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Aim: Comparison of first-line FOLFIRINOX (FFN) and nab-paclitaxel plus gemcitabine (NabGem) in patients with metastatic pancreatic ductal adenocarcinoma. Patients & methods: The authors analyzed data from 160 patients with metastatic pancreatic adenocarcinoma receiving first-line FFN (n = 43) or NabGem (n = 117). Results: FFN and NabGem were similar in median progression-free survival (24.43 vs 26.28 weeks; hazard ratio [HR]: 0.88) and medial overall survival (47.43 vs 42.86 weeks; HR: 0.90). Of the 43 patients receiving FFN, 26 (60.4%) were treated with second-line NabGem; 14/117 (12.0%) patients receiving NabGem received second-line FFN (p < 0.0001). In the FFN â NabGem and NabGem â FFN groups, median overall survival was 51.2 and 71.6 weeks (HR: 0.69; p = 0.15). In patients receiving NabGem, second-line FFN, compared with FOLFOX/CAPOX or FOLFIRI, improved median progression-free survival 2 (25.6 vs 12.1 weeks; HR: 0.47; p = 0.0067) and median overall survival 2 (39.0 vs 19.14 weeks; HR: 0.49; p = 0.032). Conclusion: First-line FFN and NabGem promote similar clinical outcomes. Second-line FFN should be considered after NabGem.
Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/etiologia , Albuminas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/análogos & derivados , Fluoruracila/efeitos adversos , Humanos , Irinotecano , Leucovorina/efeitos adversos , Oxaliplatina , Paclitaxel/efeitos adversos , Neoplasias Pancreáticas/patologia , Gencitabina , Neoplasias PancreáticasRESUMO
Patients with locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) do not present distant metastases but are not eligible for surgery upfront. Chemotherapy regimens, such as FOLFIRINOX (FFN) or nab-paclitaxel plus gemcitabine (GemNab) in combination with loco-regional treatments are generally used in this setting. However, the best treatment choice is unknown. We retrospectively analyzed the information of 225 patients with stage II-III PDAC treated at our institution between October 2011 and December 2020. A total of 94 patients with LA PDAC who are non-eligible for surgery upfront received neoadjuvant FFN or GemNab. Of the 67 patients receiving FFN, 28 (41.8%) underwent surgery after neoadjuvant therapy. Of the 27 patients treated with GemNab, 6 (22.2%) became eligible for resection. The median overall survival (OS) was 85.1 weeks and 54.3 weeks in the FFN and GemNab groups, respectively (HR = 0.54, p = 0.0109). The median OS was 189.7 weeks and 76.4 weeks in the resected and unresected cohorts, respectively (HR = 0.25, p < 0.0001). Neutropenia (37.3%), anemia (6.0%), and diarrhea (6.0%) in the FFN group and neutropenia (22.2%) and thrombocytopenia (18.5%) in the GemNab groups were the most frequent grade 3-4 side effects. Higher rates of thrombocytosis (p < 0.0001) and peripheral edema (p < 0.0001) were observed in the GemNab group. Our results suggest that the use of FFN is associated with more favorable clinical outcomes than GemNab for patients with LA PDAC. Future randomized and controlled clinical trials are needed to further elucidate the role of these regimens and loco-regional treatments in this setting.
