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Coleman R.E.,Academic Unit of Oncology | Rathbone E.,St Jamess Hospital | Brown J.E.,Academic Unit of Oncology
Nature Reviews Rheumatology | Year: 2013

The survival prospects for many patients with cancer are steadily improving. As a result, survivorship issues are of increasing importance as attempts are made to minimize the long-term adverse effects of cancer treatments. Cancer therapies can adversely affect bone health, particularly in women with breast cancer and men with prostate cancer. Strategies for screening patients at increased risk for fragility fracture, and treatment algorithms using both bone-targeted treatments and other therapeutic interventions, are being developed. Both bisphosphonates and denosumab have been evaluated as treatments to prevent or reverse the bone loss associated with cancer treatments. Zoledronic acid is the most extensively assessed agent and has been shown to prevent bone loss in patients with breast cancer experiencing a premature menopause, in postmenopausal women receiving an aromatase inhibitor and in patients with prostate cancer undergoing androgen deprivation therapy (ADT). To date, the improvements in bone mineral density have not translated into a reduced fracture rate. However, in a large phase III trial, denosumab has been shown to reduce vertebral fractures in men receiving ADT for prostate cancer. These bone-targeted treatments have also been shown to modify the course of the underlying cancer and prevent metastasis, although the beneficial effects are confined to patients with low levels of circulating reproductive hormones. © 2013 Macmillan Publishers Limited. All rights reserved.

Sudhakar J.,Vision Research Foundation | Sudhakar J.,Birla Institute of Technology and Science | Khetan V.,Medical Research Foundation | Madhusudan S.,Academic Unit of Oncology | Krishnakumar S.,Vision Research Foundation
British Journal of Ophthalmology | Year: 2014

Background: Retinoblastoma (RB) is a childhood eye tumour. Dysregulation of DNA repair may not only influence pathogenesis but could also adversely impact on response to cytotoxic chemotherapy frequently used in RB therapy. We studied the expression of human apurinic/apyrimidinic endonuclease (APE1), a key multifunctional protein involved in DNA base excision repair in RB. Methods: Expression of APE1 was evaluated by immunohistochemistry in a series of 55 RBs and in retina. In tumours, APE1 expression was analysed in cytoplasm and nucleus independently and correlated with histopathological features, including invasion, differentiation and International Intraocular Retinoblastoma Classification groups. Relative APE1 mRNA and protein expressions were evaluated by realtime PCR and western blot. The expression of APE1 in tumour groups was compared with retinal tissue. Results: APE1 cytoplasmic expression was observed in 98% and nuclear positivity was observed in 83% of tumours analysed. Tumour cells invading the optic nerve showed predominant cytoplasmic immunoreactivity. An inverse correlation between cytoplasmic and nuclear positivity was observed. Real-time PCR revealed an increase in APE1 transcripts compared with retina. Western blot revealed a decreased protein concentration compared with retinal tissue. Conclusions: This is the first study of APE1 expression in RB. Our observation suggests that subcellular localisation of APE1 is altered in RB. APE1 could be a potential drug target in RB.

Agboola A.,Olabisi Onabanjo University | Musa A.,Olabisi Onabanjo University | Banjo A.,Olabisi Onabanjo University | Ayoade B.,Olabisi Onabanjo University | And 5 more authors.
Journal of Clinical Pathology | Year: 2014

Aim: Indigenous black women with breast cancer (BC) show a high frequency of triple negative breast cancer (TNBC) comprising ER-, PR- and HER2- phenotypes and BRCA1 deficiency together with a high mortality rate, prompting speculation that risk factors could be genetic and the molecular portrait of these tumours may be different to those of Western women. Protein inhibitor of activated signal transducer (PIAS) γ implicated in the BRCA1 deficiency and triple negative BC was investigated to establish the relationship among the small ubiquitin-like modifier marker, pathological features, biomarkers expression and clinical outcome in the black women. Materials and methods: This study investigated the immunoprofiles of PIASγ in 231 Nigerian BC prepared as tissue microarrays and correlated their protein expression with clinical outcome, pathological responses and the expression of 14 other relevant biomarkers. Results: PIASγ protein expression showed a significant correlation with higher histological grade, basal-like biomarkers expression (CK14, CK5/6 and EGFR), BRCA1 regulator (MTA1), p53, PI3KCA, basal-like phenotype and TNBC. Also, an inverse correlation with steroid hormones (ER and PgR), p27, MDM4, mucin 1 and BRCA1 was observed with PIASγ expression. Univariate and multivariate survival analyses showed PIASγ expression was a predictor of poor outcome independent of tumour histological grade and ER expression. Conclusions PIASγ appears to be important in breast cancer behaviour arising from Nigerian women. PIASγ may therefore be useful for the screening of basal-like and TNBC. Also, development of novel therapies towards targeting PIASγ functional pathways may enhance the BC management among this ethnic nationality.

