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BACKGROUND: Gemcitabine (GEM)-platinum chemotherapy stands as first-line therapy for patients with recurrent/advanced biliary tract cancer (BTC), yielding progression-free survival (PFS) of 3.4-6.4 months. No standard second-line chemotherapy after GEM-platinum failure exists and data on survival benefit remain limited. MATERIAL AND METHODS: We retrospectively reviewed patients with recurrent/advanced BTC who received gemcitabine-oxaliplatin (GEMOX)-based chemotherapy followed by 5-fluorouracil-irinotecan (FOLFIRI)-based chemotherapy to evaluate the efficacy of the sequential treatment strategy. Overall survival (OS) and PFS were calculated by Kaplan-Meier method. RESULTS: Fifty-two patients were analyzed, 21 (40%) had intrahepatic, 14 (27%) had hilar/extrahepatic, and 17 (33%) had gallbladder cancer. Median age was 64 years (range 38-79 years). Prior curative intent resection of the primary tumor was performed in 23 (44.2%) patients and GEMOX adjuvant chemotherapy was given in 12 (23.1%) patients. After a median follow-up of 36.3 months, 47 (90.4%) patients completed the treatment strategy. First-sequence GEMOX and second sequence FOLFIRI achieved 4.8 months and 3.2 months median PFS, respectively. The global OS for the sequential chemotherapy was 21.9 months. The sequence of FOLFIRI resulted in a median OS of 8.4 months. CONCLUSION: The sequence of GEMOX-FOLFIRI is a potential treatment strategy for patients with recurrent/advanced BTC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Camptotecina/análogos & derivados , Carcinoma/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Neoplasias del Sistema Biliar/mortalidad , Neoplasias del Sistema Biliar/patología , Neoplasias del Sistema Biliar/cirugía , Camptotecina/uso terapéutico , Carcinoma/mortalidad , Carcinoma/patología , Carcinoma/cirugía , Ensayos Clínicos como Asunto , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/uso terapéutico , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Compuestos Organoplatinos/uso terapéutico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
AIMS: c-Met is an emerging biomarker in pancreatic ductal adenocarcinoma (PDAC); there is no consensus regarding the immunostaining scoring method for this marker. We aimed to assess the prognostic value of c-Met overexpression in resected PDAC, and to elaborate a robust and reproducible scoring method for c-Met immunostaining in this setting. METHODS AND RESULTS: c-Met immunostaining was graded according to the validated MetMab score, a classic visual scale combining surface and intensity (SI score), or a simplified score (high c-Met: ≥ 20% of tumour cells with strong membranous staining), in stage I-II PDAC. A computer-assisted classification method (Aperio software) was developed. Clinicopathological parameters were correlated with disease-free survival (DFS) and overall survival(OS). One hundred and forty-nine patients were analysed retrospectively in a two-step process. Thirty-seven samples (whole slides) were analysed as a pre-run test. Reproducibility values were optimal with the simplified score (kappa = 0.773); high c-Met expression (7/37) was associated with shorter DFS [hazard ratio (HR) 3.456, P = 0.0036] and OS (HR 4.257, P = 0.0004). c-Met expression was concordant on whole slides and tissue microarrays in 87.9% of samples, and quantifiable with a specific computer-assisted algorithm. In the whole cohort (n = 131), patients with c-Met(high) tumours (36/131) had significantly shorter DFS (9.3 versus 20.0 months, HR 2.165, P = 0.0005) and OS (18.2 versus 35.0 months, HR 1.832, P = 0.0098) in univariate and multivariate analysis. CONCLUSIONS: Simplified c-Met expression is an independent prognostic marker in stage I-II PDAC that may help to identify patients with a high risk of tumour relapse and poor survival.
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Biomarcadores de Tumor/análisis , Carcinoma Ductal Pancreático/patología , Inmunohistoquímica/métodos , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas c-met/biosíntesis , Adulto , Anciano , Carcinoma Ductal Pancreático/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Pancreáticas/mortalidad , Pronóstico , Modelos de Riesgos Proporcionales , Reproducibilidad de los Resultados , Análisis de Matrices TisularesRESUMEN
BACKGROUND: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials. METHODS/DESIGN: STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies. DISCUSSION: The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013. TRIAL REGISTRATION: STRATEGIC-1 is registered at Clinicaltrials.gov: NCT01910610, 23 July, 2013. STRATEGIC-1 is registered at EudraCT-No.: 2013-001928-19, 25 April, 2013.