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BACKGROUND: The role of combination chemotherapy has not yet been established in unresectable locally advanced pancreatic cancer (LAPC) lacking dedicated randomized trials. METHODS: This phase II trial tested the efficacy of Nab-paclitaxel (NAB-P)/Gemcitabine (G) versus G alone. Patients were randomized, 1:1 to G 1000 mg/m2 on days 1, 8 and 15 every 28 days versus NAB-P 125 mg/m2 on days 1, 8 and 15 every 28 days plus G 1000 mg/m2 on days 1, 8 and 15 every 28 days. Disease progression rate after three cycles of chemotherapy was the primary end-point. Progression-free survival (PFS), overall survival (OS) and response rate were secondary end-points. FINDINGS: A total of124 patients were enrolled. The study showed a reduction of a progressive disease from 45.6% with G to 25.4% with NAB-P/G (P = 0.01) at 3 months. Noteworthy, at 6 months in the G arm, 35.6% of patients present a metastatic spread versus 20.8% in the NAB/G arm. The response rate was 5.3% in the G arm and 27% in the NAB/G arm. Median PFS was 4 months for the G arm and 7 months for the NAB-P/G arm. Median OS was 10.6 in the G arm and 12.7 months in the NAB-P/G arm. One patient died during treatment with G due to a stroke. INTERPRETATION: NAB-P/G reduced the rate of LAPC patients progressing after three cycles of chemotherapy compared with G, especially in terms of distant relapses. It positively affects PFS. To the best of our knowledge, this is the first randomized trial providing evidence that combination chemotherapy is superior to gemcitabine alone in this setting. CLINICALTRIALS. GOV IDENTIFIER: NCT02043730.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Albuminas/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/patologia , Prognóstico , Taxa de Sobrevida , GencitabinaRESUMO
BACKGROUND: Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death. In cases with metastasis, the combination of 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine-based chemotherapy regimens are considered the standard of care. However, the optimal sequence of these regimens is unclear. METHODS: This retrospective study initially evaluated 186 patients with locally advanced/metastatic pancreatic cancer at three Italian institutions between February 2013 and October 2019. All patients had progressed after receiving gemcitabine-based first-line chemotherapy and were subsequently offered second-line FOLFIRINOX, FOLFOX-6, or FOLFIRI treatment. This study evaluated progression-free survival (PFS), overall survival from the start of second-line treatment (OS2), overall survival from the start of first-line treatment (OS1), and safety outcomes. RESULTS: A total of 77 patients received ⩾4 cycles of second-line chemotherapy and were considered eligible: 15 patients received FOLFIRINOX, 32 patients received FOLFOX-6, and 30 patients received FOLFIRI. The FOLFIRINOX group had median PFS of 26.29 weeks and median OS2 of 47.86 weeks, while the FOLFIRI group had median PFS of 10.57 weeks and median OS2 of 25.00 weeks (p = 0.038). No significant differences were observed between the FOLFIRINOX and FOLFOX-6 groups in terms of PFS (26.29 weeks versus 23.07 weeks) or OS2 (47.86 weeks versus 42.00 weeks). The most common grade 3-4 toxicities were anemia, neutropenia, and thrombocytopenia, which occurred more frequently in the FOLFIRINOX and FOLFOX-6 groups. CONCLUSION: Relative to the FOLFIRI regimen, the FOLFIRINOX regimen had a favorable toxicity profile and better survival outcomes. No significant differences were observed relative to the FOLFOX-6 regimen.
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In several tumors the PI3K/AKT/mTOR pathway is frequently disrupted, an event that results in uncontrolled cell proliferation and tumor growth. Through the years, several compounds have been developed to inhibit the pathway at different steps: the mammalian target of rapamycin (mTOR) seemed to be the most qualified target. However, this kinase has such a key role in cell survival that mechanisms of resistance are rapidly developed. Nevertheless, clinical results obtained with mTOR inhibitors in breast cancer, renal cell carcinoma, neuroendocrine tumors and mantle cell lymphoma push oncologists to actively further develop these drugs, maybe by better selecting the population to which they are offered, through the research of predictive factors of responsiveness. In this review, we aim to describe mechanisms of resistance to mTOR inhibitors, from preclinical and clinical perspectives.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linfoma de Célula do Manto , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Adulto , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Humanos , Inibidores de Proteínas QuinasesRESUMO
The optimal therapeutic strategy for locally advanced pancreatic cancer patients (LAPC) has not yet been established. Our aim is to evaluate how surgery after neoadjuvant treatment with either FOLFIRINOX (FFN) or Gemcitabine-NabPaclitaxel (GemNab) affects the clinical outcome in these patients. LAPC patients treated at our institution were retrospectively analysed to reach this goal. The group characteristics were similar: 35 patients were treated with the FOLFIRINOX regimen and 21 patients with Gemcitabine Nab-Paclitaxel. The number of patients undergoing surgery was 14 in the FFN group (40%) and six in the GemNab group (28.6%). The median Disease-Free Survival (DFS) was 77.10 weeks in the FFN group and 58.65 weeks in the Gem Nab group (p = 0.625), while the median PFS in the unresected group was 49.4 weeks in the FFN group and 30.9 in the GemNab group (p = 0.0029, 95% CI 0.138-0.862, HR 0.345). The overall survival (OS) in the resected population needs a longer follow up to be completely assessed, while the median overall survival (mOS) in the FFN group was 72.10 weeks and 53.30 weeks for the GemNab group (p = 0.06) in the unresected population. Surgery is a valuable option for LAPC patients and it is able to induce a relevant survival advantage. FOLFIRINOX and Gem-NabPaclitaxel should be offered as first options to pancreatic cancer patients in the locally advanced setting.
