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  • American Association for Cancer Research (AACR)  (9)
  • English  (9)
  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 3148-3148
    Abstract: The KEAP1/NRF2 pathway is a master regulator of several redox-sensitive genes implicated in resistance of tumour cells against chemotherapeutic drugs. Recent data suggest that epigenetic mechanisms may play a pivotal role in the regulation of KEAP1 expression. We performed a comprehensive genetic and epigenetic analysis of the KEAP1 gene in 47 Non Small Cell Lung Cancer tissues and 12 normal lung specimens. Promoter methylation analysis was performed using a quantitative methylation specific PCR assay in real time. Methylation at the KEAP1 promoter region was detected in 22 out of the 47 NSCLCs (47%) and in none of the normal tissues analyzed. Somatic mutations were detected in 7 out of the 47 tumours (15%), and loss of heterozygosity (LOH) in 10 out of the 47 (21%) of the cases. Overall, we found at least one molecular alteration in 57% of the cases. Approximately one third of the tumours had two alterations and this feature was associated with higher risk of disease progression in univariate COX regression analysis (HR=3.62; 95% CI 1.24-10.65, p=0.02). This result was confirmed by Kaplan-Meier analysis which demonstrated an association between worst outcome and KEAP1 double alterations (p=0.01, Log rank test). Our results further suggest that deregulation of the NRF2/KEAP1 system could play a pivotal role in the cancerogenesis of NSCLC. In addition identifying patients with KEAP1 genetic and epigenetic abnormalities may contribute to disease progression prediction and response to therapy in lung cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3148. doi:1538-7445.AM2012-3148
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2251-2251
    Abstract: The Keap1/Nrf2 pathway is a master regulator of antioxidants and cellular stress responses implicated in resistance of tumor cells against chemotherapeutic drugs. The link between molecular alterations of this pathway in Non Small Cell Lung Cancer (NSCLC) is well studied and appears to depend on several main factors including the existence of activating mutations in NFE2LE gene and/or loss of function mutations and methylation in the KEAP1 gene. At present, the data concerning the mechanism of alteration of Nrf2-Keap1 pathway in Small Cell Lung Cancer (SCLC) instead are almost incomplete and correlation analysis with therapeutic strategies targeting the molecular dysfunction of this pathway is ongoing. Here we present a comprehensive molecular alteration profile of the main partners of the Nrf2/keap1 axis in 12 SCLC cell lines by integrating data from SNP-Array analysis, immunofluorescence, mutation screening by direct sequencing, methylation by QMSP and expression analyses by RT-qPCR and western blotting. Our analyses confirm the global deregulation of Nrf2/Keap1 pathway in SCLC cell lines, showing an hypermethylation of the CpGs located into the P1 promoter region of the KEAP1 in 42% (5/12) of the cell lines, and a chromosomal amplification involving the NFE2LE gene locus (2q31.1) in two cell lines. Only one just described point mutation in the kelch-repeat 2 was observed in one of the cell line analysed. Our gene-alteration profile of SCLC cell lines provides new insights into the mechanism of deregulation of Nrf2-Keap1 detoxification pathway in this group of high grade neuroendocrine lung cancers, suggesting the NFE2LE gene amplification and the KEAP1 promoter hypermethylation as alternative mechanisms of dysfunctional Nrf2/Keap1 in SCLCs.Analyses on tumor tissues are ongoing to confirm these observations. Moreover, the provided full molecular data from cell lines will be useful for in vitro functional studies aimed to establish new combined therapeutic strategies in targeted cancer treatments of this aggressive lung tumor histotype. Citation Format: Lucia Anna Muscarella, Annamaria la Torre, Angelo Sparaneo, Orazio Palumbo, Clelia Tiziana Storlazzi, Teresa Balsamo, Domenico Trombetta, Fabio Pellegrini, Raffaela Barbano, Barbara Pasculli, Paolo Graziano, Montse Sanchez-cespedes, Maria Teresa Landi, Paola Parrella, Vito Michele Fazio. nrf2-keap1 axis molecular profile in small cell lung cancer cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2251. doi:10.1158/1538-7445.AM2014-2251