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Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas p21(ras)/genética , Proyectos de InvestigaciónRESUMEN
Elisidepsin (PM02734, Irvalec®) is a synthetic marine-derived cyclic peptide of the Kahalalide F family currently in phase II clinical development. Elisidepsin was shown to induce rapid oncosis in ErbB3-expressing cells. Other predictive factors of elisidepsin sensitivity remained unknown. A panel of 23 cancer cell lines of different origin was assessed for elisidepsin cytotoxicity and correlated with mutational state, mRNA and protein expression of selected genes. Elisidepsin showed potent and broad cytotoxic effects in our cancer cell line panel, being active at concentrations ranging from 0.4 to 2 µM that may be relevant for clinical settings. We have shown that elisidepsin is more active in cells harboring epithelial phenotype with high E-cadherin and low vimentin expression. In addition, high ErbB3 and Muc1 expression was correlated with sensitivity to elisidepsin, whereas the presence of KRAS activating mutations was associated with resistance. In DU-PM cells with acquired resistance to elisidepsin, ErbB3 expression was decreased, while Bcl2 was increased. DU-PM cells displayed higher sensitivity to ErbB1-inhibitors suggesting possible cross-talk of ErbB1 and ErbB3 signaling pathways. Combinations of elisidepsin with lapatinib and several chemotherapies including 5-FU and oxaliplatin resulted in synergistic effects that offer the potential of clinical use of elisidepsin in combination settings.
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Antineoplásicos/farmacología , Depsipéptidos/farmacología , Neoplasias/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Línea Celular Tumoral , Depsipéptidos/administración & dosificación , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias/genética , Neoplasias/patología , ARN Mensajero/metabolismo , Receptor Cross-Talk , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismoRESUMEN
Mammalian target of rapamycin (mTOR) regulates cellular functions by integrating intracellular signals and signals from the tumor microenvironment (TME). The PI3K-AKT-mTOR pathway is activated in 70% of head and neck squamous cell carcinoma (HNSCC) and associated with poor prognosis. This phase I-II study investigated the effect of mTOR inhibition using weekly everolimus (30 mg for dose level 1, 50 mg for dose level 2) combined with weekly induction chemotherapy (AUC2 carboplatin and 60 mg/m2 paclitaxel) in treatment-naïve patients with locally advanced T3-4/N0-3 HNSCC. Patients received 9 weekly cycles before chemoradiotherapy. Objectives were safety and antitumor activity along with tissue and blood molecular biomarkers. A total of 50 patients were enrolled. Among 41 evaluable patients treated at the recommended dose of 50 mg everolimus weekly, tolerance was good and overall response rate was 75.6%, including 20 major responses (≥50% reduction in tumor size). A significant decrease in expression of p-S6K (p-value: 0.007) and Ki67 (p-value: 0.01) was observed in post-treatment tumor tissue. Pro-immunogenic cytokine release (Th1 cytokines IFN-γ, IL-2, and TNF-ß) was observed in the peripheral blood. The combination of everolimus and chemotherapy in HNSCC was safe and achieved major tumor responses. This strategy favorably impacts the TME and might be combined with immunotherapeutic agents.
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Anaphase is the stage of the cell cycle in which duplicated chromosomes separate and move towards opposite poles of the cell. Although its chromosome movements have always been viewed as majestic, until recently anaphase lacked obvious landmarks of regulation. The picture has changed with numerous recent studies that have highlighted the raison d'être of anaphase. It is now known to be associated with a series of regulatory pathways that promote a switch from high to low cyclin-dependent kinase activity--an essential feature for proper mitotic exit. The balance between protein phosphorylation and protein dephosphorylation drives and coordinates diverse processes such as chromosome movement, spindle dynamics and cleavage furrow formation. This well-ordered sequence of events is central to successful mitosis.