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Lung cancer is the leading cause of cancer-related mortality around the world, despite effective chemotherapeutic agents, the prognosis has remained poor for a long time. The discovery of molecular changes that drive lung cancer has led to a dramatic shift in the therapeutic landscape of this disease. In "in vitro" and "in vivo" models of NSCLC (Non-Small Cell Lung Cancer), angiogenesis blockade has demonstrated an excellent anti-tumor activity, thus, a number of anti-angiogenic drugs have been approved by regulatory authorities for use in clinical practice. Much more interesting is the discovery of EGFR (Epithelial Growth Factor Receptor) mutations that predict sensitivity to the anti-EGFR Tyrosine Kinase Inhibitors (TKIs), a class of drugs that has shown to significantly improve survival when compared with standard chemotherapy in the first-line treatment of metastatic NSCLC. Nevertheless, after an initial response, resistance often occurs and prognosis becomes dismal. Biomolecular studies on cell line models have led to the discovery of mutations (e.g., T790M) that confer resistance to anti-EGFR inhibitors. Fortunately, drugs that are able to circumvent this mechanism of resistance have been developed and have been recently approved for clinical use. The discovery of robust intratumor lymphocyte infiltration in NSCLC has paved the way to several strategies able to restore the immune response. Thus, agents interfering with PD-1/PD-L1 (Programmed Death) pathways make up a significant portion of the armamentarium of cancer therapies for NSCLC. In all the above-mentioned situations, the basis of the success in treating NSCLC has started from understanding of the mutational landscape of the tumor.
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Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Imunoterapia , Neoplasias Pulmonares/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Humanos , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/farmacologiaRESUMO
BACKGROUND: Intrahepatic cholangiocarcinoma is an aggressive tumor originating in the epithelium of the bile duct, often associated with distant dissemination. The prognosis is poor and treatment is challenging due to low response rate to standard chemotherapy and lack of targeted therapies. CASE PRESENTATION: Here we report the case of a 74-year-old white woman affected by intrahepatic cholangiocarcinoma with metastatic involvement of spleen, lung, peritoneum, and intra-abdominal lymph nodes. As first-line chemotherapy, she was given cisplatin-gemcitabine chemotherapy. The treatment was well tolerated with the exception of grade 1 constipation and a single episode of grade 4 thrombocytopenia occurring after the fourth course. After the first three courses of chemotherapy a computed tomography scan evaluation demonstrated no change; her CA19-9 levels were slightly decreased. However, after the sixth course of chemotherapy a computed tomography scan revealed a dimensional enlargement of the lung metastases; her CA19-9 levels increased. She was then treated with gemcitabine alone. After 2 months of gemcitabine monotherapy a significant regression of lung and spleen metastases, as well a CA19-9 level reduction, occurred. Eight months after the start of gemcitabine monotherapy no signs of progression were reported. CONCLUSIONS: Treatment of metastatic intrahepatic cholangiocarcinoma with gemcitabine as maintenance therapy after first-line chemotherapy could be continued until clear evidence of disease progression since delayed responses are possible.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Ductos Biliares Intra-Hepáticos , Colangiocarcinoma/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Esplênicas/tratamento farmacológico , Idoso , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/secundário , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Neoplasias Pulmonares/secundário , Linfonodos , Metástase Linfática , Quimioterapia de Manutenção , Metástase Neoplásica , Neoplasias Peritoneais/secundário , Neoplasias Esplênicas/secundário , Fatores de Tempo , Resultado do Tratamento , GencitabinaRESUMO
The urokinase-type plasminogen activator receptor (uPAR) is a GPI-anchored cell membrane receptor that focuses urokinase (uPA) proteolytic activity on the cell surface. Its expression is increased in many human cancers, including non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), and correlates with a poor prognosis and early invasion and metastasis. uPAR is able to control, through a cross-talk with tyrosine kinase receptors, the shift between tumor dormancy and proliferation, that usually precedes metastasis formation. Therefore, we investigated the role of uPAR expression in RAS mutated NSCLC and CRC cells. In this study we provided evidence, for the first time, that RAS mutational condition is functionally correlated to uPAR overexpression in NSCLC and CRC cancer cell lines and patient-derived tissue samples. Moreover, oncogenic features related to uPAR overexpression in RAS mutated NSCLC and CRC, such as adhesion, migration and metastatic process may be targeted, in vitro and in vivo, by new anti-uPAR small molecules, specific inhibitors of uPAR-vitronectin interaction. Therefore, anti-uPAR drugs could represent an effective pharmacological strategy for NSCLC and CRC patients carrying RAS mutations.
