dasatinib and trastuzumab has shown to be synergistic in preclinical models. METHODS: We conducted a phase II trial combining dasatinib 100 mg once daily with trastuzumab 2 mg/kg and paclitaxel 80 mg/m2 weekly. Primary objective was objective response rate (ORR) and secondary included safety, other efficacy parameters and pharmacodynamics in tumour tissue, blood samples and skin biopsies. RESULTS: From June 2013 to December 2015, 29 patients were included. Median number of cycles was 12 (1-49). Only 6 patients discontinued due to adverse events. ORR was 79.3% (95% CI 60.3-92), clinical benefit rate 82.8% (95% CI 64.2-94.2). Median time to progression 23.9 months (95% CI 14.9-not reached [NR]), median progression-free survival 23.9 months (95% CI 10.3-NR). No grade 4 toxicity was seen. Grade 3 toxicities included: ejection fraction decrease, neutropenia, hyponatremia, fatigue and sensory neuropathy and one left ventricular systolic dysfunction. Phosphorylated (p)-SRC was reduced in peripheral blood mononuclear cells. Phosphorylated SRC, ERK and AKT were also reduced in epidermal keratinocytes. CONCLUSIONS: Dasatinib can be safely combined with trastuzumab and paclitaxel. The combination is active with an ORR of almost 80%. TRIAL REGISTRATION: NCT01306942, EudraCT 2010-023304-27.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Dasatinib/administración & dosificación , Paclitaxel/administración & dosificación , Trastuzumab/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/metabolismo , Dasatinib/efectos adversos , Esquema de Medicación , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Paclitaxel/efectos adversos , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas pp60(c-src)/metabolismo , Receptor ErbB-2/metabolismo , Análisis de Supervivencia , Trastuzumab/efectos adversos , Resultado del TratamientoRESUMEN
INTRODUCTION: FOXM1 is a transcription factor that has been implicated in the genesis of several tumors by regulating the expression of genes involved in the mitotic process. METHODS: Transcriptomic enrichment analysis was performed to evaluate deregulated pathways in breast cancer, and relapse-free survival associated with the upregulated genes of FOXM1 signature was explored using the KM Plotter online tool. Treatment with bromodomain and extraterminal (BET) inhibitor JQ1 was explored in breast cancer cell lines to evaluate FOXM1 by qPCR and proliferation by MTT colorimetric assays. RESULTS: The FOXM1 gene signature was clearly deregulated in breast cancer patients, particularly in the basal-like subgroup where it was linked with detrimental prognosis. Treatment with the BET inhibitor JQ1 reduced the expression of FOXM1, decreasing cell proliferation in a panel of cell lines, being more active in the basal-like subtype, MDA-MB-231 and HS-578T. Knockdown of FOXM1 or treatment with JQ1 reduced genes included in the FOXM1 signature. Similarly, genes downregulated by the FOXM1 small interfering RNA approach were associated with detrimental outcome in breast cancer patients. Finally, we observed that FOXM1 was amplified in the triple-negative breast cancer subtype in around 15% of patients. CONCLUSION: Our study demonstrates that activation of the FOXM1 pathway has a prognostic role in breast cancer. JQ1 can modulate the expression of the FOXM1-gene interacting network, opening the opportunity for the evaluation of this compound in breast cancer patients.
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Azepinas/farmacología , Neoplasias de la Mama/genética , Epigénesis Genética , Proteína Forkhead Box M1/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Redes Reguladoras de Genes/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Triazoles/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Biología Computacional/métodos , Femenino , Perfilación de la Expresión Génica , Humanos , TranscriptomaRESUMEN
PURPOSE: Results from clinical trials of adjuvant dose-dense chemotherapy in patients with breast cancer are inconsistent. METHODS: A systematic search of MEDLINE identified studies comparing the efficacy of dose-dense adjuvant chemotherapy to a standard treatment. The primary analysis included studies that used identical regimens in the experimental and control groups, but varied only dose density. A secondary analysis included studies that used either different drugs or doses in the experimental and the control groups. Hazard ratios (HRs) and 95% confidence intervals were computed for disease-free survival (DFS) and overall survival (OS) and pooled in a meta-analysis. Subgroup analyses and meta-regression explored drug schedules utilized in control groups and the influence of clinicopathologic variables on benefit from dose-dense therapy. RESULTS: The primary analysis included 5 studies comprising 9819 patients while the secondary analysis included 6 studies comprising 9679 patients. Dose-dense treatment significantly improved DFS (HR 0.85, p < 0.001) and OS (HR 0.86, p = 0.008) in the primary analysis. Similar results were observed in the secondary analysis. Dose-dense schedule was important primarily in studies utilizing paclitaxel every 3 weeks as the control group (interaction p = 0.04 for DFS interaction p = 0.001 for OS). A significantly greater relative magnitude of benefit was observed in pre-menopausal women and those with nodal involvement, but there was no influence of hormone receptor status on results. CONCLUSIONS: Adjuvant dose-dense regimens improve breast cancer outcomes. It remains uncertain whether the observed benefit reflects the impact of dose density or the inferiority of paclitaxel every 3 weeks as a control group.
