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ABSTRACT: MicroRNAs are small, noncoding RNAs that suppress gene expression by binding to the 3' untranslated region (UTR) and thereby repress translation or decrease messenger RNA stability. Inhibitor of differentiation 1 (ID1) is a putative stem-cell gene involved in invasion and angiogenesis. We previously showed that ID1 is regulated by Src kinases, overexpressed in human lung adenocarcinoma, and targeted by Src-dependent microRNAs. The current study focused on the association between miR-381 and ID1 in lung adenocarcinoma.
An ID1 3'UTR-luciferase reporter assay was used to determine whether miR-381 directly targets ID1. Human lung cancer cell lines were stably transduced with a precursor of miR-381 to evaluate its role on ID1 expression and to investigate changes in cell migration and invasion. The Src tyrosine kinase inhibitors saracatinib and dasatinib were used to repress ID1 expression. MiR-381 expression was measured in 18 human lung adenocarcinomas and corresponding normal lung tissue by quantitative reverse-transcription polymerase chain reaction.
ID1 is a direct target of miR-381 as shown by 3'UTR luciferase reporter assays. MiR-381 expression was negatively correlated with ID1 expression in lung cancer cell lines. Ectopic expression of miR-381 reduced ID1 mRNA and protein levels, and significantly decreased cell migration and invasion. Furthermore, miR-381 was significantly downregulated in human lung adenocarcinomas, and low miR-381 expression levels correlated with poor prognosis.
These results suggest that downregulation of miR-381 and thus induction of its target ID1 may contribute to the metastatic potential of lung adenocarcinomas. Further studies to explore potential therapeutic strategies, including Src inhibitors, are ongoing.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 05/2012; 7(7):1069-77. · 4.55 Impact Factor
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ABSTRACT: To review selected biomarkers of DNA repair and related pathways as they relate to the management of patients with non-small cell lung cancer (NSCLC), emphasizing the role of individualized, chemotherapy for advanced disease, and discussing potential applications in early disease.
The activity of molecular-targeted agents in NSCLC patients whose tumor possesses relevant biomarkers [such as epidermal growth factor receptor (EGFR) activating mutations and ALK translocations] has made personalized therapy possible. In addition, preclinical and clinical studies have shown that histopathological and biomolecular factors can correlate with clinical outcome in patients with NSCLC treated with chemotherapy. As a result, tumor histology is now routinely considered in selecting chemotherapy for NSCLC patients, such as pemetrexed for nonsquamous histology. Molecular tumor and host factors, including genes involved in DNA-repair and synthesis, are potentially even more relevant as predictive biomarkers of tumor response to chemotherapy. However, individual molecular markers and gene signatures need further validation and standardization, before routine use in the clinic can be recommended.
In the era of molecular-targeted agents, individualized therapy based on molecular biomarkers has become a reality in the treatment of patients with advanced NSCLC. Further studies are needed to optimize current treatment algorithms with regard to biomarkers for chemotherapy benefit, to refine molecular markers, and to translate these findings to early stage NSCLC.
Current opinion in oncology 03/2011; 23(2):150-7. · 4.09 Impact Factor
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ABSTRACT: • To analyse the outcome in selected patients with initially unresectable or minimally metastatic muscle-invasive urothelial bladder cancer who underwent induction chemotherapy (IC) followed by radical cystectomy (RC).
• Thirty patients with initially unresectable, locally advanced or minimally metastatic bladder cancer underwent platinum-based IC followed by RC with curative intent at our institution from 2000 to 2007. • They received a median of four cycles (range 2-6 cycles) of cisplatin and gemcitabine (n= 19), carboplatin and gemcitabine (n= 9) or other platinum combinations (n= 2). • We retrospectively analysed all 30 patients for complete pathological remission (pT0), disease free survival (DFS) and overall survival (OS). Chi-square tests, Kaplan-Meier analyses, and Cox univariate modelling were used.