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Regulação Neoplásica da Expressão Gênica , Mutação , Neoplasias/genética , Neoplasias/patologia , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Proteínas ras/genética , Animais , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas ras/metabolismoRESUMO
BACKGROUND: Several evidences suggest a marked angiogenic dependency in triple-negative breast cancer (TNBC) tumorigenesis and a potential sensitivity to anti-angiogenic agents. Herein, the putative role of Hedgehog (Hh) pathway in regulating TNBC-dependent angiogenesis was investigated. METHODS: Expression and regulation of the Hh pathway transcription factor glioma-associated oncogene homolog1 protein (GLI1) were studied on the endothelial compartment and on TNBC-initiated angiogenesis. To evaluate the translational relevance of our findings, the combination of paclitaxel with the Smo inhibitor NVP-LDE225 was tested in TNBC xenografted mice. RESULTS: Tissue microarray analysis on 200 TNBC patients showed GLI1 overexpression paired with vascular endothelial growth factor receptor 2 (VEGFR2) expression. In vitro, Hh pathway promotes TNBC progression in an autocrine manner, regulating the VEGF/VEGFR2 loop on cancer cell surface, and in a paracrine manner, orchestrating tumour vascularisation. These effects were counteracted by Smo pharmacological inhibition. In TNBC xenografted mice, scheduling NVP-LDE225 rather than bevacizumab provided a better sustained inhibition of TNBC cells proliferation and endothelial cells organisation. CONCLUSIONS: This study identifies the Hh pathway as one of the main regulators of tumour angiogenesis in TNBC, thus suggesting Hh inhibition as a potential new anti-angiogenic therapeutic option to be clinically investigated in GLI1 overexpressing TNBC patients.
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Proteínas Hedgehog/metabolismo , Neovascularização Patológica/metabolismo , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/metabolismo , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/farmacologia , Compostos de Bifenilo/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Células Endoteliais/efeitos dos fármacos , Feminino , Inativação Gênica , Proteínas Hedgehog/antagonistas & inibidores , Células Endoteliais da Veia Umbilical Humana , Humanos , Células MCF-7 , Proteínas de Membrana , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Transplante de Neoplasias , Neovascularização Patológica/tratamento farmacológico , Paclitaxel/administração & dosagem , Piridinas/administração & dosagem , RNA Mensageiro/metabolismo , Trombospondina 1/genética , Trombospondina 1/metabolismo , Análise Serial de Tecidos , Transfecção , Neoplasias de Mama Triplo Negativas/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/análise , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Adulto Jovem , Proteína GLI1 em Dedos de Zinco/análiseRESUMO
Inhibition of the mechanistic target of rapamycin (mTOR) is a promising treatment strategy for several cancer types. Rapamycin derivatives such as everolimus are allosteric mTOR inhibitors acting through interaction with the intracellular immunophilin FKBP12, a prolyl isomerase with different cellular functions. Although mTOR inhibitors have significantly improved survival of different cancer patients, resistance and lack of predictive factors of response remain unsolved issues. To elucidate the mechanisms of resistance to everolimus, we evaluated Met activation in everolimus-sensitive/resistant human cancer cells, in vitro and in vivo. Biochemical and computational analyses were performed. Everolimus-resistant cells were xenografted into mice (10/group) and studied for their response to everolimus and Met inhibitors. The statistical significance of the in vitro results was evaluated by Student's t test.Everolimus reduced Met phosphorylation in everolimus-sensitive cells. This event was mediated by the formation of a Met-FKBP12 complex, which in turn is disrupted by everolimus. Aberrant Met activation in everolimus-resistant cells and overexpression of wild-type/mutant Met caused everolimus resistance. Pharmacological inhibition and RNA silencing of Met are effective in condition of everolimus resistance (P<0.01). In mice xenografted with everolimus-resistant cells, the combination of everolimus with the Met inhibitor PHA665752 reduced tumor growth and induced a statistically significant survival advantage (combination vs control P=0.0005).FKBP12 binding is required for full Met activation and everolimus can inhibit Met. Persistent Met activation might sustain everolimus resistance. These results identify a novel everolimus mechanism of action and suggest the development of clinical strategies based on Met inhibitors in everolimus-resistant cancers.