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3926-3926
    Abstract: The maintaining of genome stability is one of the main mechanisms involved in prevention of tumor formation thus a number of intricate networks have evolved in eukaryotic cells to respond to exogenous and endogenous genotoxic stimuli. In an initial study we have analyzed mRNA expression changes of 15 genes involved in both Homologous Recombination (HR) and Non Homologous End Joining (NHEJ) pathways on paired normal and cancer tissues from 20 patients. Three genes, ATR, RAD51 and G22P1/Ku70 were differentially expressed in tumours as compared with normal tissues. To confirm data from the training set we analyzed by real-time quantitative PCR paired normal tissues and tumour specimens obtained from 55 breast cancer patients. Since high variability was found in normal tissues for each case we calculated the relative expression ratio (RER) in tumour samples as compared with normal tissue. When relative expression ratios were correlate with tumours clinical characteristics, only RAD51 showed higher RERs in the group of tumours with ER-positive/PR-negative phenotype as compared with the ER-positive/PR-positive and ER-positive/PR-negative subgroups (Kruskall-Wallis p=0.07). We used commercially available antisera to evaluate protein expression of RAD51 on a panel of 59 primary breast cancer and 3 fibroadenoma samples represented on a tissue microarray (BR641 Biomax.). RAD51 immunostaining was detected in 39 of the 58 (67%) breast cancers represented on a tissue microrray (median value 30%, range 0-70%). No staining was detected in the three fibroadenomas represented on the tissue microarray and in normal breast tissues represented in the tumor. When IHC results were compared with tumour clinicopathological characteristics, the percentage of RAD51 stained cells was higher in PR negative patients as compared with positive cases (P=0.002 Mann Whitney test) and this inverse correlation was confirmed in logistic regression analysis (P=0.0035). Interstingly all tumours ER-positive/PR-negative phenotype (12 out of 12) showed RAD51 immunostaining. Moreover, in this subgroup statistically significant higher levels of RAD51 protein were also detected as compared with ER-positive/PR-positive and ER-negative/PR-positive patients subgroups (Kruskall-Wallis p=0.004). In particular the analysis between groups demonstrated statistically significant differences between the ER-positive/PR-positive group and the ER-positive/PR-negative groups (Dunn Test P & lt;0.01). Our data suggest an involvement of the RAD51 gene in the pathogenesis and progression of breast cancer and indicate that RAD51 overexpression may represent a specific feature of a subgroup of the Luminal subtype. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3926.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P2-16-24-P2-16-24
    Abstract: Background: The outcomes of IBC pts who received NC could be different by Subtypes Methods: From 2000 to 2018 we treated 400 II-III stage IBC patients (pts) with NC. We recorded baseline characteristics, type of NC, type of surgery, pCR (defined as the absence of invasive cells in the breast and the lymph nodes regardless of DCIS), biological features of RT. pCR and survival outcomes (in term of Disease Free Survival-DFS, Relapse Free Survival-RFS and Overall Survival-OS) also on the basis of both pre- and post- NC Ki67 levels were assessed Results: Median age was 50 yrs (r. 25-75). Population consisted of: Luminal A (LA): 3.7% Luminal B (LB): 28.25% Luminal HER2 (LHER2): 28% HER2+HR- 13.5% Triple Negative (TN):21.25% Unknown:5.3% The NC was based on tri-weekly or dose-dense (only 22 cases) anthracyclines (A) followed by weekly taxanes (T) in HER2- (249), associated with weekly carboplatin (C) in more recent cases (48) of TN and T + trastuzumab (H) ± A (40) or C (102) in HER2+ pts. All pts but 18 did received surgery: 8 for distant metastases occurrence and 10 because still on NC. Quadrantectomy was performed in 205(52%) pts. pCR was achieved in 125 (31%) pts of which 30 with non invasive residual; further 10 patients showed RT ≤1 mm Relationship between pCR and SubtypesLA (%)LB (%)LHER2 (%)HER2+HR-TN (%)pCR6.715.938.450.041.2No pCR93.384.161.650.058.8p Value & lt;0.001 pCR was reached in 41.5% in case of proliferation index by Ki67 ≥ 20% and in particular if & gt; ki67 was & gt; 40% regardless of Subtypes (p=0.001). All 166 HER2 + patients except 24 received H obtaining pCR in 70 (45.8%) of cases regardless chemotherapy type. pCR were 30.7% and 50% according to A- vs C-based regimen respectively. Twenty-six of 48 TN pts receiving C addition underwent S with pCR. The median Fup was 44.12 months (r: 1.35-232.6). The pCR was positively associated with DFS (HR 0.17, 95% CI 0.07-0.40), RFS (HR 0.26, 95% CI 0.13-0.50) and OS (HR 0.17, 95% CI 0.06-0.49) in overall population The association between pCR and long-term outcomes (DFS and RFS, but not OS) was greater in TN pts (EFS: HR 0.11, 95% CI 0.01-0.90; RFS: 0.12, 95% CI 0.06-0.71), in LHER2 (EFS: HR 0.20, 95% CI 0.04-0.87; RFS: 0.24, 95% CI 0.07-0.84) and in HER2+ (EFS: HR 0.11, 95% CI 0.01-0.90; RFS: 0.24, 95% CI 0.06-0.73) than in LA and LB. Postoperative low level of Ki67 ( & lt; 10%) reduced the risk of both relapse (HR = 0.37 ci 0.17-0.76) and death (HR = 0.29 ci 0.12-0.70) compared with pts with higher Ki67 levels. Conclusions: The pCR rate was significantly higher in aggressive Subtypes (HER2+ and TN) than luminals. Pts achieving pCR showed better RFS and OS compared to no pCR pts. Interestingly high pre-NC PI seems to predict the possibility obtaing pCR, while post-NC PI seems to be of prognostic value in pts who do not receive pCR, in particular in LB subtypes. Citation Format: Antonella Ferro, Alessia Caldara, Elisabetta Grego, Carlo Messina, Gabriella Berlanda, Paolo Cristofolini, Fabio Gasperetti, Salvatore Mussari, Carmine Fantò, Marvi Valentini, Marco Pellegrini, Mattia Barbareschi, Nicola Mirabassi, Giuseppe Carbone, Roberta Biondi, Renza Triolo, Silvia Lazzeri, Vincenzo Sabatino, Paola Bondioli, Orazio Caffo. Impact of pathologic complete response (pCR) and and biological features of residual tumor (RT) on prognosis after neoadjuvant chemotherapy (NC) in various invasive breast cancer (IBC) subtypes [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-24.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 664-664
    Abstract: The KEAP1 (Kelch-like ECH-Associated Protein 1) is an adaptor protein that mediates the ubiquitination/degradation of genes regulating cell survival and apoptosis under oxidative stress conditions. We investigated the possible contribution of KEAP1 genetic and epigenetic abnormalities to development and progression of breast cancer. Methylation status of the KEAP1 promoter was evaluated in 102 primary breast cancers, 14 pre-invasive lesions, 38 paired normal breast tissues and 6 normal breast from reductive mammoplasty by Quantitative Methylation Specific PCR (QMSP). Aberrant promoter methylation was detected in 52 out of the 102 primary breast cancer cases (51%) and 10 out of 14 pre-invasive lesions (71%). No mutations of the KEAP1 gene were identified in the 20 breast cancer cases analyzed by fluorescence based direct sequencing. Methylation was more frequent in the subgroup of patients identified as ER positive-HER2 negative tumors (66.7%) as compared with triple negative breast cancers (35%) (p=0.02, Mann Whitney U-test). Interactions between ER, PR, HER2 expression and KEAP1 methylation on the mortality were investigated by RECPAM multivariable statistical analysis, identifying