• Before IC, 30 patients were deemed unresectable because of locally advanced tumour classification (cT4, 18/30) and/or clinically suspected lymph node (LN) metastasis (21/30) or suspected distant metastasis (3/30). • At re-staging after IC there was a complete regression of all enlarged LN in 16/21 patients, a partial LN response in one patient or stable LN size in the remaining four patients. • After RC, 9/30 (30%) of patients had attained pT0. • The median follow-up was 28 months (range 4-97 months). The 5-year DFS and OS rates were 42% and 46%, respectively, for all patients. • In the pT0 patients, the DFS (83%) and OS (71%) rates were significantly higher than in non-pT0 patients.
• Patients undergoing IC followed by RC showed encouraging response and survival rates, suggesting that selected patients with initially unresectable bladder cancer benefit from this combined regimen.
BJU International 03/2011; 107(6):894-7. · 2.84 Impact Factor
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ABSTRACT: Inhibitor of differentiation 1 (ID1) plays a role in cellular differentiation, proliferation, angiogenesis and tumor invasion. As shown recently, ID1 is positively regulated by the tyrosine kinase SRC in lung carcinoma cell lines and with that appears as a potential new therapeutic target in non-small cell carcinoma (NSCLC). To substantiate this hypothesis we examined ID1, SRC and matrix metalloproteinase-9 (MMP-9) immunohistochemically in human NSCLC specimens.
From 61 consecutive patient tissue samples of a tumor tissue bank a one core tissue microarray (TMA) was produced and whole slide tissue samples of preinvasive lesions used. The staining of commercial antibodies was assessed by the H-score. Statistical analyses based on Spearman's rank correlation coefficient.
ID1 was expressed in the nucleus in 70% of squamous cell carcinomas and 50% of non-squamous cell carcinomas and in vascular endothelium of non-tumor tissue. Cytoplasmic staining was found in all samples for SRC and in 93% for MMP-9. ID1-positive tissue samples co-expressed SRC and MMP-9 in 94%. In non-squamous cell carcinomas, H-scores of ID1 and SRC correlated with each other (p=0.04). H-score of MMP-9 correlated with tumor grade (p=0.04). The carcinoma findings were reflected in preinvasive lesions.
We describe for the first time the immunohistochemical expression of ID1 in the majority of NSCLC samples. The almost general co-expression of ID1, SRC and MMP-9 supports their cooperation in vivo and warrants further investigation of ID1 as a therapeutic target.
Lung cancer (Amsterdam, Netherlands) 03/2011; 71(3):306-11. · 3.14 Impact Factor
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ABSTRACT: We assessed adherence to the European Society of Medical Oncology (ESMO)/Multinational Association of Supportive Care in Cancer recommendations for prophylaxis of chemotherapy-induced nausea and vomiting (CINV) at our institution.
The charts of 299 patients starting a new chemotherapy between November 2008 and April 2009 were reviewed. Baseline characteristics and prophylaxis of CINV during the first cycle were recorded, and adherence to ESMO recommendations was determined. Chi-square tests and logistic regression were used to test for predictors of adherence.
Prophylaxis of acute CINV was not adherent in 39% of the patients: 39 of 54 patients with low emetogenic chemotherapy had a serotonin antagonist, and 24 of 100 with moderately emetogenic therapy had a neurokinin antagonist. Nevertheless, 71% of the patients treated with highly emetogenic therapy received the guideline-specified prescription. Prophylaxis of delayed CINV was not adherent in 89% of the patients: 101 of 125 patients with highly or moderately emetogenic single-day chemotherapy received a serotonin antagonist. Male gender (odds ratio (OR) 0.484, 95% confidence interval (CI) 0.291-0.806; P = 0.005) and hematologic neoplasia (OR 2.151, 95% CI 1.19-3.887; P = 0.011) were independent predictors of non-adherence. Age (OR 0.981, 95% CI 0.964-0.998; P = 0.029) and inpatient treatment (OR 0.457, 95% CI 0.25-0.836; P = 0.011) indicated a lower risk of non-adherence.