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Resistencia a Medicamentos Antineoplásicos , Everolimo/farmacologia , Regulação Neoplásica da Expressão Gênica , Receptores Proteína Tirosina Quinases/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Sítio Alostérico , Animais , Linhagem Celular Tumoral , Feminino , Células HCT116 , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fosforilação , Interferência de RNARESUMO
Resistance to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, often related to Ras or secondary EGFR mutations, is a relevant clinical issue in Non-Small Cell Lung Cancer (NSCLC). Although Src TK has been involved in such resistance, clinical development of its inhibitors has been so far limited. To better define the molecular targets of the Src TKIs saracatinib, dasatinib and bosutinib, we used a variety of in vitro/in vivo studies. Kinase assays supported by docking analysis demonstrated that all the compounds directly inhibit EGFR TK variants. However, in live cells only saracatinib efficiently reduced EGFR activation, while dasatinib was the most effective agent in inhibiting Src TK. Consistently, a pronounced anti-proliferative effect was achieved with saracatinib, in EGFR mutant cells, or with dasatinib, in wt EGFR/Ras mutant cells, poorly dependent on EGFR and erlotinib-resistant. We then identified the most effective drug combinations to overcome resistance to EGFR inhibitors, both in vitro and in nude mice: in T790M EGFR erlotinib-resistant cells, saracatinib with the anti-EGFR mAb cetuximab; in Ras mutant erlotinib-resistant models, dasatinib with the MEK inhibitor selumetinib. Src inhibitors may act with different mechanisms in NSCLCs, depending on EGFR/Ras mutational profile, and may be integrated with EGFR or MEK inhibitors for different cohorts of NSCLCs.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas ras/metabolismo , Quinases da Família src/antagonistas & inibidores , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzodioxóis/administração & dosagem , Benzodioxóis/farmacologia , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Cetuximab/administração & dosagem , Cetuximab/farmacologia , Dasatinibe/administração & dosagem , Dasatinibe/farmacologia , Receptores ErbB/genética , Cloridrato de Erlotinib/administração & dosagem , Cloridrato de Erlotinib/farmacologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/metabolismo , Quinazolinas/administração & dosagem , Quinazolinas/farmacologia , Interferência de RNA , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas ras/genética , Quinases da Família src/genética , Quinases da Família src/metabolismoRESUMO
INTRODUCTION: Src tyrosine kinase overactivation has been correlated with a poor response to human epidermal growth factor receptor 2 (HER2) inhibitors in breast cancer. To identify the mechanism by which Src overexpression sustains this resistance, we tested a panel of breast cancer cell lines either sensitive or resistant to lapatinib. METHODS: To determine the role of Src in lapatinib resistance, we evaluated the effects of Src inhibition/silencing in vitro on survival, migration, and invasion of lapatinib-resistant cells. In vivo experiments were performed in JIMT-1 lapatinib-resistant cells orthotopically implanted in nude mice. We used artificial metastasis assays to evaluate the effect of Src inhibition on the invasiveness of lapatinib-resistant cells. Src-dependent signal transduction was investigated with Western blot and ELISA analyses. RESULTS: Src activation was higher in lapatinib-resistant than in lapatinib-sensitive cells. The selective small-molecule Src inhibitor saracatinib combined with lapatinib synergistically inhibited the proliferation, migration, and invasion of lapatinib-resistant cells. Saracatinib combined with lapatinib significantly prolonged survival of JIMT-1-xenografted mice compared with saracatinib alone, and impaired the formation of lung metastases. Unexpectedly, in lapatinib-resistant cells, Src preferentially interacted with epidermal growth factor receptor (EGFR) rather than with HER2. Moreover, EGFR targeting and lapatinib synergistically inhibited survival, migration, and invasion of resistant cells, thereby counteracting Src-mediated resistance. These findings demonstrate that Src activation in lapatinib-resistant cells depends on EGFR-dependent rather than on HER2-dependent signaling. CONCLUSIONS: Complete pharmacologic EGFR/HER2 inhibition is required to reverse Src-dependent resistance to lapatinib in breast cancer.
