Harrogate, United Kingdom
Harrogate, United Kingdom

Yorkshire Cancer Research is a registered charity that funds research, principally in Yorkshire, into the causes and cures of cancer. They do this by fundraising in Yorkshire and providing awards to Yorkshire based academic institutions. Through publishing and sharing the results of this research with the world's scientific community, Yorkshire Cancer Research hopes to develop more effective treatments for cancer sufferers world-wide.Yorkshire Cancer Research raises its money in Yorkshire and spends it in Yorkshire at its five centres of excellence based at Bradford University, Hull University, Leeds University, Sheffield University and York University and their associated teaching hospitals.They are the most successful regional medical research charity in the UK and fund internationally recognised research which focuses on a variety of cancers including: breast cancer, bowel cancer, cervical cancer, non-Hodgkin Lymphoma, ovarian cancer, prostate cancer, skin cancer and genetics of cancers. Yorkshire Cancer Research is not a regional division of a national charity - they are an independent charity, based and operating in Yorkshire only.Yorkshire Cancer Research are members of the Association of Medical Research Charities and the National Cancer Research Institute Wikipedia.

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Maitland N.,Yorkshire Cancer Research
Human gene therapy | Year: 2010

Destruction of cancer cells by genetically modified viral and nonviral vectors has been the aim of many research programs. The ability to target cytotoxic gene therapies to the cells of interest is an essential prerequisite, and the treatment has always had the potential to provide better and more long-lasting therapy than existing chemotherapies. However, the potency of these infectious agents requires effective testing systems, in which hypotheses can be explored both in vitro and in vivo before the establishment of clinical trials in humans. The real prospect of off-target effects should be eliminated in the preclinical stage, if current prejudices against such therapies are to be overcome. In this review we have set out, using adenoviral vectors as a commonly used example, to discuss some of the key parameters required to develop more effective testing, and to critically assess the current cellular models for the development and testing of prostate cancer biotherapy. Only by developing models that more closely mirror human tissues will we be able to translate literature publications into clinical trials and hence into acceptable alternative treatments for the most commonly diagnosed cancer in humans.

Wilson C.,Yorkshire Cancer Research | Coleman R.E.,Yorkshire Cancer Research
Current Opinion in Supportive and Palliative Care | Year: 2011

Purpose of review The use of bone-targeting agents in the adjuvant setting has focused on two main areas: prevention of chemotherapy-induced bone loss (CTIBL) and the potential antitumour effects in preventing development of metastasis. Here, we review recent advances within these two areas. Recent findings Trials of oral and intravenous bisphosphonates for prevention of CTIBL in breast cancer have informed both UK and European guidelines on management. A large randomized trial of denosumab, an antibody to RANK ligand, in prostate cancer has demonstrated prevention of bone loss and a reduction in fractures. The data supporting the use of bone-targeted agents in prevention of metastasis are less consistent, with variable findings from the randomized controlled trials in both breast and prostate cancer reported to date. However, the emerging evidence suggests that modification of the bone microenvironment does influence the clinical course of both early breast cancer and castrate-resistant prostate cancer, particularly in clinical settings in which bone metabolism is no longer primarily regulated by reproductive hormones. Summary The role of bisphosphonates in CTIBL in breast cancer is now defined, but in other malignancies more evidence is needed prior to recommendation as standard treatment. In the role of preventing metastasis, results of ongoing studies are awaited to help clarify populations of patients who will derive benefit. Alternative therapies including the RANKL inhibitor denosumab may provide an alternative adjuvant treatment strategy. Combination therapy with adjuvant bone-targeted agents is yet to be investigated. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Baxter E.W.,Yorkshire Cancer Research | Milner J.,Yorkshire Cancer Research
Journal of Neuro-Oncology | Year: 2010

Medulloblastomas are highly malignant, poorly differentiated childhood tumours arising in the cerebellum. These tumors rarely lose TP53, which is the most commonly mutated gene in cancer. Recent work has shown that the basal level of p53 plays an important role in maternal reproduction by maintaining the expression of LIF in the uterus. Since LIF can maintain the undifferentiated state of stem cells we set out to ask if p53 regulates LIF in the human medulloblastoma cell lines DAOY and D283MED. We also used p53-/- and p53+/+ isogenic HCT116 colorectal carcinoma cell lines, already reported to exhibit p53- dependent expression of the LIF D transcript, to establish the extent of p 53-dependency for LIF M and T alternative transcripts. Whilst all three known, full-length alternative transcripts are more abundant in p 53+/+ cells, the alternative LIF M and T transcripts appear particularly sensitive to p53. In the p53 wild-type medulloblastoma cell line D283MED chromatin immunoprecipitation experiments showed p53 binding to the LIF gene. The mutant p53 expressed in line DAOY did not bind to this region or to the p21WAF1 p53 binding site. RNA interference against either WIP1 or SIRT1 stabilized p53 and enhanced the transcription of LIF in D283MED cells. Interestingly, siRNA against WIP1 or SIRT1 also induced increased apoptosis in the medulloblastoma line D283MED and, over a longer time period, in DAOYcells. We speculate that suppression of p53 function by combined WIP1-mediated dephosphorylation and SIRT1 deacetylation enables medulloblastoma cell survival but p53-dependent and independent apoptotic pathways remain intact. Thus small molecule inhibitors of SIRT1 may be useful in treatment of medulloblastoma. © Springer Science+Business Media, LLC. 2009.

