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1.
BMC Cancer ; 22(1): 820, 2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35897060

RESUMO

BACKGROUND: Initial systemic therapy for patients with metastatic colorectal cancer (mCRC) is usually based on two- or three-drug chemotherapy regimens with fluoropyrimidine (5-fluorouracil (5-FU) or capecitabine), oxaliplatin and/or irinotecan, combined with either anti-VEGF (bevacizumab) or, for RAS wild-type (WT) tumors, anti-EGFR antibodies (panitumumab or cetuximab). Recommendations for patients who are not eligible for intensive combination therapies are limited and include fluoropyrimidine plus bevacizumab or single agent anti-EGFR antibody treatment. The use of a monochemotherapy concept of trifluridine/ tipiracil in combination with monoclonal antibodies is not approved for first-line therapy, yet. Results from the phase II TASCO trial evaluating trifluridine/ tipiracil plus bevacicumab in first-line treatment of mCRC patients and from the phase I/II APOLLON trial investigating trifluridine/ tipiracil plus panitumumab in pre-treated mCRC patients suggest favourable activity and tolerability of these new therapeutic approaches. METHODS: FIRE-8 ( NCT05007132 ) is a prospective, randomized, open-label, multicenter phase II study which aims to evaluate the efficacy of first-line treatment with trifluridine/tipiracil (35 mg/m2 body surface area (BSA), orally twice daily on days 1-5 and 8-12, q28 days) plus either the anti-EGFR antibody panitumumab (6 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm A] or (as control arm) the anti-VEGF antibody bevacizumab (5 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm B] in RAS WT mCRC patients. The primary objective is to demonstrate an improved objective response rate (ORR) according to RECIST 1.1 from 30% (control arm) to 55% with panitumumab. With a power of 80% and a two-sided significance level of 0.05, 138 evaluable patients are needed. Given an estimated drop-out rate of 10%, 153 patients will be enrolled. DISCUSSION: To the best of our knowledge, this is the first phase II trial to evaluate the efficacy of trifluridine/tipiracil plus panitumumab in first-line treatment of RAS WT mCRC patients. The administration of anti-EGFR antibodies rather than anti-VEGF antibodies in combination with trifluridine/tipiracil may result in an increased initial efficacy. TRIAL REGISTRATION: EU Clinical Trials Register (EudraCT) 2019-004223-20 . Registered October 22, 2019, ClinicalTrials.gov NCT05007132 . Registered on August 12, 2021.


Assuntos
Neoplasias Colorretais , Trifluridina , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Peso Corporal , Ensaios Clínicos Fase II como Assunto , Neoplasias Colorretais/patologia , Fluoruracila , Humanos , Estudos Multicêntricos como Assunto , Panitumumabe/uso terapêutico , Estudos Prospectivos , Pirrolidinas , Ensaios Clínicos Controlados Aleatórios como Assunto , Timina , Trifluridina/uso terapêutico
2.
ESMO Open ; 9(9): 103703, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39260162

RESUMO

BACKGROUND: Neoadjuvant chemotherapy is an option for patients with locally advanced rectal cancer at low risk for local recurrence. This randomized phase II trial investigated whether the addition of aflibercept to modified FOLFOX6 (mFOLFOX6) could improve the rates of centrally confirmed pathological complete remissions (pCR) and (disease-free) survival in magnetic resonance imaging (MRI)-staged cT3 rectal cancer. PATIENTS AND METHODS: Patients with rectal cancer fulfilling the following criteria were included: lower border of tumor >5 cm and <16 cm from anal verge; circumferential resection margin >2 mm and T3-tumor with a maximum infiltration of 10 mm, as determined by MRI. Patients were randomized 1 : 2 to six cycles mFOLFOX6 ± aflibercept. Surgery was scheduled 4 weeks after chemotherapy. Primary endpoint was the rate of centrally confirmed pCR. The study was designed to detect an improvement of pCR from 10% to 27% (power 80%, type I error 20%). RESULTS: A total of 119 randomized patients started treatment (39 patients mFOLFOX6, arm A, and 80 mFOLFOX + aflibercept, arm B). The incidence of all grade adverse events was similar in both arms, however, adverse events grade ≥3 were more than twice as high in the experimental arm due to hypertension. Surgical complications were comparable. Aflibercept did not improve the pCR rate (arm A 26% versus arm B 19%, P = 0.47) and more patients in arm B had node positivity. With a median follow-up of 40.1 months, the 4-year disease-free survival was 83% in arm A and 85% in arm B (P = 0.82). Only two patients in arm A and one patient in arm B developed local recurrence. CONCLUSIONS: In patients with locally advanced rectal cancer and MRI-defined low risk of local recurrence, neoadjuvant mFOLFOX6 + aflibercept was feasible and did not compromise surgery. Survival data were favorable in both arms, but pCR rates were not increased by the addition of aflibercept.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Fluoruracila , Leucovorina , Imageamento por Ressonância Magnética , Terapia Neoadjuvante , Compostos Organoplatínicos , Receptores de Fatores de Crescimento do Endotélio Vascular , Proteínas Recombinantes de Fusão , Neoplasias Retais , Humanos , Masculino , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/diagnóstico por imagem , Feminino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluoruracila/uso terapêutico , Fluoruracila/farmacologia , Leucovorina/uso terapêutico , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes de Fusão/administração & dosagem , Terapia Neoadjuvante/métodos , Idoso , Compostos Organoplatínicos/uso terapêutico , Imageamento por Ressonância Magnética/métodos , Adulto , Estadiamento de Neoplasias , Intervalo Livre de Doença
3.
Eur J Cancer ; 146: 95-106, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33588150

