Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 11 de 11
Filter
1.
Ann Oncol ; 2024 Jun 08.
Article in English | MEDLINE | ID: mdl-38857846

ABSTRACT

BACKGROUND: Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. The RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC. PATIENTS AND METHODS: This phase II trial was conducted within the Italian TYME network. Eligible patients had treatment-naïve advanced TC. They received ramucirumab, carboplatin and paclitaxel for six cycles, followed by ramucirumab maintenance until disease progression or intolerable toxicity. Primary endpoint was objective response rate (ORR) according to RECIST v1.1 as assessed by the investigator. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Centralized radiologic review was carried out. RESULTS: From November 2018 to June 2023, 52 patients were screened and 35 were enrolled. Median age was 60.8 years, 71.4% of patients were male and 85.7% had Masaoka-Koga stage IVB. The Eastern Cooperative Oncology Group performance status was 0 in 68.5% and 1 in 31.4% of patients. At the present analysis carried out some months after the interim analysis (earlier than expected) on 35 patients, ORR was 80.0% [95% confidence interval (CI) 63.1% to 91.6%]. At the centralized radiological review of 33/35 assessable patients, ORR was 57.6% (95% CI 39.2% to 74.5%). After a median follow-up of 31.6 months, median PFS was 18.1 months (95% CI 10.8-52.3 months) and median OS was 43.8 months (95% CI 31.9 months-not reached). Thirty-two out of 35 patients (91.4%) experienced at least one treatment-related adverse event (AE), of which 48.6% were AE ≥ grade 3. CONCLUSIONS: In previously untreated advanced TC, the addition of ramucirumab to carboplatin and paclitaxel showed the highest activity compared to historical controls, with a manageable safety profile. Despite the small number of patients, given the rarity of the disease, the trial results support the consideration of this combination as first-line treatment in TC.

2.
ESMO Open ; 6(1): 100034, 2021 02.
Article in English | MEDLINE | ID: mdl-33422766

ABSTRACT

BACKGROUND: Platinum-based therapy, combined or not with immune checkpoint inhibitors, represents a front-line choice for patients with non-small-cell lung cancer (NSCLC). Despite the improved outcomes in the last years for this malignancy, only a sub-group of patients have long-term benefit. Excision repair cross-complementation group 1 (ERCC1) has been considered a potential biomarker to predict the outcome of platinum-based chemotherapy in NSCLC. However, the ERCC1 gene is transcribed in four splice variants where the isoform 202 was described as the only one active and able to complex Xeroderma pigmentosum group F-complementing protein (XPF). Here, we prospectively investigated if the active form of ERCC1, as assessed by the ERCC1/XPF complex (ERCC1/XPF), could predict the sensitivity to platinum compounds. PATIENTS AND METHODS: Prospectively enrolled, patients with advanced NSCLC treated with a first-line regimen containing platinum were centrally evaluated for ERCC1/XPF by a proximity ligation assay. Overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were analyzed. RESULTS: The absence of the ERCC1/XPF in the tumor suggested a trend of worst outcomes in terms of both OS [hazard ratio (HR) 1.41, 95% confidence interval (CI) 0.67-2.94, P = 0.373] and PFS (HR 1.61, 95% CI 0.88-3.03, P = 0.123). ORR was marginally influenced in ERCC1/XPF-negative and -positive groups [odds ratio (stable disease + progressive disease versus complete response + partial response) 0.87, 95% CI 0.25-3.07, P = 0.832]. CONCLUSION: The lack of ERCC1/XPF complex in NSCLC tumor cells might delineate a group of patients with poor outcomes when treated with platinum compounds. ERCC1/XPF absence might well identify patients for whom a different therapeutic approach could be necessary.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , DNA-Binding Proteins/genetics , Endonucleases/genetics , Humans , Lung Neoplasms/drug therapy , Platinum/therapeutic use , Prospective Studies
3.
Ann Oncol ; 26(10): 2079-84, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26209642