Guise T.A.,Indiana University | Brufsky A.,University of Pittsburgh | Coleman R.E.,Yorkshire Cancer Research
Current Medical Research and Opinion | Year: 2010

Bone is the preferred site of metastasis for breast cancer, and presence of skeletal lesions is associated with significant morbidity and poor prognosis. Skeletal-related effects such as pain, pathologic fractures, spinal compression, and hypercalcemia are frequent consequences of skeletal lesions of breast cancer that have debilitating effects on the patients' quality of life. In addition to direct cancer effects on the skeleton, therapies commonly used to treat patients with breast cancer such as chemotherapy and aromatase inhibitors (AI) result in cancer therapy-induced bone loss (CTIBL) which is associated with increased risk of skeletal complications such as fractures. Bisphosphonates are a class of antiresorptive drugs that are now firmly established as the cornerstone of the management of skeletal-related events due to breast cancer. Other novel bone-targeting agents such as the anti-receptor activator of NF-κB ligand (RANKL) monoclonal antibody denosumab are also showing promising activity in the treatment of bone metastasis secondary to breast cancer. Moreover, recent provocative evidence suggests that bisphosphonates might also exhibit antitumor activity via direct and indirect mechanisms. The goal of this review is to summarize the pathophysiology of osteolytic bone lesions secondary to breast cancer, provide clinical evidence of currently available bone-targeted drugs in the treatment of bone metastasis and CTIBL, and explore the antitumor activity of current bone-targeted agents in patients with breast cancer. © 2010 Informa UK Ltd.

Hadji P.,University of Marburg | Coleman R.,Weston Park Hospital | Coleman R.,Yorkshire Cancer Research | Gnant M.,Medical University of Vienna
Critical Reviews in Oncology/Hematology | Year: 2013

Patients with breast cancer face substantial challenges to bone health from bone metastases, as well as from chemotherapy and endocrine therapies that generally elicit disease control at the cost of increased bone turnover. Consequently, maintaining bone health is of critical importance for these patients. Recently reported results from BOLERO-2 showed significant clinical benefits with adding everolimus to exemestane therapy in postmenopausal women with estrogen-receptor-positive breast cancer recurring or progressing despite nonsteroidal aromatase inhibitor therapy. Moreover, exploratory analyses from BOLERO-2 showed that adding everolimus may have beneficial effects on bone turnover and progressive disease in bone in this patient population. These results are supported by preclinical studies in which mTOR inhibition was associated with decreased osteoclast survival and activity. Thus, everolimus therapy may be able to ameliorate the negative effects of estrogen suppression on bone health. This review discusses the effects of mTOR inhibition on bone health during endocrine therapy. © 2013 The Authors.

Coleman R.,Yorkshire Cancer Research | Body J.J.,Free University of Colombia | Aapro M.,Multidisciplinary Oncology Institute | Hadji P.,University of Marburg | Herrstedt J.,University of Southern Denmark
Annals of Oncology | Year: 2014

There are three distinct areas of cancer management that make bone health in cancer patients of increasing clinical importance. First, bone metastases are common in many solid tumours, notably those arising from the breast, prostate and lung, as well as multiple myeloma, and may cause major morbidity including fractures, severe pain, nerve compression and hypercalcaemia. Through optimum multidisciplinary management of patients with bone metastases, including the use of bone-targeted treatments such as potent bisphosphonates or denosumab, it has been possible to transform the course of advanced cancer for many patients resulting in a major reduction in skeletal complications, reduced bone pain and improved quality of life. Secondly, many of the treatments we use to treat cancer patients have effects on reproductive hormones, which are critical for the maintenance of normal bone remodelling. This endocrine disturbance results in accelerated bone loss and an increased risk of osteoporosis and fractures that can have a significant negative impact on the lives of the rapidly expanding number of long-term cancer survivors. Finally, the bone marrow micro-environment is also intimately involved in the metastatic processes required for cancer dissemination, and there are emerging data showing that, at least in some clinical situations, the use of bone-targeted treatments can reduce metastasis to bone and has potential impact on patient survival. © The Author 2014.

Rane J.K.,Yorkshire Cancer Research | Pellacani D.,Yorkshire Cancer Research | Maitland N.J.,Yorkshire Cancer Research
Nature Reviews Urology | Year: 2012

The development of novel therapies such as abiraterone acetate and sipuleucel-T has improved the outlook for patients with advanced-stage and castration-resistant prostate cancer. However, the beneficial effects of these drugs are only measured in months. Moreover, the National Institute for Health and Clinical Excellence in the UK had ruled that the use of abiraterone acetate was not cost-effective before cost revision by the manufacturers. The FDA statement asserting that the use of 5α-reductase inhibitors for prostate cancer chemoprevention could increase the risk of developing high-grade prostate cancer also indirectly questions the value of direct androgen response manipulation for long-term benefit. These reports illustrate the need for a fresh and comprehensive analysis of advanced prostate cancer pathology to promote the next generation of effective adjuvant therapies. One such avenue is that of differentiation therapy, which seeks to promote the differentiation of cancer stem cells into a phenotype more sensitive to anticancer therapy than their parents. Using differentiation therapy with current antiandrogen therapies should augment our armoury of treatment for the management of advanced prostate cancer. © 2012 Macmillan Publishers Limited. All rights reserved.