RESUMO

BACKGROUND: Targeting the epidermal growth factor receptor pathway remains controversial in pancreatic cancer. Afatinib is an oral irreversible ErbB family blocker approved in non-small-cell lung cancer. This open-label, multicenter, randomised phase II trial evaluated gemcitabine plus afatinib (Gem/afatinib) versus gemcitabine (Gem) alone as first-line treatment for metastatic pancreatic cancer. PATIENTS AND METHODS: Patients were randomised in a 2:1 ratio to either Gem (1000 mg/m2 weekly for three weeks followed by one week of rest, repeated every four weeks) and afatinib (40 mg orally once daily) or Gem alone. Overall survival (OS) was the primary study end-point. The novel BOTh©™ methodology was implemented to derive a quantitative estimate for the 'Burden of Therapy/Toxicity' (BOTh) for each patient on every day during the clinical study. RESULTS: One hundred nineteen patients from 25 centres were randomised, 79 patients for Gem/afatinib and 40 for Gem. Median OS was 7.3 months in the Gem/afatinib arm versus 7.4 months in the Gem-alone arm (hazard ratio [HR]: 1.06, p = 0.80). Median progression-free survival was identical in both arms (3.9 months versus 3.9 months, HR: 0.85, p = 0.43). Adverse events were more frequent in the Gem/afatinib arm, especially diarrhoea (71% vs. 13%) and skin rash (65% vs. 5%). The BOTh©™ analysis revealed a significantly higher burden of toxicity in the combination arm (p = 0.0005). CONCLUSION: The addition of afatinib to Gem did not improve treatment efficacy and was more toxic. The BOTh©™ methodology allowed a detailed insight into the course of treatment-related adverse events over the study period. The trial was registered at clinicaltrials.gov (NCT01728818) and Eudra-CT (2011-004063-77).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Afatinib/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/secundário , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Gencitabina
4.
Leukemia ; 18(12): 1964-70, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15483673

RESUMO

In the present work we investigated the role and biological significance of mitogen activated protein kinases (MAPK) in B-cell chronic lymphocytic leukaemia (B-CLL). The MAPK p38 was constitutively activated in B-CLL, but not in normal peripheral B cells. In addition, we demonstrated that the upstream kinases of p38, MKK3/6 were also constitutively activated in B-CLL cells. Furthermore, we determined by EMSA that the p38 MAP kinase pathway was not linked to the constitutive high expression of NF-kappaB, a critical survival factor of B-CLL cells. Recently, it has been shown that serum levels of angiogenic factors like VEGF, bFGF and MMP-9 are elevated in the serum of CLL patients and correlate with an unfavorable prognosis. We showed that the constitutive expression of MMP-9 was dependent on p38-activity and inhibition of p38 strongly downregulated MMP-9 expression. Coculture of B-CLL cells and stromal cells can protect spontaneous apoptosis of leukemic B cells. To determine the role of permanently activated p38 and MMP-9 expression, we cocultured B-CLL cells with bone marrow stromal cells. Survival of B-CLL cells on stroma was severely impaired when p38 was inhibited. Furthermore, blockade of MMP-9 activity also antagonized the antiapoptotic effect of stromal cells.


Assuntos
Células da Medula Óssea/enzimologia , Regulação Enzimológica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/enzimologia , Metaloproteinase 9 da Matriz/metabolismo , Células Estromais/enzimologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Apoptose , Técnicas de Cocultura , Ensaio de Desvio de Mobilidade Eletroforética , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , MAP Quinase Quinase 3/metabolismo , MAP Quinase Quinase 6/metabolismo , Inibidores de Metaloproteinases de Matriz , NF-kappa B/genética , NF-kappa B/metabolismo , Regiões Promotoras Genéticas , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
6.
Exp Hematol ; 28(5): 558-68, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10812246

