108 results found
Laaniste L, Srivastava P, Stylianou T, et al., Integrated systems-genetic analyses reveal a network target for delaying glioma progression, Annals of Clinical and Translational Neurology, ISSN: 2328-9503
Objective: To identify a convergent, multitarget proliferation characteristic for astrocytomatransformation that could be targeted for therapy discovery. Methods: Using an integrated functionalgenomics approach, we prioritised networks associated with astrocytoma progression using thefollowing criteria: differential co-expression between grade II and grade III IDH1-mutated and 1p/19qeuploid astrocytomas, preferential enrichment for genetic risk to cancer, association with patientsurvival and sample-level genomic features. Drugs targeting the identified multitarget networkcharacteristic for astrocytoma transformation were computationally predicted using drug transcriptionalperturbation data and validated using primary human astrocytoma cells. Results: A single network, M2,consisting of 177 genes, was associated with glioma progression on the basis of the above criteria.Functionally, M2 encoded physically interacting proteins regulating cell cycle processes and analysisof genome-wide gene-regulatory interactions using mutual information and DNA-protein interactionsrevealed the known regulators of cell cycle processes FoxM1, B-Myb and E2F2 as key regulators ofM2. These results suggest functional disruption of M2 via gene mutation or altered expression as aconvergent pathway regulating astrocytoma transformation. By considering M2 as a multitarget drugtarget regulating astrocytoma transformation, we identified several drugs predicted to restore M2expression in anaplastic astrocytoma toward its low-grade profile and of these, we validated the knownantiproliferative drug resveratrol as down-regulating multiple nodes of M2 including at nanomolarconcentrations achievable in human cerebrospinal fluid by oral dosing. Interpretation: Our resultsidentify M2 as a multitarget network characteristic for astrocytoma progression and encourage M2-based drug screening to identify new compounds for preventing glioma transformation.
Renziehausen A, Tsiailanis AD, Perryman R, et al., Encapsulation of temozolomide in a calixarene nanocapsule improves its stability and enhances its therapeutic efficacy against glioblastoma, Molecular Cancer Therapeutics, Pages: molcanther.1250.2018-molcanther.1250.2018, ISSN: 1535-7163
The alkylating agent temozolomide (TMZ) is the first-line chemotherapeutic for glioblastoma (GBM), a common and aggressive primary brain tumour in adults. However, its poor stability and unfavourable pharmacokinetic profile limit its clinical efficacy. There is an unmet need to tailor the therapeutic window of TMZ, either through complex derivatization or by utilizing pharmaceutical excipients. To enhance stability and aqueous solubility, we encapsulated TMZ in a p-sulphonatocalixarene (Calix) nanocapsule and employed 1H-NMR, LC-MS and UV-Vis spectroscopy to chart the stability of this novel TMZ@Calix complex according to FDA and EMA guidelines. LC-MS/MS plasma stability assays were conducted in mice to further explore the stability profile of TMZ@Calix in vivo. The therapeutic efficacy of TMZ@Calix was compared to that of unbound TMZ in GBM cell lines and patient derived primary cells with known O6-methylguanine-DNA methyltransferase (MGMT) expression status and in vivo in an intracranial U87 xenograft mouse model. Encapsulation significantly enhanced the stability of TMZ in all conditions tested. TMZ@Calix was more potent than native TMZ at inhibiting the growth of established GBM cell lines and patient derived primary lines expressing MGMT and highly resistant to TMZ. In vivo, native TMZ was rapidly degraded in mouse plasma, whereas the stability of TMZ@Calix was enhanced 3-fold with increased therapeutic efficacy in an orthotopic model. In the absence of new effective therapies, this novel formulation is of clinical importance serving as an inexpensive and highly efficient treatment that could be made readily available to GBM patients and warrants further pre-clinical and clinical evaluation.