Contrary to older studies reporting frequent omissions of corticosteroids, the current study demonstrated significant overuse of serotonin antagonists for prophylaxis of delayed CINV.
Supportive Care in Cancer 01/2011; 20(1):141-7. · 2.09 Impact Factor
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ABSTRACT: Src tyrosine kinases regulate multiple genetic and signaling pathways involved in the proliferation, survival, angiogenesis, invasion, and migration of various types of cancer cells They are frequently expressed and activated in many cancer types, including lung cancer. Several Src inhibitors, including dasatinib, saracatinib, bosutinib, and KX2-391, are currently being investigated in clinical trials. Preliminary results of the use of single-agent Src inhibitors in unselected patients with lung cancer show that these inhibitors have a favorable safety profile and anticancer activity. Their combination with cytotoxic chemotherapy, other targeted therapy, and radiation therapy is currently being explored. In this review, we summarize the rationale for and the current status of Src inhibitor development and discuss future directions based on emerging preclinical data.
Clinical Lung Cancer 07/2010; 11(4):238-42. · 2.94 Impact Factor
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Oliver Gautschi
Clinical Lung Cancer 03/2010; 11(2):80-1. · 2.94 Impact Factor
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David R Gandara,
Tomoya Kawaguchi,
John Crowley,
James Moon,
Kiyoyuki Furuse,
Masaaki Kawahara,
Satoshi Teramukai,
Yuichiro Ohe,
Kaoru Kubota,
Stephen K Williamson, Oliver Gautschi,
Heinz Josef Lenz,
Howard L McLeod,
Primo N Lara,
Charles Arthur Coltman,
Masahiro Fukuoka,
Nagahiro Saijo,
Masanori Fukushima,
Philip C Mack
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ABSTRACT: PURPOSE To explore whether population-related pharmacogenomics contribute to differences in patient outcomes between clinical trials performed in Japan and the United States, given similar study designs, eligibility criteria, staging, and treatment regimens. METHODS We prospectively designed and conducted three phase III trials (Four-Arm Cooperative Study, LC00-03, and S0003) in advanced-stage, non-small-cell lung cancer, each with a common arm of paclitaxel plus carboplatin. Genomic DNA was collected from patients in LC00-03 and S0003 who received paclitaxel (225 mg/m(2)) and carboplatin (area under the concentration-time curve, 6). Genotypic variants of CYP3A4, CYP3A5, CYP2C8, NR1I2-206, ABCB1, ERCC1, and ERCC2 were analyzed by pyrosequencing or by PCR restriction fragment length polymorphism. Results were assessed by Cox model for survival and by logistic regression for response and toxicity. Results Clinical results were similar in the two Japanese trials, and were significantly different from the US trial, for survival, neutropenia, febrile neutropenia, and anemia. There was a significant difference between Japanese and US patients in genotypic distribution for CYP3A4*1B (P = .01), CYP3A5*3C (P = .03), ERCC1 118 (P < .0001), ERCC2 K751Q (P < .001), and CYP2C8 R139K (P = .01). Genotypic associations were observed between CYP3A4*1B for progression-free survival (hazard ratio [HR], 0.36; 95% CI, 0.14 to 0.94; P = .04) and ERCC2 K751Q for response (HR, 0.33; 95% CI, 0.13 to 0.83; P = .02). For grade 4 neutropenia, the HR for ABCB1 3425C-->T was 1.84 (95% CI, 0.77 to 4.48; P = .19). CONCLUSION Differences in allelic distribution for genes involved in paclitaxel disposition or DNA repair were observed between Japanese and US patients. In an exploratory analysis, genotype-related associations with patient outcomes were observed for CYP3A4*1B and ERCC2 K751Q. This common-arm approach facilitates the prospective study of population-related pharmacogenomics in which ethnic differences in antineoplastic drug disposition are anticipated.