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Neoplasias da Mama/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Quinazolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Quinases da Família src/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzodioxóis/farmacologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Receptores ErbB/metabolismo , Feminino , Humanos , Lapatinib , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/genética , Transplante de Neoplasias , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , RNA Interferente Pequeno , Receptor ErbB-2/metabolismo , Transdução de Sinais/genética , Transplante Heterólogo , Quinases da Família src/genética , Quinases da Família src/metabolismoRESUMO
The mTOR inhibitor everolimus is currently approved for the treatment of renal cell carcinoma (RCC) and several Toll-like receptor 9 (TLR9) agonists, including immunomodulatory oligonucleotides (IMOs), have been tested for their therapeutic potential against advanced RCC. However, no clinical trials investigating the combination of mTOR inhibitors with TLR9 agonists in RCC patients have been performed to date. Our results may pave the way to translate this combinatorial approach to the clinical setting.
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A low-intensity laser is used in treating herpes labialis based on the biostimulative effect, albeit the photobiological basis is not well understood. In this work experimental models based on Escherichia coli cultures and plasmids were used to evaluate effects of low-intensity red laser on DNA at fluences for treatment of herpes labialis. To this end, survival and transformation efficiency of plasmids in E. coli AB1157 (wild type), BH20 (fpg/mutM(-)) and BW9091 (xthA(-)), content of the supercoiled form of plasmid DNA, as well as nucleic acids and protein content from bacterial cultures exposed to the laser, were evaluated. The data indicate low-intensity red laser: (i) alters the survival of plasmids in wild type, fpg/mutM(-) and xthA(-)E. coli cultures depending of growth phase, (ii) alters the content of the supercoiled form of plasmids in the wild type and fpg/mutM(-)E. coli cells, (iii) alters the content of nucleic acids and proteins in wild type E. coli cells, (iv) alters the transformation efficiency of plasmids in wild type and fpg/mutM(-)E. coli competent cells. These data could be used to understand positive effects of low-intensity lasers on herpes labialis treatment.
