108 results found
Abaitua F, Crook T, O'Neill K, et al., 2014, TARGETING COLLAGEN REGULATION IN GLIOBLASTOMA MULTIFORME, NEURO-ONCOLOGY, Vol: 16, ISSN: 1522-8517
Langer J, Elustondo FA, Chan ECY, et al., 2014, METABOLOMIC ANALYSIS OF GLIOBLASTOMA MULTIFORME UPON ARGININE DEPRIVATION TREATMENT, NEURO-ONCOLOGY, Vol: 16, ISSN: 1522-8517
Abaitua F, Crook T, O'Neill K, et al., 2014, TARGETING COLLAGEN REGULATION IN GLIOBLASTOMA MULTIFORME, Meeting of the British-Neuro-Oncology-Society (BNOS), Publisher: OXFORD UNIV PRESS INC, ISSN: 1522-8517
Langer JK, Chan ECY, Antti H, et al., 2014, METABOLOMIC ANALYSIS OF GLIOBLASTOMA MULTIFORME UPON ARGININE DEPRIVATION TREATMENT, Meeting of the British-Neuro-Oncology-Society (BNOS), Publisher: OXFORD UNIV PRESS INC, ISSN: 1522-8517
Qiao B, Oneill K, Syed N, 2014, SCOTIN EXPRESSION AND SURVIVAL IN GBM, Meeting of the British-Neuro-Oncology-Society (BNOS), Publisher: OXFORD UNIV PRESS INC, ISSN: 1522-8517
Asavarut P, O'Neill K, Syed N, et al., 2014, Chimeric adeno-associated virus and bacteriophage: a potential targeted gene therapy vector for malignant glioma., Ther Deliv, Vol: 5, Pages: 975-990
The incipient development of gene therapy for cancer has fuelled its progression from bench to bedside in mere decades. Of all malignancies that exist, gliomas are the largest class of brain tumors, and are renowned for their aggressiveness and resistance to therapy. In order for gene therapy to achieve clinical success, a multitude of barriers ranging from glioma tumor physiology to vector biology must be overcome. Many viral gene delivery systems have been subjected to clinical investigation; however, with highly limited success. In this review, the current progress and challenges of gene therapy for malignant glioma are discussed. Moreover, we highlight the hybrid adeno-associated virus and bacteriophage vector as a potential candidate for targeted gene delivery to brain tumors.
Hatzimichael E, Syed N, Lo Nigro C, et al., 2014, A blood test to identify when melanoma metastasizes: a reality for melanoma management?, Melanoma Manag, Vol: 1, Pages: 11-14
Hatzimichael E, Syed N, Lo Nigro C, et al., 2014, How detection of epigenetic alterations of blood-borne DNA could improve melanoma diagnosis, EXPERT REVIEW OF MOLECULAR DIAGNOSTICS, Vol: 14, Pages: 639-642, ISSN: 1473-7159
Allen MD, Phuong L, Hudson C, et al., 2014, Prognostic and Therapeutic Impact of Argininosuccinate Synthetase 1 Control in Bladder Cancer as Monitored Longitudinally by PET Imaging, CANCER RESEARCH, Vol: 74, Pages: 896-907, ISSN: 0008-5472
Lo Nigro C, Wang H, McHugh A, et al., 2013, Methylated Tissue Factor Pathway Inhibitor 2 (TFP12) DNA in Serum Is a Biomarker of Metastatic Melanoma, JOURNAL OF INVESTIGATIVE DERMATOLOGY, Vol: 133, Pages: 1278-1285, ISSN: 0022-202X
Przystal JM, Umukoro E, Stoneham CA, et al., 2013, Proteasome inhibition in cancer is associated with enhanced tumor targeting by the adeno-associated virus/phage, MOLECULAR ONCOLOGY, Vol: 7, Pages: 55-66, ISSN: 1574-7891
Syed N, Langer J, Janczar K, et al., 2013, Epigenetic status of argininosuccinate synthetase and argininosuccinate lyase modulates autophagy and cell death in glioblastoma., Cell Death & Disease, Vol: 4, ISSN: 2041-4889
Arginine deprivation, either by nutritional starvation or exposure to ADI-PEG20, induces adaptive transcriptional upregulation ofASS1 and ASL in glioblastoma multiforme ex vivo cultures and cell lines. This adaptive transcriptional upregulation is blocked byneoplasia-specific CpG island methylation in either gene, causing arginine auxotrophy and cell death. In cells with methylatedASS1 or ASL CpG islands, ADI-PEG20 initially induces a protective autophagic response, but abrogation of this by chloroquineaccelerates and potentiates cytotoxicity. Concomitant methylation in the CpG islands of both ASS1 and ASL, observed in asubset of cases, confers hypersensitivity to ADI-PEG20. Cancer stem cells positive for CD133 and methylation in the ASL CpGisland retain sensitivity to ADI-PEG20. Our results show for the first time that epigenetic changes occur in both of the two keygenes of arginine biosynthesis in human cancer and confer sensitivity to therapeutic arginine deprivation. We demonstrate thatmethylation status of the CpG islands, rather than expression levels per se of the genes, predicts sensitivity to argininedeprivation. Our results suggest a novel therapeutic strategy for this invariably fatal central nervous system neoplasm for whichwe have identified robust biomarkers and which overcomes the limitations to conventional chemotherapy imposed by the blood/brain barrier.