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Anafase/fisiología , Quinasas Ciclina-Dependientes/metabolismo , Mitosis/fisiología , Cromosomas , Fosforilación , Proteínas/metabolismo , Huso Acromático/fisiología , Levaduras/genética , Levaduras/fisiologíaRESUMEN
BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) are aggressive lymphomas accounting for approximately a third of non-Hodgkin lymphomas. Prohibitin 1 (PHB1) and prohibitin 2 (PHB2) are scaffold proteins that promote mitochondria homeostasis and consequently cell survival, but biological functions of cytoplasmic PHBs remain largely unknown in DLBCL. METHODS: PHB expression was analyzed in 82 DLBCL biopsies and five DLBCL cell lines by immunohistochemistry (IHC) and Western blotting. Pharmacological inhibition of PHB using the synthetic flavagline FL3 was realized in vitro to gain insight PHB cellular functions. Effects of FL3 on DLBCL cell line viability, apoptosis, C-Raf-ERK-MNK-eIF4E signaling pathway and eIF4F complex formation and activity were evaluated by XTT assay, annexin V-FITC/PI dual staining and Western blotting respectively. Subcutaneous DLBCL xenograft model in SCID mice was also performed to determine in vivo FL3 effect. RESULTS: As in DLBCL cell lines, PHB1 and PHB2 were expressed in germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subtypes. In patient samples, high PHB levels were associated with higher serum LDH (PHB1 and PHB2), IPIaa (PHB2), and Ki-67 (PHB2) expression. Higher PHB1 expression tends to be associated with shorter event-free survival (EFS) in patients, especially in male patients. FL3 induced apoptosis of DLBCL cell lines that was associated with inhibition of the ERK-MNK-eIF4E signaling pathway, including aggressive double/triple-hit DLBCL cell lines. This resulted in altered eIF4F complex formation and activity leading to a reduction of Bcl-2 and c-Myc expression levels. Moreover, FL3 strongly downregulated DLBCL cellular levels of Akt protein and AKT mRNA. FL3 antitumor activity was also confirmed in vivo in a murine xenograft model. CONCLUSION: Our data indicate that PHB overexpression is associated with markers of tumor aggressiveness in DLBCL, and that targeting PHBs may be a therapeutic option, notably in aggressive subtypes.
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Benzofuranos/administración & dosificación , Citoplasma/metabolismo , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Proteínas Represoras/metabolismo , Regulación hacia Arriba , Animales , Benzofuranos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Masculino , Ratones , Ratones SCID , Prohibitinas , Factores Sexuales , Análisis de Supervivencia , Regulación hacia Arriba/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Transforming Growth Factor (TGF)-ß inhibitors have been in development for decades with the outmost results of being promising candidates. From the latest clinical results at the 2016 ASCO meeting converging evidences suggest that we have moved from promising to effective drug nominees.
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OBJECTIVES: The hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-MET) ligand/receptor axis has been implicated in pathogenesis of malignant diseases including squamous cell carcinoma of the head and neck (SCCHN). Overexpression of c-MET has been reported as a common molecular abnormality in SCCHN, although its prognostic and predictive value remains to be validated. METHODS: We systematically searched literature for studies evaluating c-MET expression on immunohistochemistry in newly diagnosed, non-metastatic SCCHN. The c-MET expressing cases were classified into three categories according to predefined cut-off values for positivity. Our aim was to assess the prevalence of c-MET expression and its relationship with selected clinicopathological variables. RESULTS: Twenty-eight studies with 2019 cases were included. Relative frequencies of c-MET expression above cut-off levels I, II, and III were 81.8%, 63.8%, and 46.2%, respectively. Differences between these three values were statistically significant (p<1.0×10-6). Above cut-off level II, c-MET positivity was associated with worse overall survival (p=4.0×10-6), positive nodal status (p=1.0×10-4), higher disease stage (p=7.0×10-4), older age (p=2.1×10-3), disease recurrence (p=2.0×10-2), and primary tumour localization in the oral cavity (p=2.3×10-2). Above cut-off level III, c-MET positivity was associated with worse disease-free or progression-free survival (p=9.0×10-6), p16 negativity (p=2.4×10-4), worse overall survival (p=4.0×10-4), positive epidermal growth factor receptor (EGFR) status (p=7.2×10-4), and larger primary tumours (p=4.6×10-3). CONCLUSION: In SCCHN, immunohistochemical overexpression of c-MET above cut-off levels III and particularly II was associated with inferior survival outcomes and advanced disease. Moreover, it represents a promising predictive biomarker for c-MET targeting, yet the optimal scoring method remains to be defined.
