NIHRDataInsights/HRCSData huggingface dataset:
Title: Screening, timely diagnosis and inequalities in breast cancer survival
Funder: Cancer Research UK

Abstract: Background Disparities in breast cancer survival exist between socio-economic and ethnic groups in England. There is increasing evidence that these differences are due in part to differences in timely diagnosis leading to later stage of disease at presentation for women from more deprived areas and of some minority ethnic groups. Reducing these disparities in survival might be achieved by the promotion of screening attendance in these groups. Aims We aim to provide robust, quantitative evidence of the effectiveness of mammography screening for reducing inequalities in survival. We will conduct a detailed examination of survival according to mode of presentation. We will examine ‘cure’ in relation to screening. We will develop guidance on how the concept of population ‘cure’ might be used to promote timely diagnosis and screening uptake. We will also perform an exploratory analysis examining the disease pathway between first reported symptom and final outcome in a small sample of breast cancer patients in order to investigate differences in practitioner delay. Methods We will estimate relative survival for five socio-economic and three ethnic groups. We will estimate the excess hazard ratio (EHR) of death between deprivation and ethnic groups in order to assess the significance of referral time, stage of disease and mode of presentation. We will adjust for the effects of tumour pathology, pre-existing comorbidities and treatment received, as well as the three screening-related biases of lead time, length time and overdiagnosis. We will estimate the proportion ‘cured’ amongst women with screen-detected breast cancer. We will present our findings in terms of avoidable deaths. We will describe the disease pathways from primary care to final outcome and investigate how these vary with survival. How the results of this research will be used The results will provide robust indication of the true impact of screen-detection for women of different socio-economic groups and of different ethnicities and so show the potential of screening to reduce inequalities in survival. We propose to develop guidance which will be targeted at policy makers in order that they are better equipped to use survival statistics in health promotion. The initial exploratory analysis will enable hypotheses about how survival differences are related to health system delays to be developed further.


Research activity codes: 4.3 INFLUENCES AND IMPACT;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: CRUKD/12/011: A Phase I dose escalation trial of HDAC inhibitor CHR2845 for cancer associated inflammation in hepatocellular carcinoma
Funder: Cancer Research UK

Abstract: Primary liver cancer, which consists predominantly of hepatocellular carcinoma (HCC) is the fifth most commonly diagnosed cancer globally, and the third most common cause of cancer mortality. Except for sorafenib, which prolongs survival in patients with advanced HCC for 2-3 months, no effective systemic therapy exists for these patients. However, sorafenib is not approved by NICE in the UK. HCC almost never occurs in a background of a healthy liver, and there is a growing understanding regarding the molecular mechanisms that induce and maintain hepatocarcinogenesis,. Along with alchohol induced liver disease, chronic Hepatitis C and B virus (HCV and HBV) infections are major risk factors for the development of HCC, and the cancer risk increases sharply in response to chronic injury at the cirrhosis stage. Activated liver macrophages are intrinsically involved in the different types of hepatic injury, including hepatitis and the ensuing hepatobiliary fibrogenesis. The Esterase Sensitive Motif (ESM) technology allows the targeted accumulation of molecules in cells of the myeloid lineage which express the human carboxylesterase-1 protein (hCE-1). This includes monocytes, macrophages and further differentiated macrophages such as Kupffer cells. CHR-2845 and its active metabolite CHR-2847 are both histone deacetylase inhibitors (HDACi) and are examples of the application of the ESM technology. The active metabolite CHR-2847 has been engineered to specifically accumulate in cells of the monocyte lineage which include tumour associated macrophages, the presence of increased numbers of which predicts poor prognosis in patients with HCC (Ding et al, 2009). Being able to specifically target monocytes and macrophages, which are key mediators in the inflammatory disease process, should enable effective targeting of a major cause of ongoing inflammation in the diseased liver and hence allow increased disease control. Besides macrophages and Kupffer cells, CHR-2847 may also accumulate in hepatocytes, and tumour cells that are derived from hepatocytes. As HDAC inhibitors normally only affect transformed cells, it is expected that there will be greater epigenetic changes induced in the transformed- compared to the non-transformed hepatocytes. Regulation of the acetylation of both histone and non-histone proteins by histone deacetylase enzymes is one of the key mechanisms involved in epigenetic control of gene expression. HDACi have demonstrated activity in both in vitro cytotoxicity, and in vivo tumour xenograft studies (Beckers et al, 2007; Hess-Stumpp et al, 2007; Qian et al, 2006; Qian et al, 2007). In addition, HDACi have been successful in the clinic (Tan et al 2010)


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/11/035: A Phase I/II dose schedule finding study of CH14.18/CHO continuous infusion combined with subcutaneous Aldesleukin IL-2 in patients with primary refractory or relapsed neuroblastoma
Funder: Cancer Research UK