Santer F.R.,Innsbruck Medical University | Erb H.H.H.,Yorkshire Cancer Research | McNeill R.V.,University of York
Seminars in Cancer Biology | Year: 2015

Androgen receptor (AR) is the main target for prostate cancer therapy. Clinical approaches for AR inactivation include chemical castration, inhibition of androgen synthesis and AR antagonists (anti-androgens). However, treatment resistance occurs for which an important number of therapy escape mechanisms have been identified. Herein, we summarise the current knowledge of molecular mechanisms underlying therapy resistance in prostate cancer. Moreover, the tumour escape mechanisms are arranged into the concepts of target modification, bypass signalling, histologic transformation, cancer stem cells and miscellaneous mechanisms. This may help researchers to compare and understand same or similar concepts of therapy resistance in prostate cancer and other cancer types. © 2015 The Authors.

Barrett-Lee P.,Velindre Hospital | Casbard A.,University of Cardiff | Abraham J.,Velindre Hospital | Hood K.,University of Cardiff | And 7 more authors.
The Lancet Oncology | Year: 2014

Background: Bisphosphonates are routinely used in the treatment of metastatic bone disease from breast cancer to reduce pain and bone destruction. Zoledronic acid given by intravenous infusion has been widely used, but places a substantial logistical burden on both patient and hospital. As a result, the use of oral ibandronic acid has increased, despite the absence of comparative data. In the ZICE trial, we compared oral ibandronic acid with intravenous zoledronic acid for the treatment of metastatic breast cancer to bone. Methods: This phase 3, open-label, parallel group active-controlled, multicentre, randomised, non-inferiority phase 3 study was done in 99 UK hospitals. Eligibility criteria included at least one radiologically confirmed bone metastasis from a histologically confirmed breast cancer. Patients with ECOG performance status 0 to 2 and clinical decision to treat with bisphosphonates within 3 months of randomisation were randomly assigned to receive 96 weeks of treatment with either intravenous zoledronic acid at 4 mg every 3-4 weeks or oral ibandronic acid 50 mg daily. Randomisation (1:1) was done via a central computerised system within stratified block sizes of four. Randomisation was stratified on whether patients had current or planned treatment with chemotherapy; current or planned treatment with hormone therapy; and whether they had a previous skeletal-related event within the last 3 months or had planned radiotherapy treatment to the bone or planned orthopaedic surgery due to bone metastases. The primary non-inferiority endpoint was the frequency and timing of skeletal-related events over 96 weeks, analysed using a per-protocol analysis. All active (non-withdrawn) patients have now reached the 96-week timepoint and the trial is now in long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT00326820. Findings: Between Jan 13, 2006, and Oct 4, 2010, 705 patients were randomly assigned to receive ibandronic acid and 699 to receive zoledronic acid; three patients withdrew immediately after randomisation. The per-protocol analysis included 654 patients in the ibandronic acid group and 672 in the zoledronic acid group. Annual rates of skeletal-related events were 0·499 (95% CI 0·454-0·549) with ibandronic acid and 0·435 (0·393-0·480) with zoledronic acid; the rate ratio for skeletal-related events was 1·148 (95% CI 0·967-1·362). The upper CI was greater than the margin of non-inferiority of 1·08; therefore, we could not reject the null hypothesis that ibandronic acid was inferior to zoledronic acid. More patients in the zoledronic acid group had renal toxic effects than in the ibandronic acid group (226 [32%] of 697 vs 172 [24%] of 704) but rates of osteonecrosis of the jaw were low in both groups (nine [1%] of 697 vs five [<1%] of 704). The most common grade 3 or 4 adverse events were fatigue (97 [14%] of 697 patients allocated zoledronic acid vs 98 [14%] of 704 allocated ibandronic acid), increased bone pain (92 [13%] vs 86 [12%]), joint pain (42 [6%] vs 38 [5%]), infection (33 [5%] vs 24 [3%]), and nausea or vomiting (38 [5%] vs 41 [6%]). Interpretation: Our results suggest that zoledronic acid is preferable to ibandronic acid in preventing skeletal-related events caused by bone metastases. However, both drugs have acceptable side-effect profiles and the oral formulation is more convenient, and could still be considered if the patient has a strong preference or if difficulties occur with intravenous infusions. Funding: Roche Products Ltd (educational grant), supported by National Institute for Health Research Cancer Network, following endorsement by Cancer Research UK (CRUKE/04/022). © 2014 Elsevier Ltd.

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