four prognostic classes at different mortality risks. Triple negative breast cancer patients with KEAP1 methylation had higher mortality risk than patients without triple negative breast cancer (HR=14.73, 95% CI: 3.65-59.37). Both univariable and multivariable COX regression analyses showed that KEAP1 methylation was associated with a better progression free survival in patients treated with epirubicin/cyclophosfamide and docetaxel as sequential chemotherapy (HR=0.096; 95%CI: 0.011-0.832 p=0.03 and HR=0.082 95%CI: 0.007-0.934 P=0.04 respectively). Our data indicate that aberrant promoter methylation of the KEAP1 gene promoter is involved in breast cancerogenesis. In addition identifying patients with KEAP1 epigenetic abnormalities may contribute to disease progression prediction in breast cancer patients. Citation Format: Raffaela Barbano, Lucia Anna Muscarella, Barbara Pasculli, Vanna Maria Valori, Andrea Fontana, Michelina Coco, Annamaria la Torre, Teresa Balsamo, Maria Luana Poeta, Giovanni Francesco Marangi, Evaristo Maiello, Marina Castelvetere, Fabio Pellegrini, Roberto Murgo, Vito Michele Fazio, Paola Parrella. Aberrant KEAP1 promoter methylation is associated with disease progression in breast cancer patients treated with epirubicin/cyclophosfamide and docetaxel chemotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 664. doi:10.1158/1538-7445.AM2013-664
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 6
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1477-1477
    Abstract: Several prognostic factors are currently used to stratify breast cancer patients based on the risk of disease progression. However, even patients classified as at low risk can progress and die for the disease. MicroRNA-10b (miR-10b) has a prominent role in regulating tumor invasion and metastasis by targeting the HOXD10 transcriptional repressor and has been found up-regulated in several tumor types including breast cancer. We evaluated the expression of miR-10b in paired tumor and normal specimens obtained from a prospective cohort of breast cancer patients with at least 36 months follow-up enrolled according to the REMARK guidelines (n=150). RNA quality was measured and only samples with RNA Integrity Number (RIN) ≥7.0 were analyzed. The relative expression of miR-10b in tumor as compared to its normal counterpart (RER) was determined by RT-qPCR. miR-10b RERs were higher in the subgroup of patients with synchronous metastases (n=11, Median 0.25; IQR 0.11-1.02) as compared with patients without metastases (n=90, Median 0.09; IQR 0.04-0.29) (p=0.028). In the subgroup of patients without synchronous metastases (n=90), higher miR-10b RERs were associated with increased risk of disease progression and death in both univariable (HR 4.35, p=0.021 and HR 6.02, p=0.015 respectively) and multivariable (HR 13.37, p & lt;0.001, and HR 15.39, p=0.003 respectively) Cox regression models. The addition of miR-10b RERs to the Nottingham Prognostic Index (NPI) provided an improvement in discrimination power and risk reclassification abilities for the clinical outcomes at 36 months. Survival C-indices significantly increased from 0.849 to 0.889 (p=0.009) for OS and from 0.735 to 0.767 (p=0.050) for DFS. Our results provide evidences that the addition of miR-10b RERs to the prognostic factors used in clinical routine could improve the prediction abilities for both overall mortality and disease progression in breast cancer patients. Citation Format: Paola Parrella, Raffaela Barbano, Barbara Pasculli, Andrea Fontana, Massimiliano Copetti, Vanna Maria Valori, Maria Luana Poeta, Giuseppe Perrone, Michelina Coco, Teresa Balsamo, Fabio Pellegrini, Andrea Onetti Muda, Evaristo Maiello, Roberto Murgo, Vito Michele Fazio. Evaluation of microRNA-10b prognostic significance in a prospective cohort of breast cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1477. doi:10.1158/1538-7445.AM2014-1477
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 7
