Dean Fennell's research while affiliated with University of Leicester and other places

Publications (56)

Article
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Aim: To assess the correlation between KDM6B and estrogen receptor β (ERβ) expression in malignant pleural mesothelioma (MPM). Materials & methods: We evaluated gene expression by in silico analysis of microarray data, real-time PCR and western blot in MPM tumors and cell lines. Results & conclusion: We report a strong positive correlation bet...
Article
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In this report, we show that malignant pleural mesothelioma (MPM) patients whose tumors express high levels of AKT1 exhibit a significantly worse prognosis, whereas no significant correlation with AKT3 expression is observed. We provide data that establish a phosphorylation independent role of AKT1 in affecting MPM cell shape and anchorage independ...
Article
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This trial was designed to evaluate the activity and safety of ganetespib in combination with docetaxel in advanced NSCLC and to identify patient populations most likely to benefit from the combination. Patients with one prior systemic therapy for advanced disease were eligible. Docetaxel (75mg/m(2) on Day 1) was administered alone or with ganetesp...
Article
Malignant pleural mesothelioma (MPM) is an uncommon cancer with poor survival. We have used data collected for the UK National Lung Cancer Audit to assess current practice and to highlight regional variation in the management of mesothelioma patients, as well as to describe survival patterns in subgroups. Our data on 8740 cases seen in hospitals in...
Article
Vorinostat is a histone deacetylase inhibitor that changes gene expression and protein activity. On the basis of the clinical benefit reported in patients with malignant pleural mesothelioma treated in a phase 1 study of vorinostat, we designed this phase 3 trial to investigate whether vorinostat given as a second-line or third-line therapy improve...
Article
Modern imaging techniques that can provide functional information on tumor vascularization, metabolic activity, or cellularity have seen significant improvements over the past decade. However, most of these techniques are currently not broadly utilized neither in clinical trials nor in clinical routine, although there is a large agreement on the fa...
Article
Background The National Lung Cancer Audit records outcomes in lung cancer and mesothelioma on a population scale, in order to explain the wide variations seen within the UK and between the UK and other countries and ultimately improving outcomes. Methods All cases of mesothelioma submitted to the audit by English Trusts 2006–2011 were analysed. A h...
Article
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Estrogen receptor (ER)-β has been shown to possess a tumor suppressive effect, and is a potential target for cancer therapy. Using gene-expression meta-analysis of human malignant pleural mesothelioma, we identified an ESR2 (ERβ coding gene) signature. High ESR2 expression was strongly associated with low succinate dehydrogenase B (SDHB) (which enc...
Article
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Advances in the management of non-small cell lung cancer (NSCLC) over the past 30 years have led to small increases in 5-year survival rates across Europe, though further improvements may require new treatment strategies. In order to improve efficiency and reduce the cost of development, future trials for new targeted agents in NSCLC should aim to...
Article
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Malignant pleural mesothelioma (MPM) is a highly pro-inflammatory malignancy that is rapidly fatal and increasing in incidence. Cytokine signaling within the pro-inflammatory tumor microenvironment makes a critical contribution to the development of MPM and its resistance to conventional chemotherapy approaches. SMAC mimetic compounds (SMCs) are a...
Article
Tissue microarrays (TMAs) represent a powerful method for undertaking large-scale tissue-based biomarker studies. While TMAs offer several advantages, there are a number of issues specific to their use which need to be considered when employing this method. Given the investment in TMA-based research, guidance on design and execution of experiments...
Article
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Failure to efficiently induce apoptosis contributes to cisplatin resistance in non-small-cell lung cancer (NSCLC). Although BCL-2-associated X protein (BAX) and BCL-2 antagonist killer (BAK) are critical regulators of the mitochondrial apoptosis pathway, their requirement has not been robustly established in relation to cisplatin. Here, we show tha...
Article
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The cancer stem-cell (CSC) hypothesis suggests that there is a small subset of cancer cells that are responsible for tumor initiation and growth, possessing properties such as indefinite self-renewal, slow replication, intrinsic resistance to chemotherapy and radiotherapy, and an ability to give rise to differentiated progeny. Through the use of xe...