ABSTRACT

BACKGROUND: The prognostic and predictive role of KRAS mutations in advanced nonsmall-cell lung cancer (NSCLC) is still unclear. TAILOR prospectively assessed the prognostic and predictive value of KRAS mutations in NSCLC patients treated with erlotinib or docetaxel in second line. PATIENTS AND METHODS: NSCLC patients from 52 Italian hospitals were genotyped for KRAS and EGFR mutational status in two independent laboratories. Wild-type EGFR patients (N = 218) received first-line platinum-based chemotherapy and were randomly allocated at progression to erlotinib or docetaxel. Overall survival (OS) according to KRAS mutational status was the primary end point. RESULTS: KRAS mutations were present in 23% of TAILOR randomized cases. The presence of a KRAS mutation did not adversely affect progression-free (PFS) or overall (OS) survival [hazard ratio (HR) PFS = 1.01, 95% confidence interval (CI) 0.71-1.41, P = 0.977; OS = 1.24, 95% CI 0.87-1.77, P = 0.233], nor influenced treatment outcome (test for interaction: OS P = 0.965; PFS P = 0.417). Patients randomized to docetaxel treatment experienced longer survival independently from the KRAS mutational status of their tumors (HR: mutated KRAS 0.81, 95% CI 0.45-1.47; wild-type KRAS 0.79, 95% CI 0.57-1.10). CONCLUSION: In TAILOR, KRAS was neither prognostic nor predictive of benefit for either docetaxel or erlotinib. Docetaxel remains superior independently from KRAS status for second-line treatment in EGFR wild-type advanced NSCLC patients. CLINICAL TRIAL REGISTRATION: NCT00637910.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , Lung Neoplasms/genetics , Mutation/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Adenocarcinoma/drug therapy , Adenocarcinoma/genetics , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Docetaxel , Erlotinib Hydrochloride/administration & dosage , Follow-Up Studies , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Neoplasm Staging , Prognosis , Prospective Studies , Survival Rate , Taxoids/administration & dosage
4.
Pharmacogenomics J ; 14(5): 401-10, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25001881

ABSTRACT

Drug resistance in epithelial ovarian cancer (EOC) limits the efficacy of therapies for this malignancy. This phenomenon might be partially explained by strong inter-individual genomic heterogeneity. Single nucleotide polymorphisms (SNPs) located in specific genes involved in platinum-based drugs inactivation and the metabolism and extrusion of taxanes could be relevant in terms of drugs response prediction. In this paper, we review candidates for genetic markers of treatment outcomes in ovarian cancer. Although an association between SNPs and response to chemotherapy has been detected in several studies, no clear conclusions can be drawn because of conflicting results. Genetic variants in determining response to chemotherapy and clinical outcome need to be clarified in EOC to allow stratification of patients, which would help optimize therapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Female , Genetic Variation/genetics , Humans , Polymorphism, Single Nucleotide/genetics , Treatment Outcome
5.
Pharmacogenomics J ; 13(2): 159-72, 2013 Apr.
Article in English | MEDLINE | ID: mdl-22158331

ABSTRACT

Epithelial ovarian cancer has a poor prognosis owing to late diagnosis and frequent relapse after first-line therapy. Analysis of individual genetic variability could aid in the identification of markers, which could help in stratifying patients with the aim of optimizing individual therapy. In this study we assessed polymorphisms in three genes important in drugs' response in 97 early and 235 late-stage ovarian cancer patients. The Asp1104His polymorphism in xpg, a gene important for removal of platinum adducts, was associated with progression-free survival in early- and late-stage ovarian cancer. Our data indicate that a simple diagnostic analysis such as xpg genotyping can help in predicting response, and extension to other possibly relevant genotypes could be useful in selecting patients with epithelial ovarian cancer for optimal therapy and hence increase the chance of response.


Subject(s)
DNA-Binding Proteins/genetics , Endonucleases/genetics , Nuclear Proteins/genetics , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Transcription Factors/genetics , Adult , Aged , Aged, 80 and over , Biomarkers, Pharmacological/metabolism , DNA Damage/drug effects , DNA Damage/genetics , DNA Repair , Disease-Free Survival , Female , Genetic Association Studies , Humans , Middle Aged , Ovarian Neoplasms/pathology , Platinum/administration & dosage , Platinum/adverse effects , Polymorphism, Genetic , Prognosis , Promoter Regions, Genetic , Proto-Oncogene Proteins c-mdm2/genetics , Treatment Outcome
7.
Cell Death Differ ; 15(5): 849-58, 2008 May.
Article in English | MEDLINE | ID: mdl-18259191

ABSTRACT

Regulation of the p73 gene is complex due to the presence of two promoters and the very complex mRNA maturation in both the N-terminal and C-terminal parts of the protein. We have found an additional regulation mechanism for the p73-alpha form that occurs through proteolytic cleavage connected to the activity of the serine protease HtrA2. Following apoptotic stimuli, HtrA2 accumulates in the nucleus and cleaves p73alpha in the C-terminal portion, enabling the protein to increase its transactivation activity on the apoptotic gene bax but not on the cell-cycle regulator gene p21. In the presence of HtrA2, p73 is more prone to cause caspase activation and nuclei fragmentation: p73 needs HtrA2 to activate and enhance its apoptotic functions. This new relation between p73 and HtrA2 may help to understand the different behavior of the p73 protein in cell physiology and in the responses of cancer cells to chemotherapy.