Hall PE, Lewis R, Syed N, et al., 2019, A Phase I Study of Pegylated Arginine Deiminase ( Pegargiminase), Cisplatin, and Pemetrexed in Argininosuccinate Synthetase 1-Deficient Recurrent High-grade Glioma, CLINICAL CANCER RESEARCH, Vol: 25, Pages: 2708-2716, ISSN: 1078-0432
Atkinson A, Renziehausen A, Wang H, et al., 2019, The collagen prolyl hydroxylases are bifunctional growth regulators in melanoma, Journal of Investigative Dermatology, Vol: 139, Pages: 1118-1126, ISSN: 0022-202X
Appropriate post-translational processing of collagen requires prolyl hydroxylation, catalyzed by the prolyl 3- (C-P3H) and prolyl 4- (C-P4H) hydroxylases is essential for normal cell function. Here we have investigated the expression, transcriptional regulation and function of the C-P3H and C-P4H families in melanoma. We show that the CP3H family exemplified by Leprel1 and Leprel2 are subject to methylation-dependent transcriptional silencing in primary and metastatic melanoma consistent with a tumour suppressor function. In contrast, although there is transcriptional silencing of P4HA3 in a sub-set of melanomas, the CP4H family members P4HA1, P4HA2 and P4HA3 are often over-expressed in melanoma, expression being prognostic of worse clinical outcomes. Consistent with tumour suppressor function, ectopic expression of Leprel1 and Leprel2 inhibits melanoma proliferation, whereas P4HA2 and P4HA3 increase proliferation and particularly invasiveness of melanoma cells. Pharmacological inhibition with multiple selective C-P4H inhibitors reduces proliferation and inhibits invasiveness of melanoma cells. Together, our data identify the C-P3H and C-P4H families as potentially important regulators of melanoma growth and invasiveness and suggest that selective inhibition of C-P4H is an attractive strategy to reduce the invasive properties of melanoma cells.
Rossi AP, Syed N, Wetmore C, et al., 2019, THE KETONE BODY B-HYDROXYBUTYRATE ACTS AS AN EPIGENETIC MODIFIER AND INCREASES RADIATION-INDUCED DNA DAMAGE IN DIFFUSE INTRINSIC PONTINE GLIOMA, 5th Biennial Conference of the Society-for-Neuro-Oncology on Pediatric Neuro-Oncology Basic and Translational Research, Publisher: OXFORD UNIV PRESS INC, Pages: 77-77, ISSN: 1522-8517
Renziehausen A, Wang H, Rao B, et al., 2019, The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention, Publisher: NATURE PUBLISHING GROUP, Pages: 2320-2336, ISSN: 0950-9232
Chatziathanasiadou MV, Stylos EK, Giannopoulou E, et al., 2019, Development of a validated LC-MS/MS method for the in vitro and in vivo quantitation of sunitinib in glioblastoma cells and cancer patients, Journal of Pharmaceutical and Biomedical Analysis, Vol: 164, Pages: 690-697, ISSN: 0731-7085
Sunitinib is a multi-targeted tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor and is currently being investigated against other forms of malignant tumors. Recently great interest has emerged for the application of sunitinib to glioblastoma treatment. In order to have a method with broad applicability it will be of importance to have access to a method that could be applied both in human plasma and cell uptake studies. No method has been reported thus far for the estimation of sunitinib uptake in glioma cells. We therefore set out to develop a method that could be applied for quantifying sunitinib in human plasma and in cell uptake studies. The method was validated and accredited according to ISO 17025:2005 guideline in human plasma and successfully applied to cancer patient plasma. Also, the method was effectively recruited to establish a protocol for the evaluation of sunitinib accumulation into M095K glioma cells. This method could significantly contribute to developmental phases in repurposing this drug in different cancer types.
Przystal JM, Hajji N, Khozoie C, et al., 2018, Efficacy of arginine depletion by ADI-PEG20 in an intracranial model of GBM, Cell Death and Disease, Vol: 9, ISSN: 2041-4889
Glioblastoma multiforme (GBM) remains a cancer with a poor prognosis and few effective therapeutic options. Successful medical management of GBM is limited by the restricted access of drugs to the central nervous system (CNS) caused by the blood brain barrier (BBB). We previously showed that a subset of GBM are arginine auxotrophic because of transcriptional silencing of ASS1 and/or ASL and are sensitive to pegylated arginine deiminase (ADI-PEG20). However, it is unknown whether depletion of arginine in peripheral blood in vivo has therapeutic activity against intracranial disease. In the present work, we describe the efficacy of ADI-PEG20 in an intracranial model of human GBM in which tumour growth and regression are assessed in real time by measurement of luciferase activity. Animals bearing intracranial human GBM tumours of varying ASS status were treated with ADI-PEG20 alone or in combination with temozolomide and monitored for tumour growth and regression. Monotherapy ADI-PEG20 significantly reduces the intracranial growth of ASS1 negative GBM and extends survival of mice carrying ASS1 negative GBM without obvious toxicity. The combination of ADI-PEG20 with temozolomide (TMZ) demonstrates enhanced effects in both ASS1 negative and ASS1 positive backgrounds.Our data provide proof of principle for a therapeutic strategy for GBM using peripheral blood arginine depletion that does not require BBB passage of drug and is well tolerated. The ability of ADI-PEG20 to cytoreduce GBM and enhance the effects of temozolomide argues strongly for its early clinical evaluation in the treatment of GBM.
