Publications
144 results found
Nevedomskaya E, Perryman R, Solanki S, et al., 2015, A systems oncology approach identifies NT5E as a key metabolic regulator in tumor cells and modulator of platinum sensitivity, Journal of Proteome Research, Vol: 15, Pages: 280-290, ISSN: 1535-3893
Altered metabolism in tumor cells is required for rapid proliferation but also can influence other phenotypes that affect clinical outcomes such as metastasis and sensitivity to chemotherapy. Here, a genome-wide association study (GWAS)-guided integration of NCI-60 transcriptome and metabolome data identified ecto-5′-nucleotidase (NT5E or CD73) as a major determinant of metabolic phenotypes in cancer cells. NT5E expression and associated metabolome variations were also correlated with sensitivity to several chemotherapeutics including platinum-based treatment. NT5E mRNA levels were observed to be elevated in cells upon in vitro and in vivo acquisition of platinum resistance in ovarian cancer cells, and specific targeting of NT5E increased tumor cell sensitivity to platinum. We observed that tumor NT5E levels were prognostic for outcomes in ovarian cancer and were elevated after treatment with platinum, supporting the translational relevance of our findings. In this work, we integrated and analyzed a plethora of public data, demonstating the merit of such a systems oncology approach for the discovery of novel players in cancer biology and therapy. We experimentally validated the main findings of the NT5E gene being involved in both intrinsic and acquired resistance to platinum-based drugs. We propose that the efficacy of conventional chemotherapy could be improved by NT5E inhibition and that NT5E expression may be a useful prognostic and predictive clinical biomarker.
Pazmandi J, O'Neill KS, Scheck AC, et al., 2015, The ketogenic diet alters the expression of microRNAs that play key roles in tumor development, 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
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- Citations: 2
Abaitua F, Przystal J, Hajitou A, et al., 2015, Arginine deprivation using ADI-PEG20 leads to regression of an ASS1-ve intracranial GBM tumor in mice and potentiates gamma irradiation of ASS1+ve GBM in vitro, 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Yata T, Lee ELQ, Suwan K, et al., 2015, Modulation of extracellular matrix in cancer is associated with enhanced tumor cell targeting by bacteriophage vectors, Molecular Cancer, Vol: 14, ISSN: 1476-4598
Ingemarsdotter CK, Tookman LA, Browne A, et al., 2015, Paclitaxel resistance increases oncolytic adenovirus efficacy via upregulated CAR expression and dysfunctional cell cycle control, MOLECULAR ONCOLOGY, Vol: 9, Pages: 791-805, ISSN: 1574-7891
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- Citations: 29
Abaitua F, Crook T, O'Neill K, et al., 2014, TARGETING COLLAGEN REGULATION IN GLIOBLASTOMA MULTIFORME, NEURO-ONCOLOGY, Vol: 16, ISSN: 1522-8517
Channathodiyil P, Kardooni H, Khozoie C, et al., 2014, EPIGENETIC INACTIVATION OF ARGININE BIOSYNTHESIS PATHWAY IN PAEDIATRIC HIGH GRADE GLIOMA, 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
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
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
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
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
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- Citations: 2
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
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- Citations: 106
Lo Nigro C, Wang H, McHugh A, et al., 2013, Methylated Tissue Factor Pathway Inhibitor 2 (<i>TFP12</i>) DNA in Serum Is a Biomarker of Metastatic Melanoma, JOURNAL OF INVESTIGATIVE DERMATOLOGY, Vol: 133, Pages: 1278-1285, ISSN: 0022-202X
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- Citations: 35
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
Bacteriophage (phage), which are viruses that infect bacteria only, have shown promise as vehicles for targeted cancer gene therapy, albeit with poor efficiency. Recently, we generated an improved version of phage vectors by incorporating cis genetic elements of adeno‐associated virus (AAV). This novel AAV/phage hybrid (AAVP) efficiently delivered systemically administered therapeutic genes to various tumor targets by displaying an integrin tumor‐targeting ligand on the phage capsid. However, inherent limitations in bacteriophage mean that these AAVP vectors still need to be improved. One of the limitations of AAVP in mammalian cells may be its susceptibility to proteasomal degradation. The proteasome is upregulated in cancer and it is known that it constitutes a barrier to gene delivery by certain eukaryotic viruses. We report here that inhibition of proteasome improved targeted reporter gene delivery by AAVP in cancer cells in vitro and in tumors in vivo after intravenous vector administration to tumor‐bearing mice. We also show enhanced targeted tumor cell killing by AAVP upon proteasome inhibition. The AAVP particles persisted significantly in cancer cells in vitro and in tumors in vivo after systemic administration, and accumulated polyubiquitinated coat proteins. Our results suggest that the proteasome is indeed a barrier to tumor targeting by AAVP and indicate that a combination of proteasome‐inhibiting drugs and AAVP should be considered for clinical anticancer therapy.