Journal of Clinical Oncology 06/2009; 27(21):3540-6. · 18.37 Impact Factor
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ABSTRACT: With the emergence of Src inhibitors in clinical trials, improved knowledge of the molecular responses of cancer cells to these agents is warranted. This will facilitate the development of tests to identify patients who may benefit from these agents, allow drug activity to be monitored and rationalize the combination of these agents with other treatment modalities.
This study evaluated the molecular and functional effects of Src inhibitor AZD0530 in human lung cancer cells, by Western blotting and reverse transcription-polymerase chain reaction, and by assays for cell viability, migration, and invasion.
Src was activated in four of five cell lines tested and the level corresponded with the invasive potential and the histologic subtype. Clinically relevant, submicromolar concentrations of AZD0530 blocked Src and focal adhesion kinase, resulting in significant inhibition of cell migration and Matrigel invasion. Reactivation of STAT3 and up-regulation of JAK indicated a potential mechanism of resistance. AZD0530 gave a potent and sustained blockage of AKT and enhanced the sensitivity to irradiation.
The results indicated that AZD0530, aside from being a potent inhibitor of tumor cell invasion which could translate to inhibition of disease progression in the clinic, may also lower resistance of lung cancer cells to pro-apoptotic signals.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 03/2009; 4(4):448-54. · 4.55 Impact Factor
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Oliver Gautschi,
Clifford G Tepper,
Phillip R Purnell,
Yoshihiro Izumiya,
Christopher P Evans,
Tim P Green,
Pierre Y Desprez,
Primo N Lara,
David R Gandara,
Philip C Mack,
Hsing-Jien Kung
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ABSTRACT: Deregulated activation of the Src tyrosine kinase and heightened Id1 expression are independent mediators of aggressive tumor biology. The present report implicates Src signaling as a critical regulator of Id1 gene expression. Microarray analyses showed that Id family genes were among the most highly down-regulated by incubation of A549 lung carcinoma cells with the small-molecule Src inhibitor AZD0530. Id1 transcript and protein levels were potently reduced in a dose-dependent manner concomitantly with the reduction of activated Src levels. These effects were conserved across a panel of lung, breast, prostate, and colon cancer cell lines and confirmed by the ability of PP2, Src siRNA, and Src-blocking peptides to suppress Id1 expression. PP2, AZD0530, and dominant-negative Src abrogated Id1 promoter activity, which was induced by constitutively active Src. The Src-responsive region of the Id1 promoter was mapped to a region 1,199 to 1,360 bps upstream of the translation start site and contained a Smad-binding element. Src was also required for bone morphogenetic protein-2 (BMP-2)-induced Id1 expression and promoter activity, was moderately activated by BMP-2, and complexed with Smad1/5. Conversely, Src inhibitors blocked Smad1/5 nuclear translocation and binding to the Src-responsive region of the Id1 promoter. Consistent with a role for Src and Id1 in cancer cell invasion, Src inhibitors and Id1 siRNA decreased cancer cell invasion, which was increased by Id1 overexpression. Taken together, these results reveal that Src positively interacts with the BMP-Smad-Id pathway and provide new ways for targeted inhibition of Id1.
Cancer Research 05/2008; 68(7):2250-8. · 7.86 Impact Factor
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ABSTRACT: The human aurora family of serine-threonine kinases comprises three members, which act in concert with many other proteins to control chromosome assembly and segregation during mitosis. Aurora dysfunction can cause aneuploidy, mitotic arrest, and cell death. Aurora kinases are strongly expressed in a broad range of cancer types. Aurora A expression in tumors is often associated with gene amplification, genetic instability, poor histologic differentiation, and poor prognosis. Aurora B is frequently expressed at high levels in a variety of tumors, often coincidently with aurora A, and expression level has also been associated with increased genetic instability and clinical outcome. Further, aurora kinase gene polymorphisms are associated with increased risk or early onset of cancer. The expression of aurora C in cancer is less well studied. In recent years, several small-molecule aurora kinase inhibitors have been developed that exhibit preclinical activity against a wide range of solid tumors. Preliminary clinical data from phase I trials have largely been consistent with cytostatic effects, with disease stabilization as the best response achieved in solid tumors. Objective responses have been noted in leukemia patients, although this might conceivably be due to inhibition of the Abl kinase. Current challenges include the optimization of drug administration, the identification of potential biomarkers of tumor sensitivity, and combination studies with cytotoxic drugs. Here, we summarize the most recent preclinical and clinical data and discuss new directions in the development of aurora kinase inhibitors as antineoplastic agents.