Subject(s)
Apoptosis/physiology , DNA-Binding Proteins/metabolism , Gene Expression Regulation , Mitochondrial Proteins/metabolism , Nuclear Proteins/metabolism , Serine Endopeptidases/metabolism , Tumor Suppressor Proteins/metabolism , bcl-2-Associated X Protein , Cell Line, Tumor , Cell Nucleus/metabolism , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , DNA-Binding Proteins/genetics , High-Temperature Requirement A Serine Peptidase 2 , Humans , Mitochondrial Proteins/genetics , Nuclear Proteins/genetics , Promoter Regions, Genetic , Protein Isoforms/genetics , Protein Isoforms/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Serine Endopeptidases/genetics , Tumor Protein p73 , Tumor Suppressor Proteins/genetics , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolism
8.
Ann Oncol ; 19(3): 501-7, 2008 Mar.
Article in English | MEDLINE | ID: mdl-17998283

ABSTRACT

BACKGROUND: P63 belongs to the 'p53 family' whose role in cancer progression has been recently revisited in light of the plethora of splicing variants that are generated. We analyzed the expression of the full-length TAp63 gene and its dominant-negative form deltaNp63 in ovarian cancer biopsies to correlate their expression with clinical outcome. MATERIALS AND METHODS: Real-time RT-PCR analysis was used to determine the levels of TAp63 and deltaNp63 in 83 stage I and in 86 stage III ovarian cancer biopsies and in seven human ovarian cancer cell. RESULTS: TAp63 levels were comparable in stage I and stage III, but deltaNp63 levels increased 77-fold in stage III, independently of the p53 status. Patients with high deltaNp63 expression had the worst overall survival (OS); patients with a deltaNp63/TAp63 ratio >2 had a poor OS. Patients with a high deltaNp63/TAp63 ratio were those with a poor response to platinum-based therapy. CONCLUSIONS: Data indicate a role for deltaNp63 as a potential biomarker to predict patient's outcome and tumor progression in ovarian cancer. This would have particularly clinical relevance in ovarian cancer where the high rate of mortality reflects our lack of knowledge of molecular mechanisms underlying cell progression toward malignancy.


Subject(s)
Biomarkers, Tumor/analysis , DNA-Binding Proteins/analysis , Ovarian Neoplasms/genetics , Ovarian Neoplasms/mortality , Trans-Activators/analysis , Tumor Suppressor Proteins/analysis , Biopsy , Disease Progression , Female , Humans , Middle Aged , Mutation , Neoplasm Staging , Ovarian Neoplasms/pathology , Survival Analysis , Transcription Factors
9.
Cell Death Differ ; 12(7): 805-14, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15877106

ABSTRACT

The p73 gene has a complex regulation, which leads to the expression of different isoforms, often with opposite biological effects. We have generated in the human colocarcinoma cell line HCT116, expressing a wild-type p53, an inducible DNp73alpha expressing system. Two clones (HCT116/DN3 and HCT116/DN14), upon doxycycline addition, show a strong expression of DNp73alpha. In vitro the two DNp73alpha overexpressing clones grow at similar rate of the control transfected clone (HCT116/8a) and similarly respond to DNA damage. When injected in mice, HCT116/DN3, HCT116/DN14, and HCT116/8a cells grew similarly in the absence or presence of tetracycline. In HCT116/DN3 and HCT116/DN14 tumors, tetracycline induced a strong expression of DNp73alpha both as mRNA and protein. These results indicate that in this system the overexpression of the DNp73alpha does not induce a more aggressive phenotype and does not seem to be associated with a reduced response of the cells to treatment with anticancer agents.


Subject(s)
DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Neoplasms/drug therapy , Neoplasms/pathology , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Animals , Antibiotics, Antineoplastic/pharmacology , Cell Proliferation/drug effects , DNA Damage/drug effects , Doxorubicin/pharmacology , Doxycycline/pharmacology , Gene Expression , Genes, Tumor Suppressor , HCT116 Cells , Humans , Mice , Neoplasms/genetics , Phenotype , Tumor Protein p73 , Tumor Suppressor Proteins
10.
Oncogene ; 20(50): 7293-300, 2001 Nov 01.
Article in English | MEDLINE | ID: mdl-11704858