RESUMO

OBJECTIVE: CpG-oligodeoxynucleotides (CpG-ODN) have been shown to induce proliferation, cytokine production, and surface molecule regulation in normal and malignant human B cells. In the present study, we investigated the potential of CpG-ODN to induce functional high-affinity receptors in leukemic and normal B cells and the effects of costimulation with IL-2 on proliferation, cytokine secretion, and surface molecule regulation. METHODS: Highly purified B cells from B-CLL patients and normal controls were stimulated with CpG-ODN with or without IL-2. Expression of CD25 was determined using FACS, and the presence of high-affinity IL-2 receptors was determined by scatchard analysis. Costimulatory effects of IL-2 and CpG-ODN were investigated using proliferation assays, ELISA (IL-6, TNF-alpha), and FACS analysis (CD80, CD86 expression). Reactivity of autologous and allogeneic T cells toward activated B-CLL cells was determined in mixed lymphocyte reactions and Interferon-gamma Elispot assays. RESULTS: The CpG-ODN DSP30 caused a significantly stronger induction of the IL-2 receptor alpha chain in malignant as compared with normal B cells (p = 0.03). This resulted in the expression of functional high-affinity IL-2 receptors in B-CLL cells, but fewer numbers of receptors with less affinity were expressed in normal B cells. Although addition of IL-2 to CpG-ODN-stimulated cells augmented proliferation in both normal B cells and B-CLL cells, no costimulatory effect on cytokine production or surface molecule expression could be observed in normal B cells. In contrast, TNF-alpha and IL-6 production was increased in B-CLL cells, and the expression of CD80 and CD86 was further enhanced when IL-2 was used as a costimulus. Autologous and allogeneic immune recognition of B-CLL cells stimulated with CpG-ODN and IL-2 was increased compared with B-CLL cells stimulated with CpG-ODN alone. CONCLUSION: Stimulation of B-CLL cells with CpG-ODN and IL-2 might be an attractive strategy for potential immunotherapies for B-CLL patients.


Assuntos
Adjuvantes Imunológicos/farmacologia , Linfócitos B/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Oligodesoxirribonucleotídeos , Oligonucleotídeos/farmacologia , Receptores de Interleucina-2/genética , Antígenos CD/genética , Linfócitos B/efeitos dos fármacos , Antígeno B7-1/genética , Antígeno B7-2 , Citometria de Fluxo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Interleucina-2/farmacologia , Interleucina-6/genética , Cinética , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/patologia , Glicoproteínas de Membrana/genética , Valores de Referência , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/genética
7.
Oncogene ; 34(5): 578-88, 2015 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-24509876

RESUMO

Lung cancer is the leading cause of cancer-related deaths worldwide. Recently, we have shown that Notch1 inhibition resulted in substantial cell death of non-small cell lung cancer (NSCLC) cells in vitro. New compounds targeting Notch signal transduction have been developed and are now being tested in clinical trials. However, the tumorigenic role of individual Notch receptors in vivo remains largely unclear. Using a Kras(G12D)-driven endogenous NSCLC mouse model, we analyzed the effect of conditional Notch1 and Notch2 receptor deletion on NSCLC tumorigenesis. Notch1 deficiency led to a reduced early tumor formation and lower activity of MAPK compared with the controls. Unexpectedly, Notch2 deletion resulted in a dramatically increased carcinogenesis and increased MAPK activity. These mice died significantly earlier due to rapidly growing tumor burden. We found that Notch1 regulates Ras/MAPK pathway via HES1-induced repression of the DUSP1 promoter encoding a phosphatase specifically suppressing pERK1/2. Interestingly, Notch1 but not Notch2 ablation leads to decreased HES1 and DUSP1 expression. However, Notch2-depleted tumors showed an appreciable increase in ß-catenin expression, a known activator of HES1 and important lung cancer oncogene. Characteristically for ß-catenin upregulation, we found that the majority of Notch2-deficient tumors revealed an undifferentiated phenotype as determined by their morphology, E-Cadherin and TTF1 expression levels. In addition, these carcinomas showed aggressive growth patterns with bronchus invasion and obstruction. Together, we show that Notch2 mediates differentiation and has tumor suppressor functions during lung carcinogenesis, whereas Notch1 promotes tumor initiation and progression. These data are further supported by immunohistochemical analysis of human NSCLC samples showing loss or downregulation of Notch2 compared with normal lung tissue. In conclusion, this is the first study characterizing the in vivo functions of Notch1 and Notch2 in Kras(G12D)-driven NSCLC tumorigenesis. These data highlight the clinical importance of a thorough understanding of Notch signaling especially with regard to Notch-targeted therapies.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Transformação Celular Neoplásica/genética , Receptor Notch1/biossíntese , Receptor Notch2/biossíntese , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/genética , Modelos Animais de Doenças , Fosfatase 1 de Especificidade Dupla/biossíntese , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/biossíntese , Humanos , Camundongos , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor Notch1/genética , Receptor Notch2/genética , Transdução de Sinais/genética , Fatores de Transcrição HES-1 , beta Catenina/biossíntese
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