Clinical Cancer Research 04/2008; 14(6):1639-48. · 7.74 Impact Factor
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ABSTRACT: Cancer immunotherapy has made great progress because of advances in immunology and molecular biology. Increased understanding of mechanisms by which lung cancer cells escape the immune system and recognition of key tumor antigens and immune system components involved in tumor ignorance have led to the development of a variety of lung cancer vaccines. Immunotherapy has advanced from using nonspecific immunomodulatory agents to lung cancer-specific tumor antigens and tumor cell-derived vaccines. While understanding of immune processes and malignancy has improved, there is great opportunity for further research of vaccine therapies in non-small-cell lung cancer. Herein, we review the development and evolution of early lung cancer vaccine trials.
Clinical Lung Cancer 03/2008; 9 Suppl 1:S20-7. · 2.94 Impact Factor
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ABSTRACT: At present, selection of chemotherapy regimens for individual patients remains largely an empirical process. Nevertheless, developing pharmacogenomic approaches for selection of chemotherapy through predictive biomarkers now appears feasible because of improved understanding of underlying molecular mechanisms. Although diverse terminology has been applied to such pharmacogenomic approaches (individualizing, customizing, or personalizing therapy), all rely on commonly shared principles for assessing tumor- or host-related factors. Herein, we summarize emerging data regarding pharmacogenomic approaches to treatment selection for non-small-cell lung cancer, focusing primarily on biomarkers relevant to 2 important chemotherapeutic drug classes: platinum compounds and antimicrotubule agents. The results of pilot studies and the first randomized prospective trial testing this concept are described, including limitations in the clinical setting of advanced-stage disease. Methodologic and technical aspects of pharmacogenomic approaches are elucidated, recommendations for clinical application are provided, and new directions in this field are projected.
Clinical Lung Cancer 01/2008; 9 Suppl 3:S129-38. · 2.94 Impact Factor
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ABSTRACT: The association of simian virus 40 (SV40) with malignant pleural mesothelioma is currently under debate. In some malignancies of viral aetiology, viral DNA can be detected in the patients' serum or plasma. To characterize the prevalence of SV40 in Swiss mesothelioma patients, we optimized a real-time PCR for quantitative detection of SV40 DNA in plasma, and used a monoclonal antibody for immunohistochemical detection of SV40 in mesothelioma tissue microarrays. Real-time PCR was linear over five orders of magnitude, and sensitive to a single gene copy. Repeat PCR determinations showed excellent reproducibility. However, SV40 status varied for independent DNA isolates of single samples. We noted that SV40 detection rates by PCR were drastically reduced by the implementation of strict room compartmentalization and decontamination procedures. Therefore, we systematically addressed common sources of contamination and found no cross-reactivity with DNA of other polyomaviruses. Contamination during PCR was rare and plasmid contamination was infrequent. SV40 DNA was reproducibly detected in only 4 of 78 (5.1%) plasma samples. SV40 DNA levels were low and not consistently observed in paired plasma and tumour samples from the same patient. Immunohistochemical analysis revealed a weak but reproducible SV40 staining in 16 of 341 (4.7%) mesotheliomas. Our data support the occurrence of non-reproducible SV40 PCR amplifications and underscore the importance of proper sample handling and analysis. SV40 DNA and protein were found at low prevalence (5%) in plasma and tumour tissue, respectively. This suggests that SV40 does not appear to play a major role in the development of mesothelioma.