Syed N, Mubarak M, Stylos E, et al., Development and validation of simple step protein precipitation UHPLC-MS/MS methods for quantitation of temozolomide in patient plasma samples Journal: Journal of Pharmaceutical and Biomedical Analysis, Journal of Pharmaceutical and Biomedical Analysis
Kiryushko D, Pankratova S, Klingelhofer J, et al., 2018, The S100A4 protein signals through the ErbB4 receptor to promote neuronal survival., Theranostics, Vol: 8, Pages: 3977-3990, ISSN: 1838-7640
Understanding the mechanisms of neurodegeneration is crucial for development of therapies to treat neurological disorders. S100 proteins are extensively expressed in the injured brain but S100's roleand signalling in neural cells remain elusive. We recently demonstrated that the S100A4 protein protects neurons in brain injury and designed S100A4-derived peptides mimicking its beneficial effects. Here we show that neuroprotection by S100A4 involves the growth factor family receptorErbB4 and its ligand Neuregulin 1 (NRG), key regulators of neuronal plasticity and implicated in multiple brain pathologies. The neuroprotective effect of S100A4 depends on ErbB4 expression andthe ErbB4 signalling partners ErbB2/Akt, and is reduced by functional blockade of NRG/ErbB4 in cell models of neurodegeneration. We also detect binding of S100A4 with ErbB1 (EGFR) and ErbB3. S100A4-derived peptides interact with, and signal through ErbB, are neuroprotective inprimary and immortalized dopaminergic neurons, and do not affect cell proliferation/motility - features which make them promising as potential neuroprotectants. Our data suggest that the S100- ErbB axis may be an important mechanism regulating neuronal survival and plasticity
Hajji N, García-Domínguez DJ, Hontecillas-Prieto L, et al., 2018, The bitter side of epigenetics: variability and resistance to chemotherapy, Epigenomics, ISSN: 1750-1911
One of the major obstacles to the development of effective new cancer treatments and the main factor for the increasing number of clinical trial failures appears to be the paucity of accurate, reproducible and robust drug resistance testing methods. Most research assessing the resistance of cancers to chemotherapy has concentrated on genetic-based molecular mechanisms, while the role of epigenetics in drug resistance has been generally overlooked. This is rather surprising given that an increasing body of evidence pointing to the fact that epigenetic mechanism alterations appear to play a pivotal role in cancer initiation, progression and development of chemoresistance. This resulted in a series of clinical trials involving epi-drug as single treatment or combined with cancer conventional drugs. In this review, we provided the main mechanisms by which the epigenetic regulators control the resistance to cancer drugs.
Hall PE, Lewis R, Syed N, et al., 2018, A phase I expansion study of pegargiminase, cisplatin, and pemetrexed in argininosuccinate synthetase 1-negative recurrent high grade gliomas (HGGs)., Journal of Clinical Oncology, Vol: 36, Pages: e14085-e14085, ISSN: 0732-183X
Moren L, Perryman R, Crook T, et al., 2018, Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM (vol 18, 167, 2018), BMC CANCER, Vol: 18, ISSN: 1471-2407
Moren L, Perryman R, Crook T, et al., 2018, Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM, BMC CANCER, Vol: 18, ISSN: 1471-2407
Williams M, Cross H, Jenkinson MD, et al., 2018, THE KETOGENIC DIET FOR PATIENTS WITH BRAIN TUMOURS: TWO PARALLEL RANDOMISED TRIALS, Meeting of the British-Neuro-Oncology-Society (BNOS), Publisher: OXFORD UNIV PRESS INC, Pages: 7-8, ISSN: 1522-8517
Woolf EC, Bhattacharya A, Rossi AP, et al., 2017, THE KETONE BODY beta-HYDROXYBUTYRATE CHEMO- AND RADIO-SENSITIZES MALIGNANT GLIOMA CELLS BY INHIBITING HISTONE DEACETYLASE ACTIVITY AND DOWNREGULATING EXPRESSION OF RAD51, Joint Conference of 22nd Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology / Conference of the Society-for-CNS-Interstitial-Delivery-of-the-Therapeutics (SCIDOT) on Therapeutic Delivery to the CNS, Publisher: OXFORD UNIV PRESS INC, Pages: 83-83, ISSN: 1522-8517