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Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/patología , Proteínas Proto-Oncogénicas c-met/fisiología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/fisiopatología , Transición Epitelial-Mesenquimal , Femenino , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/fisiopatología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas c-met/genética , Carcinoma de Células Escamosas de Cabeza y Cuello , Análisis de SupervivenciaRESUMEN
Like other previous treatments and approaches, sorafenib, an antiangiogenic drug, failed to show any benefit in the adjuvant setting for hepatocellular carcinoma in a large clinical trial. We discuss reasons and implications of these negative results and the implications for clinical practice and future research. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00692770 . Registered 5 June 2008. This study has been completed.
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Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma Hepatocelular/terapia , Ablación por Catéter , Hepatectomía , Neoplasias Hepáticas/terapia , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Inhibidores de la Angiogénesis/efectos adversos , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Ablación por Catéter/efectos adversos , Ablación por Catéter/mortalidad , Quimioterapia Adyuvante , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Hepatectomía/efectos adversos , Hepatectomía/mortalidad , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Recurrencia Local de Neoplasia , Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Sorafenib , Factores de Tiempo , Resultado del TratamientoRESUMEN
Angiogenesis is hallmark of clear cell renal cell carcinogenesis. Anti-angiogenic therapies have been successful in improving disease outcome; however, most patients treated with anti-angiogenic agents will eventually progress. In this study we report that clear cell renal cell carcinoma was associated with vasculogenic mimicry in both mice and human with tumor cells expressing endothelial markers in the vicinity of tumor vessels. We show that vasculogenic mimicry was efficiently targeted by sunitinib but eventually associated with tumor resistance and a more aggressive phenotype both in vitro and in vivo. Re-challenging these resistant tumors in mice, we showed that second-line treatment with everolimus particularly affected vasculogenic mimicry and tumor cell differentiation compared to sorafenib and axitinib. Finally, our results highlighted the phenotypic and genotypic changes at the tumor cell and microenvironment levels during sunitinib response and progression and the subsequent improvement second-line therapies bring to the current renal cell carcinoma treatment paradigm.
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Carcinoma de Células Renales/tratamiento farmacológico , Everolimus/farmacología , Indoles/farmacología , Neoplasias Renales/tratamiento farmacológico , Pirroles/farmacología , Inhibidores de la Angiogénesis/farmacología , Animales , Axitinib , Carcinoma de Células Renales/irrigación sanguínea , Carcinoma de Células Renales/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Imidazoles/farmacología , Indazoles/farmacología , Neoplasias Renales/irrigación sanguínea , Neoplasias Renales/patología , Ratones , Ratones Desnudos , Neovascularización Patológica/tratamiento farmacológico , Distribución Aleatoria , Sunitinib , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The TGFß signaling pathway has pleiotropic functions regulating cell growth, differentiation, apoptosis, motility and invasion, extracellular matrix production, angiogenesis, and immune response. TGFß signaling deregulation is frequent in tumors and has crucial roles in tumor initiation, development and metastasis. TGFß signaling inhibition is an emerging strategy for cancer therapy. The role of the TGFß pathway as a tumor-promoter or suppressor at the cancer cell level is still a matter of debate, due to its differential effects at the early and late stages of carcinogenesis. In contrast, at the microenvironment level, the TGFß pathway contributes to generate a favorable microenvironment for tumor growth and metastasis throughout all the steps of carcinogenesis. Then, targeting the TGFß pathway in cancer may be considered primarily as a microenvironment-targeted strategy. In this review, we focus on the TGFß pathway as a target for cancer therapy. In the first part, we provide a comprehensive overview of the roles played by this pathway and its deregulation in cancer, at the cancer cell and microenvironment levels. We go on to describe the preclinical and clinical results of pharmacological strategies to target the TGFß pathway, with a highlight on the effects on tumor microenvironment. We then explore the perspectives to optimize TGFß inhibition therapy in different tumor settings.