Article
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Inhibition of the PI3K (phosphoinositide 3-kinase)/Akt/mTORC1 (mammalian target of rapamycin complex 1) and Ras/MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase]/ERK pathways for cancer therapy has been pursued for over a decade with limited success. Emerging data have indicated that only discrete subs...
Article
When grown in 3D cultures as spheroids, cancer cells acquire a multicellular resistance to apoptosis that resembles that of solid tumors. We have previously found in lung cancer and mesothelioma that multicellular resistance lies at the level of mitochondria and can be reduced by manipulating the Bcl-2 repertoire with BH3-mimetics. One mechanism fo...
Article
Circulating tumour cells (CTCs) have attracted much recent interest in cancer research as a potential biomarker and as a means of studying the process of metastasis. It has long been understood that metastasis is a hallmark of malignancy, and conceptual theories on the basis of metastasis from the nineteenth century foretold the existence of a tumo...
Article
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We have previously demonstrated that Tcf-4 regulates osteopontin (OPN) in rat breast epithelial cells, Rama37. In this report, we have examined the importance of this regulation in human breast cancer. The regulatory roles of Tcf-4 on cell invasion and OPN expression were investigated. The mRNA expression of Tcf-4 and OPN, and survival of breast ca...
Article
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Non-small-cell lung cancer (NSCLC) remains by far the major cause of cancer-related death in the Western world in both men and women. The majority of patients will be diagnosed with metastatic disease, and chemotherapy doublets remain the cornerstone of treatment for these patients. However, chemotherapy has a minimal impact on long-term survival a...
Article
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Three-dimensional (3D) cultures are a valuable platform to study acquired multicellular apoptotic resistance of cancer. We used spheroids of cell lines and actual tumor to study resistance to the proteasome inhibitor bortezomib in mesothelioma, a highly chemoresistant tumor. Spheroids from mesothelioma cell lines acquired resistance to bortezomib b...
Article
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Tissue microarray (TMA) is a high throughput analysis tool to identify new diagnostic and prognostic markers in human cancers. However, standard automated method in tumour detection on both routine histochemical and immunohistochemistry (IHC) images is under developed. This paper presents a robust automated tumour cell segmentation model which can...
Article
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Direct pharmacological targeting of the anti-apoptotic B-cell lymphoma-2 (BCL-2) family is an attractive therapeutic strategy for treating cancer. Obatoclax is a pan-BCL-2 family inhibitor currently in clinical development. Here we show that, although obatoclax can induce mitochondrial apoptosis dependent on BCL-2 associated x protein/BCL-2 antagon...
Article
Malignant pleural mesothelioma is a highly invasive tumor arising from the mesothelial cells of serosal surfaces. Several chemotherapeutic agents have been tested for the treatment of this disease and doublet cisplatin with antifolates has been demonstrated to have significant efficacy in Phase III studies. However, the benefit of these treatments...
Article
Background: Failure to induce apoptosis is a major limitation of conventional chemotherapy for lung cancer. Resistance to apoptosis contributes to this chemoresistant phenotype. New therapeutic strategies are therefore required to bypass block in apoptosis. Obatoclax (obx) is a small molecule inhibitor of pro‐survival BCL‐2 family proteins currentl...
Conference Paper
The molecular mechanism underlying mitochondrial BAK activation during apoptosis remains highly controversial. Two seemingly conflicting models known as the agonism model and the de-repressor model have been proposed. In the agonism model, BAK requires activator BH3 only proteins to initiate a series of events that results in cell apoptosis. In the...
Article
The molecular mechanism underlying mitochondrial BAK activation during apoptosis remains highly controversial. Two seemingly conflicting models have been proposed. In the activation model, BAK requires so‐called activating BH3 only proteins (aBH3) to initiate its conformation change. In the other, displacement from inhibitory pro‐survival BCL‐2 pro...