Lung Cancer 10/2007; 57(3):282-91. · 3.43 Impact Factor
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ABSTRACT: Chemotherapy continues to play an essential role in the treatment of most stages of non-small-cell lung cancer (NSCLC). In fact, within the past 5 years, this role has greatly expanded into adjuvant therapy for early-stage resected disease. Likewise, agents targeting the epidermal growth factor receptor (EGFR), particularly the tyrosine kinase inhibitors gefitinib and erlotinib, have proven to be clinically active in patients with advanced-stage NSCLC. Because of these findings, it is logical to expect that combinations of these 2 classes of antineoplastic agents would prove more efficacious than either one alone. Yet 4 large randomized phase III trials of chemotherapy with or without an EGFR tyrosine kinase inhibitor in unselected patients with advanced-stage NSCLC, altogether totaling > 4000 patients, did not demonstrate improvement in clinical outcomes with the combination. Whether these negative results will be reproduced in ongoing combination studies of chemotherapy plus monoclonal antibodies directed against EGFR remain to be determined. Herein, we review recent preclinical and clinical data addressing this topic and explore the biologic rationale for developing new combination strategies based on patient selection by molecular and clinical factors, or by pharmacodynamic parameters.
Clinical Lung Cancer 03/2007; 8 Suppl 2:S61-7. · 2.94 Impact Factor
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ABSTRACT: To review the evidence implicating the deregulation of cyclin D1 in the pathogenesis of non-small cell lung cancer (NSCLC), and to discuss the opportunities for targeted clinical intervention.
Data published until June 2006 are summarized, and previously unpublished results from our own research are included.
In normal cells, cyclin D1 complexes with and activates cyclin-dependent kinases (CDK) and acts as a transcriptional regulator. The protein is frequently overexpressed in a wide range of cancers, sometimes coincident with CCND1 (cyclin D1) gene amplification (5-20% of tumours). A low level of somatic mutations have been seen in certain tumours. CCND1 is amplified in NSCLC and cyclin D1 is frequently overexpressed in tumours and pre-invasive bronchial lesions, generally from one parental allele. Mutation analyses revealed a frequent CCND1 gene polymorphism (A870G) that modulates alternative splicing and allows expression of an alternative cyclin D1 transcript (transcript cyclin D1b). The encoded cyclin D1b protein lacks a specific phosphorylation site required for nuclear export. Genotype has been correlated with the risk and/or severity of disease or drug response across a range of malignancies, including lung cancer. Together, these findings suggest a strong pathological role for cyclin D1 deregulation in bronchial neoplasia.
Current data indicate that cyclin D1 overexpression is not a consequence of, but rather a pivotal element in the process of malignant transformation in the lung and other tissues. This understanding may open new avenues for lung cancer diagnosis, treatment and prevention.
Lung Cancer 02/2007; 55(1):1-14. · 3.43 Impact Factor
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ABSTRACT: Aurora kinases (A, B, and C) are essential for spindle assembly, centrosome maturation, chromosomal segregation, and cytokinesis. Aurora kinases A and B are overexpressed in many cancers, including non-small-cell lung cancer and mesothelioma. Small-molecule inhibitors selective for aurora kinases have shown promising activity in preclinical tumor models. To date, phase I studies with aurora kinase inhibitors have shown that myelosuppression is the dose-limiting toxicity, and disease stabilization was achieved in a number of tumor types, including non-small-cell lung cancer. Phase II trials are under way in selected tumor types. This article reviews the biology of aurora kinases, their potential role in the treatment of lung cancer, and challenges in the clinical development of this unique class of antineoplastic agents.
