Papers by Lyndon Gommersall
Biomarkers in cancer, 2018
High-risk non-muscle invasive bladder cancer (HR-NMIBC) is a clinically unpredictable disease. De... more High-risk non-muscle invasive bladder cancer (HR-NMIBC) is a clinically unpredictable disease. Despite clinical risk estimation tools, many patients are undertreated with intra-vesical therapies alone, whereas others may be over-treated with early radical surgery. Molecular biomarkers, particularly DNA methylation, have been reported as predictive of tumour/patient outcomes in numerous solid organ and haematologic malignancies; however, there are few reports in HR-NMIBC and none using genome-wide array assessment. We therefore sought to identify novel DNA methylation markers of HR-NMIBC clinical outcomes that might predict tumour behaviour at initial diagnosis and help guide patient management. A total of 21 primary initial diagnosis HR-NMIBC tumours were analysed by Illumina HumanMethylation450 BeadChip arrays and subsequently bisulphite Pyrosequencing. In all, 7 had not recurred at 1 year after resection and 14 had recurred and/or progressed despite intra-vesical BCG. A further in...
Trends in Urology & Men's Health, 2016
Expert Opin Pharmacother, 2002
... Monthly Focus: Oncologic Luteinising hormone releasing hormone analogues in the treatment of ... more ... Monthly Focus: Oncologic Luteinising hormone releasing hormone analogues in the treatment of prostate cancer Lyndon M Gommersall†, Dickon Hayne, Iqbal S Shergill, Manit Arya & DMAWallace Department of Urology, University Hospital, Birmingham, UK ...
The Lancet Oncology, Sep 1, 2004
Metastatic renal-cell carcinoma (RCC) is resistant to chemotherapy, and patients with this diseas... more Metastatic renal-cell carcinoma (RCC) is resistant to chemotherapy, and patients with this disease have a poor outlook. Immunotherapy by use of cytokines and vaccines against tumour antigens has shown encouraging results in a small group of patients. Advances in the understanding of the graft-versus-tumour effect in haematological malignant disorders have led to the use of stem-cell transplantation for treatment of solid-organ malignant diseases such as RCC. Techniques of bone-marrow ablation have been superseded by safer conditioning regimens, with occasional complete remission and partial remission in some patients. Graft-versus-host disease, engraftment failure, and disease progression remain important obstacles to the widespread use of new techniques for metastatic RCC. Here, we summarise important issues surrounding immunotherapy for RCC, the problems encountered with use of immunotherapy, and the present use of non-myeloablative techniques for treatment of this disease.
Epigenetics, 2016
High-grade non-muscle invasive bladder cancer (HG-NMIBC) is a clinically unpredictable disease wi... more High-grade non-muscle invasive bladder cancer (HG-NMIBC) is a clinically unpredictable disease with greater risks of recurrence and progression relative to their low-intermediategrade counterparts. The molecular events, including those affecting the epigenome, that characterise this disease entity in the context of tumour development, recurrence and progression, are incompletely understood. We therefore interrogated genome-wide DNA methylation using HumanMethylation450 BeadChip-arrays in 21 primary HG-NMIBC tumours relative to normal bladder controls. Using strict inclusion-exclusion criteria we identified 1,057 hypermethylated CpGs within gene promoter-associated CpG islands, representing 256 genes. Bisulphite Pyrosequencing validated the array data and examined 25 array-identified candidate genes in an independent cohort of 30 HG-NMIBC and 18 lowintermediate-grade NMIBC. These analyses revealed significantly higher methylation frequencies in high-grade tumours relative to low-intermediate-grade tumours for the ATP5G2, IRX1 and VAX2 genes (p<0.05), and similarly significant increases in mean levels of methylation in high-grade tumours for the ATP5G2, VAX2, INSRR, PRDM14, VSX1, TFAP2b, PRRX1, and HIST1H4F genes (p<0.05). Although inappropriate promoter methylation was not invariantly associated with reduced transcript expression, a significant association was apparent for the ARHGEF4, PON3, STAT5a, and VAX2 gene transcripts (p<0.05). Herein, we present the first genome-wide DNA methylation analysis in a unique HG-NMIBC cohort, showing extensive and discrete methylation changes relative to normal bladder and low-intermediate-grade tumours. The genes we identified hold significant potential as targets for novel therapeutic intervention either alone, or in combination, with more conventional therapeutic options in the treatment of this clinically unpredictable disease.