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Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/mortalidad , Quimioterapia Adyuvante , Esquema de Medicación , Femenino , Humanos , Estadificación de Neoplasias , Modelos de Riesgos ProporcionalesRESUMEN
PURPOSE: Although obesity is a risk factor for breast cancer, little effort has been made in the identification of druggable molecular alterations in obese-breast cancer patients. Tumors are controlled by their surrounding microenvironment, in which the adipose tissue is a main component. In this work, we intended to describe molecular alterations at a transcriptomic and protein-protein interaction (PPI) level between obese and non-obese patients. METHODS AND RESULTS: Gene expression data of 269 primary breast tumors were compared between normal-weight (BMI < 25, n = 130) and obese (IMC > 30, n = 139) patients. No significant differences were found for the global breast cancer population. However, within the luminal A subtype, upregulation of 81 genes was observed in the obese group (FC ≥ 1.4). Next, we explored the association of these genes with patient outcome, observing that 39 were linked with detrimental outcome. Their PPI map formed highly compact cluster and functional annotation analyses showed that cell cycle, cell proliferation, cell differentiation, and cellular response to extracellular stimuli were the more altered functions. Combined analyses of genes within the described functions are correlated with poor outcome. PPI network analyses for each function were to search for druggable opportunities. We identified 16 potentially druggable candidates. Among them, NEK2, BIRC5, and TOP2A were also found to be amplified in breast cancer, suggesting that they could act as strategic players in the obese-deregulated transcriptome. CONCLUSION: In summary, our in silico analysis describes molecular alterations of luminal A tumors and proposes a druggable PPI network in obese patients with potential for translation to the clinical practice.
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Neoplasias de la Mama/genética , ADN-Topoisomerasas de Tipo II/genética , Quinasas Relacionadas con NIMA/genética , Obesidad/genética , Proteínas de Unión a Poli-ADP-Ribosa/genética , Survivin/genética , Índice de Masa Corporal , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/patología , Etnicidad/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Estadificación de Neoplasias , Obesidad/complicaciones , Obesidad/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Supervivencia sin Progresión , Mapas de Interacción de Proteínas/genética , Transcriptoma/genéticaRESUMEN
BACKGROUND: Limited data exist about the role of the lay media in the dissemination of results of randomized controlled trials (RCTs) in common cancers. METHODS: Completed phase III RCTs evaluating new drugs in common cancers between January 2005 and October 2016 were identified from ClinicalTrials.gov. Lay media reporting was identified by searching LexisNexis Academic. Scientific reporting was defined as presentation at an academic conference or publication in full. Associations between reporting in the lay media before scientific reporting and study design and sponsorship were evaluated using logistic regression. RESULTS: Of 180 RCTs identified, 52% were reported in the lay media and in 27%, lay media reporting occurred before scientific reporting with an increasing trend over time (p = 0.009). Reporting in the lay media before scientific reporting was associated with positive results (OR: 2.10, p = 0.04), targeted therapy compared to chemotherapy (OR: 4.75, p = 0.006), immunotherapy compared to chemotherapy (OR: 7.60, p = 0.02), and prostate cancer compared to breast cancer (OR: 3.25, p = 0.02). CONCLUSIONS: Over a quarter of all RCTs in common cancers are reported in the lay media before they are reported scientifically with an increasing proportion over time. Positive trials, studies in prostate cancer, and trials of immunotherapy are associated with early reporting in the lay media.
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Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Ensayos Clínicos Fase III como Asunto/estadística & datos numéricos , Humanos , Edición/estadística & datos numéricos , Proyectos de InvestigaciónRESUMEN
Expression of high levels of immune cells including neutrophils has been associated with detrimental outcome in several solid tumors and new strategies to decrease their presence and activity are currently under clinical development. Here, we review some of the relevant literature of the role of neutrophils in different stages of the oncogenic process including tumor initiation, growth, proliferation or metastatic spreading and also focus on how neutrophil counts or the neutrophil-to-lymphocyte ratio may be used as a prognostic and predictive biomarker. Strategies to avoid the deleterious effects of neutrophils in cancer and to reduce their activity are discussed. Examples for such strategies include inhibition of CXCR1 and CXCR2 to decrease migration of neutrophils to tumoral areas or the inhibition of granulocyte colony stimulating factor to decrease the amount of neutrophils which has shown efficacy in preclinical models.
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Neoplasias , Neutrófilos , Humanos , Recuento de Leucocitos , Linfocitos , Neoplasias/diagnóstico , Neoplasias/inmunología , Neoplasias/fisiopatología , Neoplasias/terapia , Neutrófilos/inmunología , Neutrófilos/fisiología , PronósticoRESUMEN
Telomere length (TL) has been associated with several health conditions including cancer. To quantify the effect of TL on outcomes in malignancies and explore the role of type of TL measurement we conducted a librarian-led systematic search of electronic databases identified publications exploring the prognostic role of TL on cancer outcomes. Overall survival (OS) was the primary outcome measure while other time-to-event endpoints were secondary outcomes. Data from studies reporting a hazard ratio (HR) with 95% confidence interval (CI) and/or p-value were pooled in a meta-analysis. HRs were weighted by generic inverse variance and computed by random effects modeling. All statistical tests were two-sided. Sixty-one studies comprising a total of 14,720 patients were included of which 41 (67%) reported OS outcomes. Overall, the pooled HR for OS was 0.88 (95%CI=0.69-1.11, p=0.28). Long (versus short) telomeres were associated with improved outcomes in chronic lymphatic leukemia (CLL) and urothelial cancer (HR=0.45, 95%CI=0.29-0.71 and HR=0.68, 95%CI=0.46-1.00, respectively), conversely worse OS was seen with hepatocellular carcinoma (HR=1.90, 95%CI=1.51-2.38). Pooled HRs (95% CI) for progression-free survival, relapse/disease-free survival, cancer-specific survival, and treatment-free survival were 0.56 (0.41-0.76), 0.76 (0.53-1.10), 0.72 (0.48-1.10), and 0.48 (0.39-0.60), respectively. There was substantial heterogeneity of tissues and methods used for TL measurement and no clear association between TL and outcome was identified in subgroups. In conclusion, there is inconsistent effect of TL on cancer outcomes possibly due to variable methods of measurement. Standardization of measurement and reporting of TL is warranted before the prognostic value of TL can be accurately assessed.