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9_Supplement ( 2015-05-01), p. P5-21-06-P5-21-06
    Abstract: BACKGROUND: IBC is a heterogeneous disease with several subtypes molecularly identified by gene expression profile. Since subtypes defined by immuhistochemistry (IHC) panel are similar although not identical to molecular subtypes, IHC may represent an easier alternative to identify them. PURPUSE: To assess the clinical outcomes of pts who received NC for IBC and the differences by IHC-related subtypes. METHODS: We retrospectively reviewed the clinical records of the pts treated with NC for stage II-III IBC from 2000 to 2013. For each pt we recorded baseline tumor size, type of NC [which consisted of anthracyclines (A) + taxanes (T) in HER2- and T + trastuzumab (H) ± A in HER2+ pts), type of surgery, pathological response (pCR defined as the absence of invasive cells in the breast and the lymph nodes regardless of DCIS). IHC subtypes were defined according to ER and PgR expression, Ki-67 level, and HER2 status: Luminal A (LA): ER and PR+, neg HER2 and Ki67 & lt; 14% (= 3%) Luminal B (LB): ER and/or PR+, neg HER2 and Ki67≥14% (=30%) Luminal HER2 (LHER2): ER and/or PR+, positive HER2 and any Ki67 (=27%) HER2 positive (HER2+): neg ER and PR, positive HER2 and any Ki67 (=12%) Triple negative (TN): neg ER and PR, neg HER2 and any Ki67 (13%) Unknown subtype in 33 cases (15%) The loco-regional and distant RFS and OS were evaluated according to pCR. pCR and survival outcomes were also assessed on the basis of both pre- and post- NC Ki67 levels. RESULTS: In the consecutive series of 213 pts who received NC median age was 50 yrs (r. 25-75). The NC consisted of an A+T based regimen in HER2 negative (145 pts) and of a T+ H with A (31 pts) or without A (34 pts) in HER2+ disease. Only 14 did not receive surgery: 10 for distant metastases development and 4 because still on NC. Quadrantectomy was performed in 120 pts (60%). Among all pts, pCR was achieved in 44 pts(22%) with further 4 pts showing a RT ≤1 mm. Relationship between pCR and subtypes, ki67 and recurrence rate LA (%)LB (%)LHER2 (%)HER2+TN (%)Median Ki67 (%)Recurrence Rate (%)pCR012.542.527.517.5484.5No pCR10042.329.28.814.63731.5p Value     & lt;0.001 =0.001 All but 19 HER2+ pts (84) received H obtaining pCR in 38% of cases regardless chemotherapy type (A-based 35% vs Not A- 38%) The median follow-up was 45 months (range 1-166 ms). The 4y-RFS and OS were better in which achieved pCR than those did no (RFS 92 vs to 74%; p=0.0014 and OS 95 vs 78%; p=0.0074). Median Ki67 in pretreated core biopsy was 40 compared to 27% in post-NC RT. Patients with high ( & gt;30%) post-NC Ki67 levels showed significantly higher risk for disease relapse (4 y-RFS 60%; p=0.0019) and death (4y OS 71%; p=0.018) compared with patients with & lt;15% (4y-RFS 93 and OS 88%) or & gt;15-30 Ki67 levels (4y-RFS 83 and OS 82%). CONCLUSIONS: According to literature data, pts achieving pCR after NC showed better RFS and OS compared to no pCR pts. The pCR rate was significantly higher in aggressive subtypes (HER2 and TN). In HER2 disease, pCR was achieved by using chemo + H, irrespective of A-addition. Interestingly high pre-NC KI67 levels seem to predict the possibility obtaing pCR, while post-NC Ki67 levels seem to be of prognostic value in pts who do not receive pCR. Citation Format: Antonella Ferro, Alessia Caldara, Mariachiara Dipasquale, Chiara Trentin, Renza Triolo, Mattia Barbareschi, Daniela Bernardi, Marco Pellegrini, Daniela Cazzolli, Gabriella Berlanda, Fabio Gasperetti, Francesca Maines, Paolina Tuttobene, Orazio Caffo, Enzo Galligioni. Clinical outcomes according to pathological complete response (pCR) and proliferation index of residual tumor (RT) after neoadjuvant chemotherapy (NC) in invasive breast cancer (IBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-21-06.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 8
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 18 ( 2013-09-15), p. 5027-5038