Article
The treatment of advanced non-small cell lung cancer (NSCLC) has evolved substantially during the last years. Chemotherapy remains the cornerstone of treatment and prolongs survival with a positive impact on quality of life. However, we seem to have reached a plateau of activity in the treatment of NSCLC. Recently, the addition of bevacizumab or ce...
Article
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We found that procaspase 8 was overexpressed in non-small-cell lung cancers (NSCLCs) compared with matched normal tissues. The caspase 8 inhibitor FLICE-inhibitory protein (FLIP) was also overexpressed in the majority of NSCLCs. Silencing FLIP induced caspase 8 activation and apoptosis in NSCLC cell lines, but not in normal lung cell lines. Apoptos...
Article
Background: Malignant pleural mesothelioma (MPM) is an uncommon disease whose incidence is increasing worldwide over the past 30 years. Surgical resection and radiotherapy represent the standard treatment in patient with resectable MPM. Chemotherapy is also necessary to reduce incidence of distant metastases, but the optimal setting of treatment (...
Article
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Death receptors can directly (type I cells) or indirectly induce apoptosis by activating mitochondrial-regulated apoptosis (type II cells). The level of caspase 8 activation is thought to determine whether a cell is type I or II, with type II cells less efficient at activating this caspase following death receptor activation. FLICE-inhibitory prote...
Article
Malignant pleural mesothelioma (MPM) is a rapidly progressive invariably lethal tumor. Treatment options remain limited and the outcome in relapsed disease is poor warranting new therapeutic options. Following our previous experience in the first-line setting, we conducted a phase 2 open-label non-comparative study to assess the safety and efficacy...
Article
Full-text available
Bortezomib (Velcade, PS341) was licensed in 2003 as a first-in-class 20S proteasome inhibitor indicated for treatment of multiple myeloma, and is currently being evaluated clinically in a range of solid tumours. The mechanisms underlying its cancer cell toxicity are complex. A growing body of evidence suggests proteasome inhibition-dependent regula...
Article
Robust quantitative estimation of average whole cell mitochondrial dysfunction is a useful tool for assessing sensitivity to apoptotic stimuli induced either by novel agents, or following manipulation of apoptotic threshold by pharmacological or functional genomics approaches. We have mathematically modelled the kinetics of whole cell mitochondrial...
Article
Cholangiocarcinoma cells express high levels of the antiapoptotic proteins Bcl-X(L) and Mcl-1 and are markedly chemo- and radioresistant. Mitochondria have emerged as central players in apoptosis. Antiapoptotic members of the Bcl-2 protein family localise to the outer mitochondrial membrane and regulate mitochondrial release of apoptogenic proteins...
Article
Resistance to apoptosis is a major obstacle preventing effective therapy for malignancy. Mitochondria localized anti-death proteins of the Bcl-2 family play a central role in inhibiting apoptosis and therefore present valid targets for novel therapy. The peripheral benzodiazepine receptor (PBR) shares a close physical association with the permeabil...
Article
Antisense oligonucleotides owe their efficacy to an ability to induce RNase H-dependent suppression of RNA translation, for sufficient time to allow physiological proteolysis. The magnitude and time delay preceding the protein nadir concentration determine the extent and timing of maximum antisense oligonucleotide activity. Antisense oligonucleotid...
Article
Cytofluorometric analysis allows single-cell resolution of all-or-none programmed cell death (apoptosis) responses and permits direct measurement of cumulative frequency distributions (CFDs) of apoptosis sensitivity from which the median apoptosis tolerance can be estimated. Robust estimation of susceptibility to apoptosis within neoplastic cell po...
Chapter
Greater understanding of the molecular basis of many diseases has led to exploration of"gene silencing"strategies of which antisense oligonucleotides have been in the forefront. Developments in this field have now entered the clinical arena with variable results. However, it is becoming clear that some of these molecules may eventually become medic...

Citations

... Multicellular spheroids were generated in non-adsorbent round-bottomed 96-well plates, as previously described [55]. The 96-well plates were coated with a 1:24 dilution of polyHEMA (120 mg mL −1 ) in 95% ethanol and dried at 37 • C for 24 h. ...