Tzouliana S, Hajji N, Perryman R, et al., 2017, THE KETOGENIC DIET ALTERS THE EPIGENETIC LANDSCAPE OF GBM TO POTENTIATE THE EFFECTS OF CHEMO AND RADIOTHERAPY, Joint Conference of 22nd Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology / Conference of the Society-for-CNS-Interstitial-Delivery-of-the-Therapeutics (SCIDOT) on Therapeutic Delivery to the CNS, Publisher: OXFORD UNIV PRESS INC, Pages: 96-97, ISSN: 1522-8517
Bassiri K, Ferluga S, Sharma V, et al., 2017, Global proteome and phospho-proteome analysis of Merlin-deficient meningioma and schwannoma identifies PDLIM2 as a novel therapeutic target., EBioMedicine, Vol: 16, Pages: 76-86, ISSN: 2352-3964
Loss or mutation of the tumour suppressor Merlin predisposes individuals to develop multiple nervous system tumours, including schwannomas and meningiomas, sporadically or as part of the autosomal dominant inherited condition Neurofibromatosis 2 (NF2). These tumours display largely low grade features but their presence can lead to significant morbidity. Surgery and radiotherapy remain the only treatment options despite years of research, therefore an effective therapeutic is required. Unbiased omics studies have become pivotal in the identification of differentially expressed genes and proteins that may act as drug targets or biomarkers. Here we analysed the proteome and phospho-proteome of these genetically defined tumours using primary human tumour cells to identify upregulated/activated proteins and/or pathways. We identified over 2000 proteins in comparative experiments between Merlin-deficient schwannoma and meningioma compared to human Schwann and meningeal cells respectively. Using functional enrichment analysis we highlighted several dysregulated pathways and Gene Ontology terms. We identified several proteins and phospho-proteins that are more highly expressed in tumours compared to controls. Among proteins jointly dysregulated in both tumours we focused in particular on PDZ and LIM domain protein 2 (PDLIM2) and validated its overexpression in several tumour samples, while not detecting it in normal cells. We showed that shRNA mediated knockdown of PDLIM2 in both primary meningioma and schwannoma leads to significant reductions in cellular proliferation. To our knowledge, this is the first comprehensive assessment of the NF2-related meningioma and schwannoma proteome and phospho-proteome. Taken together, our data highlight several commonly deregulated factors, and indicate that PDLIM2 may represent a novel, common target for meningioma and schwannoma.
Preston J, Stylianou J, Zeng Q, et al., 2017, THE KETOGENIC DIET INDUCES EPIGENETIC CHANGES THAT PLAY KEY ROLES IN TUMOUR DEVELOPMENT, Meeting of the British-Neuro-Oncology-Society (BNOS), Publisher: OXFORD UNIV PRESS INC, Pages: 128-128, ISSN: 1522-8517
Woolf EC, Syed N, Scheck AC, 2016, Tumor Metabolism, the Ketogenic Diet and beta-Hydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Theraphy, FRONTIERS IN MOLECULAR NEUROSCIENCE, Vol: 9, ISSN: 1662-5099
Renziehausen A, Eschbacher J, O'Neill K, et al., 2016, ANGIOTENSIN SIGNALLING IN GBM: AT2R AS A NOVEL THERAPEUTIC TARGET, 21st Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology, Publisher: OXFORD UNIV PRESS INC, Pages: 40-40, ISSN: 1522-8517
Perryman R, O'Neill K, Keun H, et al., 2016, DETERMINING THE ROLE OF NICOTINAMIDE METABOLISM IN CHEMOSENSITIVITY IN GLIOBLASTOMA MULTIFORME, 21st Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology, Publisher: OXFORD UNIV PRESS INC, Pages: 36-36, ISSN: 1522-8517
Woolf EC, Rossi AP, Silva-Nichols HB, et al., 2016, THE KETONE BODY beta-HYDROXYBUTYRATE INHIBITS HISTONE DEACETYLASE ACTIVITY AND ALTERS EXPRESSION OF DNA REPAIR PROTEINS IN MALIGNANT GLIOMA CELLS, 21st Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology, Publisher: OXFORD UNIV PRESS INC, Pages: 62-63, ISSN: 1522-8517
Lo Nigro C, Lattanzio L, Wang H, et al., 2016, Prolyl 4-(C-P4H) hydroxylases have opposing effects in malignant melanoma: implication in prognosis and therapy, Publisher: BMC, ISSN: 1479-5876
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.
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
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
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
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
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