    Abstract: Purpose: The aim of this study was to investigate the biological and clinical significance of epidermal growth factor receptor (EGFR) signaling pathway in follicular dendritic cell sarcoma (FDC-S). Experimental Design: Expression of EGFR and cognate ligands as well as activation of EGFR signaling components was assessed in clinical samples and in a primary FDC-S short-term culture (referred as FDC-AM09). Biological effects of the EGFR antagonists cetuximab and panitumumab and the MEK inhibitor UO126 on FDC-S cells were determined in vitro on FDC-AM09. Direct sequencing of KRAS, BRAF, and PI3KCA was conducted on tumor DNA. Results: We found a strong EGFR expression on dysplastic and neoplastic FDCs. On FDC-AM09, we could show that engagement of surface EGFR by cognate ligands drives the survival and proliferation of FDC-S cells, by signaling to the nucleus mainly via MAPK and STAT pathways. Among EGFR ligands, heparin-binding EGF-like growth factor, TGF-α and Betacellulin (BTC) are produced in the tumor microenvironment of FDC-S at RNA level. By extending this finding at protein level we found that BTC is abundantly produced by FDC-S cells and surrounding stromal cells. Finally, direct sequencing of tumor-derived genomic DNA showed that mutations in KRAS, NRAS, BRAF, and PI3KCA, which predicts resistance to anti-EGFR MoAb in other cancer models, are not observed in FDC-S. Conclusion: Activation of EGFR by cognate ligands produced in the tumor microenvironment sustain viability and proliferation of FDC-S indicating that the receptor blockade might be clinically relevant in this neoplasm. Clin Cancer Res; 19(18); 5027–38. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 65-65
    Abstract: The Keap1 (Kelch-like ECH-associated protein 1) protein tightly regulates the functions of Nrf2 (nuclear factor-erythroid 2-related factor 2) which plays a pivotal role in the cellular response to oxidative stress. Initial reports uncovered mutations in the KEAP1 gene in non-small cell lung cancer (NSCLC) leading to a permanent nrf2 activation. Mutations were often associated with loss of heterozigosity at the KEAP1 gene locus and promoter hypermethylation suggesting that biallelic inactivation is a common event in NSCLC. In this study, we sought to determine whether KEAP1 gene is epigenetically regulated in malignant gliomas and if promoter aberrant methylation may impact patient's outcome. We developed a Quantitative Methylation Specific PCR (QMSP) assay to analyze 86 malignant gliomas and 20 normal brain tissues. The discriminatory power of the assay was assessed by Receiving Operating Curve Characteristics (ROC) analysis. The AUC value of the curve was 0.823 (95%CI: 0.764-0.883) with an optimal cut off value of 0.133 yielding a 74% sensitivity (95%CI: 63%-82%) and an 85% specificity (95%CI: 64%-95%). Bisulfite sequencing analysis confirmed QMSP results and demonstrated a direct correlation between percentage of methylated CpGs and methylation levels (Spearman's Rho 0.929, P=0.003). Remarkably, a strong inverse correlation was observed between methylation levels and KEAP1 mRNA transcript in tumour tissue (Spearman's Rho -0.656 P=0.0001) and in a cell line before and after treatment with 2-deoxy-5 Azacytidine (P=0.003). RECPAM multivariate statistical analysis studying the interaction between MGMT and KEAP1 methylation in subjects treated with radiotherapy and temozolomide (n=70), identified three prognostic classes of glioma patients at different risk to progress. While simultaneous methylation of MGMT and KEAP1 promoters was associated with the lowest risk to progress, patients showing only MGMT methylation were the subgroup at the higher risk (HR 5.54, 95% CI 1.35-22.74). Our results indicate that that KEAP1 expression is frequently methylated in malignant gliomas and may represent a novel predictor of patient's outcome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 65. doi:10.1158/1538-7445.AM2011-65
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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