Assuntos
Escherichia coli/efeitos da radiação , Herpes Labial/genética , Lasers , Plasmídeos/metabolismo , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Ácidos Nucleicos/metabolismo , Plasmídeos/química , Transformação Bacteriana/efeitos da radiaçãoRESUMO
PURPOSE: Although the anti-EGF receptor (EGFR) monoclonal antibody cetuximab is an effective strategy in colorectal cancer therapy, its clinical use is limited by intrinsic or acquired resistance. Alterations in the "sphingolipid rheostat"-the balance between the proapoptotic molecule ceramide and the mitogenic factor sphingosine-1-phosphate (S1P)-due to sphingosine kinase 1 (SphK1) overactivation have been involved in resistance to anticancer-targeted agents. Moreover, cross-talks between SphK1 and EGFR-dependent signaling pathways have been described. EXPERIMENTAL DESIGN: We investigated SphK1 contribution to cetuximab resistance in colorectal cancer, in preclinical in vitro/in vivo models, and in tumor specimens from patients. RESULTS: SphK1 was found overexpressed and overactivated in colorectal cancer cells with intrinsic or acquired resistance to cetuximab. SphK1 contribution to resistance was supported by the demonstration that SphK1 inhibition by N,N-dimethyl-sphingosine or silencing via siRNA in resistant cells restores sensitivity to cetuximab, whereas exogenous SphK1 overexpression in sensitive cells confers resistance to these agents. Moreover, treatment of resistant cells with fingolimod (FTY720), a S1P receptor (S1PR) antagonist, resulted in resensitization to cetuximab both in vitro and in vivo, with inhibition of tumor growth, interference with signal transduction, induction of cancer cells apoptosis, and prolongation of mice survival. Finally, a correlation between SphK1 expression and cetuximab response was found in colorectal cancer patients.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Neoplasias Colorretais/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cetuximab , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Cloridrato de Fingolimode , Expressão Gênica , Humanos , Camundongos , Camundongos Nus , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Propilenoglicóis/farmacologia , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Receptores de Esfingosina-1-Fosfato , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Low-intensity red lasers are proposed for treatment of oral aphthous ulcers based on biostimulative effects. However, effects of low-intensity lasers at fluences used in clinical protocols on DNA are controversial. The aim of this work was to evaluate the effects of low-intensity red laser on survival and induction of filamentation of Escherichia coli cells, and induction of DNA lesions in bacterial plasmids. Escherichia coli cultures were exposed to laser (660 nm, 100 mW, 25 and 45 J cm(-2)) to study bacterial survival and filamentation. Also, bacterial plasmids were exposed to laser to study DNA lesions by electrophoretic profile and action of DNA repair enzymes. Data indicate that low-intensity red laser: (i) had no effect on survival of E. coli wild type, exonuclease III and formamidopyrimidine DNA glycosylase/MutM protein but decreased the survival of endonuclease III deficient cultures; (ii) induced bacterial filamentation, (iii) there was no alteration in the electrophoretic profile of plasmids in agarose gels, (iv) there was no alteration in the electrophoretic profile of plasmids incubated with formamidopyrimidine DNA glycosylase/MutM protein and endonuclease III enzymes, but it altered the electrophoretic profile of plasmids incubated with exonuclease III. Low-intensity red laser at therapeutic fluences has an effect on the survival of E. coli endonuclease III deficient cells, induces bacterial filamentation in E. coli cultures and DNA lesions targeted by exonuclease III.
Assuntos
DNA/metabolismo , Escherichia coli/efeitos da radiação , Lasers , DNA-Formamidopirimidina Glicosilase/genética , DNA-Formamidopirimidina Glicosilase/metabolismo , Escherichia coli/enzimologia , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Exodesoxirribonucleases/genética , Exodesoxirribonucleases/metabolismo , Plasmídeos/química , Plasmídeos/metabolismoRESUMO
The combination of EGFR inhibitors and anti-angiogenic drugs has a strong pre-clinical rationale, yet its use has produced controversial clinical results. We conducted two sequential phase I trials to evaluate the feasibility and the recommended dose of erlotinib when combined with fluoropyrimidine-oxaliplatin-based chemotherapy with or without bevacizumab. A total of 21 metastatic colorectal cancer (mCRC) patients were treated in two sequential phase I trials. In the first trial, 12 patients were treated with escalating doses of erlotinib plus FOLFOX. In the second, 9 patients were treated with escalating doses of erlotinib combined with oxaliplatin, capecitabine and bevacizumab. No MTD was reached in either of the trials. The only dose-limiting toxicities observed were neutropenia and diarrhea. No unexpected toxicities were noted. Hematological toxicity was the most frequently noted adverse event with infusional 5FU therapy, while gastrointestinal toxicity was the most common adverse event. In the second trial most patients withdrew from treatment due to toxicity, and less than half completed the therapeutic program as per protocol, mostly due to toxicity. In conclusion, the present study confirms the disappointing results of the double combination of EGFR inhibitors and anti-angiogenic drugs in mCRC patients.