... For example, the tumor-suppressive function of ERb was demonstrated through its knockdown in ERa+ cell lines, which induced an invasive phenotype, increased anchorage-dependent cell proliferation, and elevated EGF-R signaling (8). In the presence of estradiol, ERb overexpression reduced cell proliferation in vitro and tumor formation in vivo, effects that are in contradistinction to those of ERa (9,10). ...
... Malignant pleural mesothelioma (MPM) is an aggressive and rare tumour, originating from mesothelial cells lining the pleura [1,2]. MPM is the most common form of mesothelioma, accounting for over 90,000 deaths per year globally [1], with approximately 80% of cases caused by exposure to asbestos fibres [2]. ...
... Furthermore, the elevated intrinsic proteotoxic stress in tumor cells upregulates the activated, highaffinity form of chaperone HSP90 and hence provides a certain tumor-specific vulnerability [25]. In addition, ganetespib demonstrated a good tissue penetrance and pharmaceutical profile [26,27] and was administered in numerous clinical trials [28][29][30]. However, current radiobiology-oriented research is limited to photon and high-LET carbon ion irradiation in combinations with HSP90 inhibitors [31][32][33][34]. ...
... The observed treatment patterns generally followed recommended guidelines from ESMO [1] that were available at the time of the study, with platinum+antifolate doublet chemotherapy the most widely used treatment regimen in patients at the time of data abstraction. Previous studies that reviewed treatment patterns covering periods form 2005 to 2013, conducted in France [17], Spain [18] and the UK [19], similarly showed the dominant use of this doublet chemotherapy regimen. Our findings demonstrate that there has been little treatment innovation within the past decade. ...
... Besides the vaccines and the T-cells therapies which are coming up for the better control of MPM, the oncolytic viruses and other targets as some vascular endothelial growth factors receptors (VEGFR), the platelet-derived growth factor receptor (PDGFR), and the fibroblast growth factor receptor (FGFR) tyrosine-kinase inhibitor, are under consideration. Some phase I/II clinical trials are running at the moment to evaluate the safety of the biological effects [148][149][150][151][152]. ...
... Therefore, when changes in tumour vascularisation are evaluated, we can detect the effects of the treatment more reliably and earlier, thus avoiding prolonged use and toxicity in patients who do not respond, in addition to decreasing economic costs. Perfusion computed tomography (PCT) is an imaging tool that has attracted increasing attention because the parameters obtained can be an indirect reflection of the vascularisation and vascular physiology of the tumour [8][9][10][11][12][13][14][15][16][17][18][19][20][21], and it can be easily incorporated into routine monitoring protocols for lung cancer [22]. ...
... However, its curative effect is by no means satisfactory, with a 5-year survival rate of less than 20%. [3] Platinum-based doublet chemotherapy acts as the first-line treatment for advanced NSCLC patients without driver gene mutations; it has an objective remission rate of 25% to 35%, a median overall survival of 8 to 10 months, and a median progression-free survival of 4 to 6 months. [4] For NSCLC patients with driver gene mutations, targeted therapy has shown obvious effects in terms of prolonged lifetime and progression-free survival. ...
... (D) Cytoplasmic L-lactate level in p21 and 12M mice. Measurements were assessed in cytoplasmic fractions isolated from the cryopreserved brain cortex, essentially as described in Manente et al. (2013). Values are presented as means ± SEM of three independent measurements on six mice for each age tested, and expressed as nmol L-lactate/mg brain cortex protein. ...
... Reduced expression of SDH subunits post ARPI may hamper assembly of the SDH enzyme complex (Lemarie et al, 2011), leading to reduced SDH activity and increased succinate levels post ARPI. We found that SDH repression inhibits proteasomal degradation of AR by upregulating p-Hsp27 (Zoubeidi et al, 2007), findings consistent with studies in breast cancer, where SDH repression can also upregulate estrogen receptor (ER) b expression (Manente et al, 2013) and promote mitochondrial biogenesis via PGC1a (Chen et al, 2009). ...