Mohammed M.Z.,Academic Unit of Oncology | Vyjayanti V.N.,National Institute on Ageing | Laughton C.A.,University of Nottingham | Dekker L.V.,University of Nottingham | And 7 more authors.
British Journal of Cancer | Year: 2011

Aims:Modulation of DNA base excision repair (BER) has the potential to enhance response to chemotherapy and improve outcomes in tumours such as melanoma and glioma. APE1, a critical protein in BER that processes potentially cytotoxic abasic sites (AP sites), is a promising new target in cancer. In the current study, we aimed to develop small molecule inhibitors of APE1 for cancer therapy.Methods:An industry-standard high throughput virtual screening strategy was adopted. The Sybyl8.0 (Tripos, St Louis, MO, USA) molecular modelling software suite was used to build inhibitor templates. Similarity searching strategies were then applied using ROCS 2.3 (Open Eye Scientific, Santa Fe, NM, USA) to extract pharmacophorically related subsets of compounds from a chemically diverse database of 2.6 million compounds. The compounds in these subsets were subjected to docking against the active site of the APE1 model, using the genetic algorithm-based programme GOLD2.7 (CCDC, Cambridge, UK). Predicted ligand poses were ranked on the basis of several scoring functions. The top virtual hits with promising pharmaceutical properties underwent detailed in vitro analyses using fluorescence-based APE1 cleavage assays and counter screened using endonuclease IV cleavage assays, fluorescence quenching assays and radiolabelled oligonucleotide assays. Biochemical APE1 inhibitors were then subjected to detailed cytotoxicity analyses.Results:Several specific APE1 inhibitors were isolated by this approach. The IC 50 for APE1 inhibition ranged between 30 nM and 50 M. We demonstrated that APE1 inhibitors lead to accumulation of AP sites in genomic DNA and potentiated the cytotoxicity of alkylating agents in melanoma and glioma cell lines.Conclusions:Our study provides evidence that APE1 is an emerging drug target and could have therapeutic application in patients with melanoma and glioma. © 2011 Cancer Research UK. All rights reserved.

Fareed K.R.,Academic Unit of Oncology | Al-Attar A.,Academic Unit of Oncology | Soomro I.N.,University of Nottingham | Kaye P.V.,University of Nottingham | And 4 more authors.
British Journal of Cancer | Year: 2010

Aims:Neoadjuvant chemotherapy followed by surgery is the standard of care for patients with gastro-oesophageal adenocarcinoma. Previously, we validated the utility of the tumour regression grade (TRG) as a histopathological marker of tumour downstaging in patients receiving platinum-based neoadjuvant chemotherapy. In this study we profiled key DNA repair and damage signalling factors and correlated them with clinicopathological outcomes, including TRG response.Methods and results:Formalin-fixed human gastro-oesophageal cancers were constructed into tissue microarrays (TMAs). The first set consisted of 142 gastric/gastro-oesophageal cancer cases not exposed to neoadjuvant chemotherapy and the second set consisted of 103 gastric/gastro-oesophageal cancer cases exposed to preoperative platinum-based chemotherapy. Expressions of ERCC1, XPF, FANCD2, APE1 and p53 were investigated using immunohistochemistry.In patients who received neoadjuvant chemotherapy, favourable TRG response (TRG 1, 2 or 3) was associated with improvement in disease-specific survival (P0.038). ERCC1 nuclear expression correlated with lack of histopathological response (TRG 4 or 5) to neoadjuvant chemotherapy (P0.006) and was associated with poor disease-specific (P0.020) and overall survival (P0.040).Conclusions:We provide evidence that tumour regression and ERCC1 nuclear protein expression evaluated by immunohistochemistry are promising predictive markers in gastro-oesophageal cancer patients receiving neoadjuvant platinum-based chemotherapy. © 2010 Cancer Research UK All rights reserved.

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