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
Background:The CCAAT/enhancer binding protein delta (CEBPδ) is a member of a highly conserved family of basic region leucine zipper transcription factors. It has properties consistent with a tumour suppressor; however, other data suggest that CEBPδ may be involved in the metastatic process.Methods:We analysed the expression of CEBPδ and the methylation status of the CpG island in human breast cancer cell lines, in 107 archival cases of primary breast cancer and in two series of metastatic breast cancers using qPCR and pyrosequencing.Results:Expression of CEBPδ is downregulated in primary breast cancer by site-specific methylation in the CEBPδ CpG island. Expression is also downregulated in 50% of cases during progression from primary carcinoma to metastatic lesions. The CEBPδ CpG island is methylated in 81% metastatic breast cancer lesions, while methylation in the CEBPδ CpG island in primary cancers is associated with increased risk of relapse and metastasis.Conclusion:CCAAT/enhancer binding protein delta CpG island methylation is associated with metastasis in breast cancer. Detection of methylated CEBPδ genomic DNA may have utility as an epigenetic biomarker of primary breast carcinomas at increased risk of relapse and metastasis.
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
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- Citations: 8
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
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- Citations: 96
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
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
Coley HM, Chivers P, Syed N, et al., 2012, Methylated PLK2 predicts response to taxanes, CANCER RESEARCH, Vol: 72, ISSN: 0008-5472
Safuwan NAM, Chivers P, Crook T, et al., 2012, Epigenetics, cell cycle and drug-resistant ovarian cancer, 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
Background:Novel prognostic biomarkers and therapeutic strategies are urgently required for malignant melanoma. Ecto-5-prime-nucleotidase (NT5E; CD73) overexpression has been reported in several human cancers. The mechanism(s) underlying deregulated expression and the clinical consequences of changes in expression are not known.Methods:We used RT–PCR, qPCR, methylation-specific PCR and pyrosequencing to analyse expression and regulation of NT5E in malignant melanoma cell lines and primary and metastatic melanomas.Results:NT5E is subject to epigenetic regulation in melanoma. NT5E mRNA is downregulated by methylation-dependent transcriptional silencing in the melanoma cell lines SKMel2, SKMel23, WM35, Mel501, Mel505 and C81–61 and expression is reactivated by azacytidine. In contrast, the CpG island is unmethylated and the gene expressed in cultured normal melanocytes. In clinical cases of melanoma, methylation in the NT5E CpG island occurs in both primary and metastatic melanomas and correlates with transcriptional downregulation of NT5E mRNA. Relapse with metastatic disease, particularly to the visceral sites and brain, is more common in primary melanomas lacking NT5E methylation. Primary melanomas with methylation in NT5E show limited metastatic potential or more commonly metastasise predominantly to nodal sites rather than viscera and brain (P=0.01).Conclusion:Deregulation of NT5E expression in melanoma occurs via epigenetic changes in the NT5E CpG island. Confirmation of our results in larger clinical series would support the candidacy of NT5E as a clinical biomarker in melanoma, which could be applied in both primary and relapsed disease. Inhibition of NT5E may have therapeutic potential in melanoma, particularly in patients with more aggressive disease metastatic to viscera or the brain.
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