Hatzimichael E, Lo Nigro C, Lattanzio L, et al., 2012, The collagen prolyl hydroxylases are novel transcriptionally silenced genes in lymphoma, British Journal of Cancer, Vol: 107, Pages: 1423-1432, ISSN: 1532-1827
Cavicchioli F, Shia A, O'Leary K, et al., 2012, EPIGENETIC SILENCING OF ARGININO-SUCCINATE SYNTHASE (ASS1) DEFINES ARGININE DEPLETION THERAPY AS A NOVEL TREATMENT STRATEGY FOR BREAST CANCER, 37th Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: OXFORD UNIV PRESS, Pages: 532-533, ISSN: 0923-7534
Palmieri C, Monteverde M, Lattanzio L, et al., 2012, Site-specific CpG methylation in the CCAAT/enhancer binding protein delta (CEBP delta) CpG island in breast cancer is associated with metastatic relapse, BRITISH JOURNAL OF CANCER, Vol: 107, Pages: 732-738, ISSN: 0007-0920
Delage B, Luong P, Maharaj L, et al., 2012, Promoter methylation of argininosuccinate synthetase-1 sensitises lymphomas to arginine deiminase treatment, autophagy and caspase-dependent apoptosis, CELL DEATH & DISEASE, Vol: 3, ISSN: 2041-4889
Vivenza D, Gasco M, Monteverde M, et al., 2012, MDM2 309 polymorphism predicts outcome in platinum-treated locally advanced head and neck cancer, ORAL ONCOLOGY, Vol: 48, Pages: 602-607, ISSN: 1368-8375
Lo Nigro C, Monteverde M, Lee S, et al., 2012, NT5E CpG island methylation is a favourable breast cancer biomarker, British Journal of Cancer, Vol: 107, Pages: 75-83, ISSN: 1532-1827
BACKGROUND: Relapse risk assessment and individual treatment recommendations remain suboptimal for breast cancer patients. In thelight of existing preclinical and clinical data, we studied NT5E (50-nucleotidase, ecto) expression and NT5E CpG island methylation inbreast cancer.METHODS: We used RT–PCR, qPCR, methylation-specific PCR and pyrosequencing to analyse NT5E in breast carcinoma cell lines andprimary and breast carcinomas.RESULTS: NT5E CpG island methylation was inversely associated with NT5E expression in breast carcinoma cell lines. In clinical series,patients whose primary tumours had NT5E CpG island methylation were less likely to develop metastasis (P ¼ 0.003, OR ¼ 0.34, 95%CI: 0.17–0.69). In 3/4 paired samples, NT5E was methylated in primary tumours and demethylated in CNS metastases. Patientsprogressing to non-visceral as compared with visceral metastases were more likely to have NT5E CpG island methylation in primarytumours (P ¼ 0.01, OR ¼ 11.8). Patients with tumours lacking detectable methylation had shorter disease-free survival (DFS)(P ¼ 0.001, HR ¼ 2.7) and overall survival (OS) (P ¼ 0.001, HR ¼ 3). The favourable prognostic value of NT5E methylation wasconfirmed in oestrogen receptor negative (P ¼ 0.011, HR ¼ 3.27, 95% CI: 1.31–8.12) and in triple negative cases (P ¼ 0.004;HR ¼ 6.2, 95% CI: 1.9–20). Moreover, we observed a more favourable outcome to adjuvant chemotherapy in patients whosetumours were positive for NT5E CpG island methylation: DFS (P ¼ 0.0016, HR ¼ 5.1, 95% CI: 1.8–14.37) and OS (P ¼ 0.0005,HR ¼ 7.4, 95% CI: 2.416–23.08).CONCLUSION: NT5E CpG island methylation is a promising breast cancer biomarker
Palmieri C, Rudraraju B, Monteverde M, et al., 2012, Methylation of the calcium channel regulatory subunit alpha 2 delta-3 (CACNA2D3) predicts site-specific relapse in oestrogen receptor-positive primary breast carcinomas, British Journal of Cancer, Vol: 107, Pages: 375-381, ISSN: 1532-1827
BACKGROUND: Calcium is an important intracellular messenger that mediates many biological processes that are relevant to themalignant process. Calcium ion channels are key in controlling the intracellular calcium, and little is known about their role in humancancer.METHODS: We used qPCR and pyrosequencing to investigate expression and epigenetic regulation of the calcium channel regulatorysubunit a2d-3 (CACNA2D3) in breast cancer cell lines, primary cancers and metastatic lesions.RESULTS: Expression of CACNA2D3 mRNA is regulated in breast cancer cell lines by methylation in the CpG island located in the50 regulatory region of the gene. Expression is upregulated by