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Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Neoplasias/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Animales , Antineoplásicos/metabolismo , Ensayos Clínicos como Asunto/métodos , Sistemas de Liberación de Medicamentos/tendencias , Humanos , Neoplasias/metabolismo , Transducción de Señal/fisiología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer death by 2030. Current therapeutic options are limited, warranting an urgent need to explore innovative treatment strategies. Due to specific microenvironment constraints including an extensive desmoplastic stroma reaction, PDAC faces major metabolic challenges, principally hypoxia and nutrient deprivation. Their connection with oncogenic alterations such as KRAS mutations has brought metabolic reprogramming to the forefront of PDAC therapeutic research. The Warburg effect, glutamine addiction, and autophagy stand as the most important adaptive metabolic mechanisms of cancer cells themselves, however metabolic reprogramming is also an important feature of the tumor microenvironment, having a major impact on epigenetic reprogramming and tumor cell interactions with its complex stroma. We present a comprehensive overview of the main metabolic adaptations contributing to PDAC development and progression. A review of current and future therapies targeting this range of metabolic pathways is provided.
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Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Animales , Progresión de la Enfermedad , HumanosRESUMEN
Predictive biomarkers are becoming increasingly important tools in drug development and clinical research. The importance of using both guidelines for specimen acquisition and analytical methods for biomarker measurements that are standardized has become recognized widely as an important issue, which must be addressed in order to provide high-quality, validated assays. Herein, we review the major challenges in biomarker validation processes, including pre-analytical (sample-related), analytical, and post-analytical (data-related) aspects of assay development. Recommendations for improving biomarker assay development and method validation are proposed to facilitate the use of predictive biomarkers in clinical trials and the practice of oncology.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias/tratamiento farmacológico , Monitoreo de Drogas/métodos , Humanos , Terapia Molecular Dirigida , Pronóstico , Reproducibilidad de los ResultadosRESUMEN
Galunisertib (LY2157299) is a selective ATP-mimetic inhibitor of TGF-ß receptor (TßR)-I activation currently under clinical investigation in hepatocellular carcinoma (HCC) patients. Our study explored the effects of galunisertib in vitro in HCC cell lines and ex vivo on patient samples. Galunisertib was evaluated in HepG2, Hep3B, Huh7, JHH6 and SK-HEP1 cells as well as in SK-HEP1-derived cells tolerant to sorafenib (SK-Sora) and sunitinib (SK-Suni). Exogenous stimulation of all HCC cell lines with TGF-ß yielded downstream activation of p-Smad2 and p-Smad3 that was potently inhibited with galunisertib treatment at micromolar concentrations. Despite limited antiproliferative effects, galunisertib yielded potent anti-invasive properties. Tumor slices from 13 patients with HCC surgically resected were exposed ex vivo to 1 µM and 10 µM galunisertib, 5 µM sorafenib or a combination of both drugs for 48 hours. Galunisertib but not sorafenib decreased p-Smad2/3 downstream TGF-ß signaling. Immunohistochemistry analysis of galunisertib and sorafenib-exposed samples showed a significant decrease of the proliferative marker Ki67 and increase of the apoptotic marker caspase-3. In combination, galunisertib potentiated the effect of sorafenib efficiently by inhibiting proliferation and increasing apoptosis. Our data suggest that galunisertib may be active in patients with HCC and could potentiate the effects of sorafenib.