ABSTRACT

Tumor neovascularization is controlled by a balance between positive and negative effectors, whose production can be regulated by oncogenes and tumor suppressor genes. The aim of this study was to investigate whether the angiogenic potential of tumors could also be controlled by p73, a gene homologous to the tumor suppressor p53, whose involvement in tumor angiogenesis is known. We have studied the production of proangiogenic (VEGF, FGF-2, PIGF and PDGF) and antiangiogenic (TSP-1) factors in two p73 overexpressing clones obtained from the human ovarian carcinoma cells A2780. TSP-1 was downregulated in both clones compared to mock transfected cells, both at mRNA and protein level. Conversely, both clones showed an increased production of VEGF mRNA and protein. For both TSP-1 and VEGF, regulation of expression was partially due to modulation of the promoter activity, and was dependent on p53 status. Production of the other angiogenic factors FGF-2, PIGF and PDGF-B was also increased in p73 overexpressing clones. The two clones were more angiogenic than parental cells, as shown in vitro by their increased chemotactic activity for endothelial cells, and in vivo by the generation of more vascularized tumors. These findings suggest a potential role of p73 in tumor angiogenesis.


Subject(s)
DNA-Binding Proteins/physiology , Endothelial Growth Factors/biosynthesis , Lymphokines/biosynthesis , Neovascularization, Pathologic/genetics , Nuclear Proteins/physiology , Thrombospondin 1/biosynthesis , Animals , Blotting, Northern , Carcinoma/pathology , Chemotaxis/drug effects , Culture Media, Conditioned/chemistry , Culture Media, Conditioned/pharmacology , Culture Media, Serum-Free , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Endothelial Growth Factors/genetics , Endothelium, Vascular/cytology , Enzyme-Linked Immunosorbent Assay , Female , Fibroblast Growth Factor 2/biosynthesis , Fibroblast Growth Factor 2/genetics , Gene Expression Regulation, Neoplastic , Genes, Tumor Suppressor , Genes, p53 , Humans , Lymphokines/genetics , Membrane Proteins , Mice , Mice, Nude , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Neoplasm Transplantation , Neoplasms, Experimental/blood supply , Neovascularization, Pathologic/metabolism , Nuclear Proteins/biosynthesis , Nuclear Proteins/genetics , Ovarian Neoplasms/pathology , Platelet-Derived Growth Factor/biosynthesis , Platelet-Derived Growth Factor/genetics , Promoter Regions, Genetic , Protein Biosynthesis , Proteins/genetics , RNA, Messenger/biosynthesis , RNA, Neoplasm/biosynthesis , Recombinant Fusion Proteins/physiology , Reverse Transcriptase Polymerase Chain Reaction , Thrombospondin 1/genetics , Transfection , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/metabolism , Tumor Protein p73 , Tumor Suppressor Protein p53/physiology , Tumor Suppressor Proteins , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
11.
Cancer Res ; 61(3): 935-8, 2001 Feb 01.
Article in English | MEDLINE | ID: mdl-11221886

ABSTRACT

We examined the consequences of p73alpha overexpression on gene expression and cellular response to anticancer agents in clones from the human ovarian cancer cell line A2780. Using microarray filters, the expression of 588 genes in two clones overexpressing p73alpha (A2780/p73.4 and A2780/ p73.5) in comparison with empty vector-transfected cells was evaluated. There were clear differences in gene expression profiles. Both of the clones showed a marked increase in the expression of genes involved in DNA repair, including genes participating in nucleotide excision repair and mismatch repair. This was confirmed by reverse transcription-PCR and Northern blot analysis and was associated with an increase in the ability of p73alpha-expressing clones to repair two different DDP (cis-dichlorodiammine platinum)-damaged plasmids in a host reactivation assay. p73alpha overexpressing clones were less sensitive than parental cells to alkylating agents treatment or UV radiation but equally sensitive to the topoisomerase I inhibitor topotecan, which indicated that the increase in expression of DNA repair genes has implications for the response to DNA damaging agents.


Subject(s)
DNA Damage , DNA-Binding Proteins/biosynthesis , Nuclear Proteins/biosynthesis , Ovarian Neoplasms/genetics , Ovarian Neoplasms/metabolism , Cell Division , Cisplatin/pharmacology , Clone Cells , DNA Repair/genetics , DNA-Binding Proteins/genetics , Drug Resistance, Neoplasm , Female , Gene Expression , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Genes, Tumor Suppressor , Humans , Nuclear Proteins/genetics , Ovarian Neoplasms/drug therapy , RNA, Messenger/genetics , RNA, Messenger/metabolism , Topotecan/pharmacology , Transfection , Tumor Cells, Cultured , Tumor Protein p73 , Tumor Suppressor Protein p53/biosynthesis , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Proteins , Ultraviolet Rays/adverse effects
SELECTION OF CITATIONS
SEARCH DETAIL
...