azacytidine (AZA) in cells with CpG island methylation but unaffectedin cells lacking methylation. In primary breast carcinomas, methylation is more common in cancers, which subsequently relapsewith loco-regional and, particularly, visceral metastatic disease in both oestrogen receptor-a (ER)-positive and -negative cases.Furthermore, CACNA2D3 CpG island is frequently methylated in breast cancer that has metastasised to the central nervous system.CONCLUSION: Methylation-dependent transcriptional silencing of CACNA2D3 may contribute to the metastatic phenotype of breastcancer. Analysis of methylation in the CACNA2D3 CpG island may have potential as a biomarker for risk of development ofmetastatic disease.
Hatzimichael E, Dasoula A, Syed N, et al., 2012, Epigenetic inactivation to target the arginine biosynthetic pathway in multiple myeloma., 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Safuwan NAM, Chivers P, Crook T, et al., 2012, Epigenetics, cell cycle and drug-resistant ovarian cancer, CANCER RESEARCH, Vol: 72, ISSN: 0008-5472
Lo Nigro C, Monteverde M, Lee S, et al., 2012, NT5E promoter methylation is a favorable breast cancer epigenetic biomarker, CANCER RESEARCH, Vol: 72, ISSN: 0008-5472
Wang H, Lee S, Lo Nigro C, et al., 2012, NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity, BRITISH JOURNAL OF CANCER, Vol: 106, Pages: 1446-1452, ISSN: 0007-0920
Lo Nigro C, Vivenza D, Monteverde M, et al., 2011, High frequency of complex TP53 mutations in CNS metastases from breast cancer, British Journal of Cancer
BACKGROUND: Brain metastasis from breast cancer is usually associated with a poor prognosis and early death. Alteration of p53 maycontribute to malignant progression by abrogation of apoptosis induced by oncogene activation and by acquisition of gain-of-functionproperties, which promote tumour aggression. Mutation in TP53 occurs at high frequency in carcinomas of the lung and gastrointestinal tract, but is much less frequent, at 25%, in primary breast cancer. The frequency of TP53 alteration in the central nervoussystem (CNS) metastatic breast cancer is not known.METHODS: In all, 23 cases of histologically confirmed CNS metastatic breast cancer were identified and the coding sequence of TP53determined. TP53 was also sequenced in two control series of primary breast carcinomas from independent clinical centres.RESULTS: We demonstrate a strikingly high frequency of TP53 mutation in the CNS metastatic lesions with an over-representation ofcomplex mutations (non-sense/deletions/insertions). Complex mutations occur in metastatic lesions in both triple-negative breastcancer and hormone receptor/HER2-positive cases. Analysis of paired primary carcinomas and brain metastatic lesions revealedevidence for both clonal selection and generation of new mutations (missense and complex) in progression from a primary breastcarcinoma to brain metastasis.CONCLUSION: Mutation in TP53 is the most common genetic alteration reported during metastasis to the brain in breast cance
Syed N, 2011, Polo Like Kinase 2 Tumour Suppressor and cancer biomarker: new perspectives on drug sensitivity/resistance in ovarian cancer, Oncotarget
Lo Nigro C, Syed N, Lattanzio L, et al., 2011, The Prolyl-3-hydroxylases (P3H) and P3H-related Genes CRTAP and SC65 Are Novel Transcriptionally Silenced Genes in Burkitt's Lymphoma, European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care, Publisher: ELSEVIER SCI LTD, Pages: S107-S107, ISSN: 0959-8049
Benetatos L, Crook T, 2011, Polo-like kinase 2 (SNK/PLK2) is a novel epigenetically regulated gene in acute myeloid leukemia and myelodysplastic syndromes: genetic and epigenetic interactions, Annals of Hematology
Lo Nigro C, Lattanzio L, Monteverde M, et al., 2011, The frequency of methylation of the NT5E gene in metastatic breast cancer., J Clin Oncol, Vol: 29