European Urology Supplements, 2003
International Journal of Surgery, 2014
The Journal of Steroid Biochemistry and Molecular Biology, 2004
Normal prostate epithelial cells are acutely sensitive to the antiproliferative action of 1␣,25-d... more Normal prostate epithelial cells are acutely sensitive to the antiproliferative action of 1␣,25-dihydroxyvitamin D 3 (1␣,25(OH) 2 D 3), whilst prostate cancer cell lines and primary cultures display a range of sensitivities. We hypothesised that key antiproliferative target genes of the Vitamin D receptor (VDR) were repressed by an epigenetic mechanism in 1␣,25(OH) 2 D 3-insensitive cells. Supportively, we found elevated nuclear receptor co-repressor and reduced VDR expression correlated with reduced sensitivity to the antiproliferative action of 1␣,25(OH) 2 D 3. Furthermore, the growth suppressive actions of 1␣,25(OH) 2 D 3 can be restored by co-treatment with low doses of histone deacetylation inhibitors, such as trichostatin A (TSA) to induce apoptosis. Examination of the regulation of VDR target genes revealed that co-treatment of 1␣,25(OH) 2 D 3 plus TSA cooperatively upregulated GADD45␣. Similarly in a primary cancer cell culture, the regulation of appeared GADD45␣ repressed. These data demonstrate that prostate cancer cells utilise a mechanism involving deacetylation to suppress the responsiveness of VDR target genes and thus ablate the antiproliferative action of 1␣,25(OH) 2 D 3 .
Oncogene, 2004
We hypothesized that key antiproliferative target genes for the vitamin D receptor (VDR) were rep... more We hypothesized that key antiproliferative target genes for the vitamin D receptor (VDR) were repressed by an epigenetic mechanism in prostate cancer cells resulting in apparent hormonal insensitivity. To explore this possibility we examined nuclear receptor co-repressor expression in a panel of non malignant and malignant cell lines and primary cultures, and found frequently elevated SMRT co-repressor mRNA expression often associated with reduced sensitivity to 1α,25-dihydroxyvitamin D 3 [1α,25(OH) 2 D 3 ]. For example, PC-3 and DU-145 prostate cancer cell lines had 1.8-and 2-fold increases in SMRT mRNA relative to normal PrEC cells (p<0.05). Similarly 10/15 primary tumour cultures (including 3 matched to normal cells from the same donors) had elevated SMRT mRNA levels; generally NCoR1 and Alien were not as commonly elevated. Co-repressor proteins often have associated histone deacetylases (HDAC) and reflectively the antiproliferative action of 1α,25(OH) 2 D 3 can be 'restored' by co-treatment with low doses of HDAC inhibitors such as trichostatin A (TSA, 15 nM) to induce apoptosis in prostate cancer cell lines. To decipher the transcriptional events that lead to these cellular responses we undertook gene expression studies in PC-3 cells after co-treatment of 1α,25(OH) 2 D 3 plus TSA after 6 hr. Examination of known VDR target genes and cDNA microarray analyses revealed co-treatment of 1α,25(OH) 2 D 3 plus TSA cooperatively upregulated 8 (out of 1176) genes, including MAPK-APK2 and GADD45α. MRNA and protein time courses and inhibitor studies confirmed these patterns of regulation. Subsequently we knocked-down SMRT levels in PC-3 cells using a small interfering RNA (siRNA) approach and found that GADD45α induction by 1α ,25(OH) 2 D 3 alone became very significantly enhanced. The same distortion of gene responsiveness, with repressed induction of GADD45α was found in primary tumour cultures compared and to matched peripheral zone (normal) cultures from the same donor. These data demonstrate that elevated SMRT levels are common in prostate cancer cells, resulting in suppression of target genes associated with antiproliferative action and apparent 1α,25(OH) 2 D 3-insensitivity. This can be targeted therapeutically by combination treatments with HDAC inhibitors.
Nature Clinical Practice Oncology, 2005
Wilms&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp... more Wilms&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; tumor is a renal cancer that predominantly affects children during the first 2 years of life. The continuing success of clinical trials in Wilms&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; tumor patients over the past 30 years has led to an overall survival of 85%, and treatment-related morbidity has been reduced. Less-aggressive chemotherapeutic regimes are available for patients with validated good prognostic factors, such as low stage and favorable histology. It is becoming increasingly apparent that treatment can be optimized through stratification of patients according to tumor stage and histology. Established treatments for Wilms&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; tumor include perioperative vincristine and actinomycin, with or without doxorubicin or radiotherapy. Relapsed patients have the option of salvage chemotherapy with ifosfamide, carboplatin and etoposide, as well as high-dose chemotherapy regimes and autologous hemopoietic stem-cell rescue. Further research is required to refine these regimes and identify further the role of additional prognostic factors in this childhood disease. In this article we discuss the most-debated issues and advances that have been made in the management of Wilms&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; tumor.
The Lancet Oncology, 2004
Metastatic renal-cell carcinoma (RCC) is resistant to chemotherapy, and patients with this diseas... more Metastatic renal-cell carcinoma (RCC) is resistant to chemotherapy, and patients with this disease have a poor outlook. Immunotherapy by use of cytokines and vaccines against tumour antigens has shown encouraging results in a small group of patients. Advances in the understanding of the graft-versus-tumour effect in haematological malignant disorders have led to the use of stem-cell transplantation for treatment of solid-organ malignant diseases such as RCC. Techniques of bone-marrow ablation have been superseded by safer conditioning regimens, with occasional complete remission and partial remission in some patients. Graft-versus-host disease, engraftment failure, and disease progression remain important obstacles to the widespread use of new techniques for metastatic RCC. Here, we summarise important issues surrounding immunotherapy for RCC, the problems encountered with use of immunotherapy, and the present use of non-myeloablative techniques for treatment of this disease.