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Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Pirazoles/farmacología , Quinolinas/farmacología , Factor de Crecimiento Transformador beta1/metabolismo , Adulto , Anciano , Carcinoma Hepatocelular/tratamiento farmacológico , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular , Femenino , Células Hep G2 , Humanos , Inmunohistoquímica , Indoles/farmacología , Antígeno Ki-67/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Niacinamida/análogos & derivados , Niacinamida/farmacología , Compuestos de Fenilurea/farmacología , Pirroles/farmacología , Transducción de Señal , Sorafenib , Sunitinib , Factor de Crecimiento Transformador beta1/antagonistas & inhibidoresRESUMEN
PURPOSE: The MOSAIC (Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) study has demonstrated 3-year disease-free survival (DFS) and 6-year overall survival (OS) benefit of adjuvant oxaliplatin in stage II to III resected colon cancer. This update presents 10-year OS and OS and DFS by mismatch repair (MMR) status and BRAF mutation. METHODS: Survival actualization after 10-year follow-up was performed in 2,246 patients with resected stage II to III colon cancer. We assessed MMR status and BRAF mutation in 1,008 formalin-fixed paraffin-embedded specimens. RESULTS: After a median follow-up of 9.5 years, 10-year OS rates in the bolus/infusional fluorouracil plus leucovorin (LV5FU2) and LV5FU2 plus oxaliplatin (FOLFOX4) arms were 67.1% versus 71.7% (hazard ratio [HR], 0.85; P = .043) in the whole population, 79.5% versus 78.4% for stage II (HR, 1.00; P = .980), and 59.0% versus 67.1% for stage III (HR, 0.80; P = .016) disease. Ninety-five patients (9.4%) had MMR-deficient (dMMR) tumors, and 94 (10.4%) had BRAF mutation. BRAF mutation was not prognostic for OS (P = .965), but dMMR was an independent prognostic factor (HR, 2.02; 95% CI, 1.15 to 3.55; P = .014). HRs for DFS and OS benefit in the FOLFOX4 arm were 0.48 (95% CI, 0.20 to 1.12) and 0.41 (95% CI, 0.16 to 1.07), respectively, in patients with stage II to III dMMR and 0.50 (95% CI, 0.25 to 1.00) and 0.66 (95% CI, 0.31 to 1.42), respectively, in those with BRAF mutation. CONCLUSION: The OS benefit of oxaliplatin-based adjuvant chemotherapy, increasing over time and with the disease severity, was confirmed at 10 years in patients with stage II to III colon cancer. These updated results support the use of FOLFOX in patients with stage III disease, including those with dMMR or BRAF mutation.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Reparación de la Incompatibilidad de ADN , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Quimioterapia Adyuvante , Neoplasias del Colon/genética , Neoplasias del Colon/mortalidad , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Ácido Glutámico , Humanos , Infusiones Intravenosas , Inyecciones Intravenosas , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Oportunidad Relativa , Compuestos Organoplatinos/administración & dosificación , Pronóstico , Resultado del Tratamiento , ValinaRESUMEN
A series of 32 derivatives and isosteres of the mTOR inhibitor 2 were synthesized and compared for their cytotoxicity in radioresistant SQ20B cancer cell line. Several of these compounds, in particular 30b, were significantly more cytotoxic than 2. Importantly, 30b was shown to block both mTORC1 and Akt signaling, suggesting insensitivity to the resistance associated to Akt overactivation observed with rapamycin derivatives currently used in clinic.
Asunto(s)
Antineoplásicos/farmacología , Benzofuranos/química , Benzofuranos/farmacología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Células HT29 , Humanos , Estructura Molecular , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
High-throughput screening (HTS) hit 1 was previously identified as an inhibitor of the Akt/mTOR (Akt/mammalian target of rapamycin) signaling, which is a major target in oncology. The cytotoxicity of 1 was determined on a panel of human cancer cells lines with an IC50 comprised between 30 and 140 µM. Subsequent structure--activity relationship (SAR) studies led us to the identification of compounds that displayed an enhanced cytotoxicity. We demonstrated also that these molecules directly bind to mTOR complex 1 (mTORC1) and inhibit its kinase activity.
Asunto(s)
Benzofuranos/farmacología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Benzofuranos/química , Línea Celular Tumoral , Ensayos Analíticos de Alto Rendimiento , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Advanced pancreatic ductal adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC) are non-curable diseases with a particularly poor prognosis. Over the last decade, research has increasingly focused on the microenvironment surrounding cancer cells, and its role in tumour development and progression. PDAC and HCC differ markedly regarding their pathological features: PDAC are typically stromal-predominant, desmoplastic, poorly vascularized tumours, whereas HCC are cellular and highly vascularized. Despite these very different settings, PDAC and HCC share transforming growth factor-ß (TGF-ß) as a common key-signalling mediator, involved in epithelial-to-mesenchymal transition, invasion, and stroma-tumour dialogue. Recently, novel drugs blocking the TGF-ß pathway have entered clinical evaluation demonstrating activity in patients with advanced PDAC and HCC. TGF-ß signalling is complex and mediates both pro- and anti-tumoural activities in cancer cells depending on their context, in space and time, and their microenvironment. In this review we provide a comprehensive overview of the role of the TGF-ß pathway and its deregulation in PDAC and HCC development and progression at the cellular and microenvironment levels. We also summarize key preclinical and clinical data on the role of TGF-ß as a target for therapeutic intervention in PDAC and HCC, and explore perspectives to optimize TGF-ß inhibition therapy.