e11553 Background: Ecto-5-prime-nucleotidase (NT5E; CD73) catalyzes the conversion of purine 5-prime mononucleotides to nucleosides, the preferred substrate being AMP. Deficiency of NT5 occurs in a variety of immunodeficiency diseases and some studies have associated over-expression of NT5E with clinically aggressive neoplastic disease. Here we describe transcriptional down-regulation of the NT5E gene in breast cancer and show that this is associated with aberrant methylation in the CpG island located in its 5' regulatory sequences. METHODS: Methylation in the NT5E CpG island was analysed by methylation specific PCR (MSP) and quantitative pyrosequencing in a panel of 10 breast carcinoma cell lines and two independent clinical series of breast carcinomas, comprising 80 and 140 cases respectively and 17 brain metastatic breast cancer lesions. The breast carcinomas were predominantly invasive ductal carcinomas, untreated at the time of surgery and randomly selected from our clinical practice. Expression was assessed by qRT-PCR. RESULTS: NT5E mRNA was down-regulated in 4/10 breast carcinoma cell lines analysed. Down-regulation was associated with aberrant methylation in the CpG island located in the 5' regulatory sequences of the NT5E gene: methylation was present only in cell lines with down-regulation and the CpG island was unmethylated in cell lines which express the gene. Moreover, expression of NT5E was up-regulated by azacytidine. In clinical cases, methylation (assessed by pyrosequencing and/or MSP) was present in 28% and 41% of cases in independent clinical series of primary carcinomas. Methylation was more common in primary cases which ultimately relapsed at distant metastatic sites. Strikingly, methylation was particularly common in 9/16 brain metastatic lesions. CONCLUSIONS: In contrast to previous reports, we show that methylation of NT5E is common in metastatic breast cancer, particularly in intra-cranial metastases. Our data implicate transcriptional silen
Gasco M, Vivenza D, Monteverde M, et al., 2011, MDM2 309 single nucleotide polymorphisms (SNP) and clinical outcome in patients with advanced squamous cell carcinoma of head and neck (SCCHN)., J Clin Oncol, Vol: 29
5509 Background: Disruptive TP53 alterations have been associated with decreased survival in patients with SCCHN. A T>G polymorphism in the promoter region of mouse double minute 2 homologue (MDM2) has been associated with higher MDM2mRNA and protein levels. Overexpression of MDM2 is thought to interfere with p53-mediated apoptosis and growth inhibition. We hypothesized that the MDM2genotypes containing the G allele (GT+ GGgenotype) may be associated with worse survival in SCCHN patients (pts). METHODS: We directly sequenced the MDM2 polymorphism on both strands. We then evaluated the correlations between MDM2 polymorphism status and overall survival (OS) in 58 pts with stage III and IV SCCHN. Median follow-up was 6.5 years. All pts received cisplatin-based chemo-radiotherapy in our Department from 1997 to 2007. The Kaplan-Meier method and log-rank test were used to compare survival according to MDM2polymorphism status. Cox proportional hazards model was used to calculate hazard ratio (HR) adjusted for possible confounding variables, with 95% confidence interval (95% CI). RESULTS: Median age was 56 years; 50 pts (86%) were male and 52 pts (90%) were stage IV. The genotype frequencies for the MDM2 polymorphism were: T/T 32 (55%), T/G 17 (30%), G/G 9 (15%). Median overall survival (OS) and 5-years survival rates were significantly shorter in patients with genotypes containing the G allele (GT + GG genotype) compared to those with TT genotype (63 months vs. 124 months; log- rank p = 0.006 and 10/26 vs. 27/32; Fisher's exact p = 0.02, respectively). Notably, after adjusting for age, stage and performance status, genotypes containing the G allele appeared to be associated with worse survival (HR for death 2.90; 95% CI 1.37-6.12; p = 0.005). CONCLUSIONS: Our findings support the hypothesis that MDM2SNP309 polymorphism is an independent survival determinant among advanced stage SCCHN patients treated with cisplatin-based chemo-radiotherapy.
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