Clinical Lung Cancer 10/2006; 8(2):93-8. · 2.94 Impact Factor
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ABSTRACT: Src tyrosine kinases regulate a large number of important mechanisms in normal and cancerous cells, are overexpressed in a broad range of tumors including lung cancer, and thus represent a potential target for cancer therapy. Preclinical experiments indicate that small-molecule inhibitors of Src block tumor growth, metastasis, and angiogenesis. Phase I data from healthy volunteers also suggest that inhibitors of Src prevent bone resorption. Several phase II trials with small-molecule inhibitors of Src are under way or have been initiated in lung cancer and in other malignancies, as discussed herein.
Clinical Lung Cancer 06/2006; 7(6):381-4. · 2.94 Impact Factor
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ABSTRACT: The cyclin D1 (CCND1) A870G gene polymorphism is linked to the outcome in patients with resectable non-small cell lung cancer (NSCLC). Here, we investigated the impact of this polymorphism on smoking-induced cancer risk and clinical outcome in patients with NSCLC stages I-IV.
CCND1 A870G genotype was determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis (RFLP) of DNA extracted from blood. The study included 244 NSCLC patients and 187 healthy control subjects.
Patient characteristics were: 70% male, 77% smokers, 43% adenocarcinoma, and 27% squamous cell carcinoma. Eighty-one percent of the patients had stages III-IV disease. Median age at diagnosis was 60 years and median survival was 13 months. Genotype frequencies of patients and controls both conformed to the Hardy Weinberg equilibrium. The GG genotype significantly correlated with a history of heavy smoking (>or=40 py, P=0.02), and patients with this genotype had a significantly higher cigarette consumption than patients with AA/AG genotypes (P=0.007). The GG genotype also significantly correlated with tumor response or stabilization after a platinum-based first-line chemotherapy (P=0.04). Survival analysis revealed no significant differences among the genotypes.
Evidence was obtained that the CCND1 A870G gene polymorphism modulates smoking-induced lung cancer risk. Further studies are required to explore the underlying molecular mechanisms and to test the value of this gene polymorphism as a predictor for platinum-sensitivity in NSCLC patients.
Lung Cancer 03/2006; 51(3):303-11. · 3.43 Impact Factor
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Oliver Gautschi,
Colette Bigosch,
Barbara Huegli,
Monika Jermann,
Arthur Marx,
Eveline Chassé,
Daniel Ratschiller,
Walter Weder,
Markus Joerger,
Daniel C Betticher,
Rolf A Stahel,
Annemarie Ziegler
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ABSTRACT: Circulating cell-free DNA is present in increased amounts in the blood of cancer patients, but the clinical relevance of this phenomenon remains unclear. We conducted a clinical study to assess the value of circulating DNA as a prognostic marker in patients with non-small-cell lung cancer (NSCLC).
A standard protocol for the quantification of circulating DNA by real-time polymerase chain reaction was set up and validated at two oncology units. One hundred eighty-five informed patients with NSCLC and 46 healthy controls were included in the study. DNA concentrations were determined in paired plasma and serum samples and analyzed for a relationship with leukocyte counts and lactate dehydrogenase (LDH) levels. DNA concentrations in healthy controls and in patients were compared, and cutoff levels for plasma and serum DNA were determined. Patient survival was analyzed relative to baseline DNA concentrations, and the relationship between tumor responses and changes in DNA concentrations was assessed in patients receiving chemotherapy.
We found a significant correlation between increased plasma DNA concentrations and elevated LDH levels (P = .009), advanced tumor stage (P < .003), and poor survival (P < .001). Tumor progression after chemotherapy was significantly (P = .006) associated with increasing plasma DNA concentrations. Serum DNA concentrations strongly correlated (P < .001) with leukocyte counts.
Our data demonstrate that quantification of plasma DNA is an accurate technique amenable to standardization, which might complement current methods for the prediction of patient survival. This approach might be considered for evaluation in large prospective studies.
Journal of Clinical Oncology 11/2004; 22(20):4157-64. · 18.37 Impact Factor