Journal of Medicinal Food, 2004
We completed a multicenter study of the effects of pomegranate cold-pressed (Oil) or supercritica... more We completed a multicenter study of the effects of pomegranate cold-pressed (Oil) or supercritical CO 2-extracted (S) seed oil, fermented juice polyphenols (W), and pericarp polyphenols (P) on human prostate cancer cell xenograft growth in vivo, and/or proliferation, cell cycle distribution, apoptosis, gene expression, and invasion across Matrigel, in vitro. Oil, W, and P each acutely inhibited in vitro proliferation of LNCaP, PC-3, and DU 145 human cancer cell lines. The dose of P required to inhibit cell proliferation of the prostate cancer cell line LNCaP by 50% (ED 50) was 70 g/mL, whereas normal prostate epithelial cells (hPrEC) were significantly less affected (ED 50 ϭ 250 g/mL). These effects were mediated by changes in both cell cycle distribution and induction of apoptosis. For example, the androgen-independent cell line DU 145 showed a significant increase from 11% to 22% in G 2 /M cells (P Ͻ .05) by treatment with Oil (35 g/mL) with a modest induction of apoptosis. In other cell lines/treatments, the apoptotic response predominated, for example, in PC-3 cells treated with P, at least partially through a caspase 3-mediated pathway. These cellular effects coincided with rapid changes in mRNA levels of gene targets. Thus, 4-hour treatment of DU 145 cells with Oil (35 g/mL) resulted in significant 2.3 Ϯ 0.001-fold (mean Ϯ SEM) up-regulation of the cyclin-dependent kinase inhibitor p21 (waf1/cip1) (P Ͻ .01) and 0.6 Ϯ 0.14-fold down-regulation of c-myc (P Ͻ .05). In parallel, all agents potently suppressed PC-3 invasion through Matrigel, and furthermore P and S demonstrated potent inhibition of PC-3 xenograft growth in athymic mice. Overall, this study demonstrates significant antitumor activity of pomegranate-derived materials against human prostate cancer. KEY WORDS: • apoptosis • chemoprevention • flavonoid • p2 1 (waf/cip1) • phytoestrogen • prostate cancer • punicic acid
International Journal of Surgery, 2012
Expert Review of Molecular Diagnostics, 2005
Expert Opinion on Pharmacotherapy, 2004
Sildenafil revolutionised the treatment of erectile dysfunction (ED) on its introduction in 1998.... more Sildenafil revolutionised the treatment of erectile dysfunction (ED) on its introduction in 1998. Not only is it effective, but is, perhaps even more importantly, an extremely acceptable manner in which to treat ED (i.e., oral pharmacotherapy), compared to the other treatments that were available at that time (e.g., intracavernosal injection). Whilst sildenafil remains the market leader for ED treatment, it does have some shortcomings: its clinical efficacy is diminished in &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;difficult to treat&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; patient groups, such as diabetics, side effects, such as blue-tinged vision and headache, and the need to time the ingestion of sildenafil to 1 h prior to expected time of sexual intercourse. Recently, newer phosphodiesterase inhibitors (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;sons of…
European Urology, 2007
Objectives: We review important aspects of nanotechnology, and discuss the wide range of research... more Objectives: We review important aspects of nanotechnology, and discuss the wide range of research and clinical applications of nanomedicine in the field of urology. There is particular emphasis on key clinical and pre-clinical studies to provide an update on recent and potential applications in the care of urological patients. Methods: A directed Medline literature review of nanotechnology was performed. Important publications that have shaped our understanding of nanotechnology were selected for review and were augmented by manual searches of reference lists. Results: Nanotechnology is the study, design, creation, synthesis, manipulation, and application of functional materials, devices, and systems through control of matter at the nanometer scale. Studies demonstrate a number of important concepts. These include nanovectors, nanotubes, and nanosensors for targeted drug delivery; nanowires and nanocantilever arrays for early detection of precancerous and malignant lesions; and nanopores for DNA sequencing. These advances will lead to significant applications relevant to the diagnosis, management, and treatment of all urological conditions. Conclusions: This review is designed for the urologist to provide an overview and update on nanotechnology and its applications in the field of urology. In the future, it is widely expected that nanotechnology and nanomedicine will have a significant impact on urological research and clinical practice, allowing urologists to intervene at the cellular and molecular level. With structured, safe implementation, nanotechnologies have the potential to revolutionise urological practice in our lifetime.
Uploads
Papers by Lyndon Gommersall