Abstract: Background Chimeric 14.18 anti-GD2 monoclonal antibody produced in Chinese hamster ovary (CHO) cells, specifically recognizes the target antigen GD2, which is expressed on virtually all neuroblastoma tumours. This antibody is a chimeric protein, consisting of 30% mouse variable light and heavy chains and 70% human constant heavy and light chains. Ch14.18/CHO has already been tested in stage 4 neuroblastoma patients as a bolus infusion in phase I/II clinical trials with encouraging response rates. Aldesleukin (IL-2), has been shown to augment natural killer cell mediated antibody dependent cellular cytotoxicity which is the main mechanism of ch14.18/CHO mediated anti-neuroblastoma activity. The feasibility to combine ch14.18/CHO therapy with aldesleukin (IL-2) has been demonstrated in patients with neuroblastoma. However, side effects of ch14.18/CHO bolus infusions and i.v. infusions of aldesleukin (IL-2) are neuropathic pain requiring i.v. morphine applications and inflammatory responses including shock and capillary leak syndrome, requiring inpatient care. Clinical experience with bolus infusions of ch14.18/CHO indicates that a decrease of the infusion rate is associated with a reduction of neuropathic pain in treated patients. Furthermore, the feasibility of subcutaneous (s.c.) aldesleukin (IL-2) therapy in an outpatient setting has been demonstrated in children with stage 4 neuroblastoma. Aims This Phase I/II infusion schedule finding study aims to evaluate the safety and tolerability of ch14.18/CHO given as a continuous intravenous infusion combined with s.c aldesleukin (IL-2) and 13-cis-retinoic acid whilst maintaining immunomodulatory efficacy. It also aims to characterize the dose limiting toxicities (DLTs) and determine a maximum tolerated dose (MTD) and recommended Phase II dose in children and adolescents with high risk neuroblastoma. Methods During the infusion schedule finding cohort several schedules with different daily doses of Ch14.18/CHO (7, 10 and 15 mg/m2) and durations (7, 14, 15 and 21 days) will be evaluated. A total of 5 cycles are planned. However, decisions regarding infusion duration will be based only on the first. Once a MTD has been found an expansion cohort consisting of 20 patients will be conducted. Outcome Current treatment options for patients with relapsed or refractory neuroblastoma are very limited and as a consequence overall survival is poor. It is hoped that this study will find an infusion schedule of Ch14.18/CHO that when used in combination with aldesleukin and isotretinoin yields superior efficacy and an acceptable toxicity profile to current treatments and thus can be carried forward for further evaluation in late phase trials and offers hope for neuroblastoma patients.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Cancer screening utilisation among patients with type 2 diabetes
Funder: Cancer Research UK

Abstract: In the UK, there are 2.8 million people affected by type 2 (adult-onset) diabetes; while for the UK, there are 300,000 new cancer cases every year. While these two conditions share common lifestyle risk factors, such as obesity and smoking, surprisingly, only recently has it become clear that diabetes is linked to increased risk of cancers of the large bowel, womb, breast, kidney, bladder, liver and pancreas. It has also become clear that diabetic patients underuse nationally available cancer screening tests. Despite frequent contact with doctors and other healthcare professionals, there is a question as to whether the focus on managing the diabetes impacts on other health issues, such as cancer screening. These observations have been made in North American studies, but there are no equivalent studies from the UK. Yet, the NHS is uniquely placed to address these questions using a large clinical database of over 5 million patients, known as the General Practice Research Database (GPRD). The research team in this two-year proposal bring together investigators from across the University of Manchester, who have expertise in cancer epidemiology and screening, diabetes and the GPRD database, and will undertake two linked studies. First, they will compare screening activities for breast, cervical and bowel cancers between patients with and without type 2 diabetes. An important part of this research will involve the investigators adjusting for ‘confounders’ – for example, breast screening uptake rates are lower among women from areas of high deprivation compared with women from affluent areas, whilst type 2 diabetes is also more common in deprived populations. And second, the investigators will test the hypothesis that performance-related pay for diabetes-related activities, which has been in practice in England since 2004, during a healthcare visit (typically, an annual check-up) overshadows resources and time for preventive services, such as cancer screening. They will use a state-of-the-art statistical process known as interrupted time series analyses. Currently, the list of items on the annual check-up visits for diabetic patients (e.g. eye check, foot check) is determined at a national level and reimbursed through pay for performance. At the end of this project, the results will be used to inform national guidelines to include national cancer screening recommendations within the annual diabetes check-up list.


Research activity codes: 4.3 INFLUENCES AND IMPACT;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: CANCER AND NEOPLASMS
Title: CRUK/11/031: A Phase II trial of 177 Lutetium DOTATATE in children with primary refractory or relapsed high risk neuroblastoma
Funder: Cancer Research UK

Abstract: High-risk neuroblastoma is a common childhood cancer. Initial standard chemotherapy treatment produces responses in about two thirds of patients, many of whom will later relapse. The others have primary refractory disease. Overall cure rates are low, and so effective new treatments are needed. Many neuroblastoma cells express somatostatin receptors. Radiolabelled octreotide analogues can be used for nuclear medicine imaging and therapy of somatostatin receptor positive tumours. 68Ga DOTATATE and 177Lu DOTATATE have been shown to be effective octreotide analogues for imaging and treatment respectively of neuroendocrine cancers in adults. The primary aims of this study are to evaluate (1) the toxicity and (2) the efficacy of 177Lu DOTATATE in children with relapsed or refractory high-risk neuroblastoma. Secondary, translational, aims are (1) to investigate 68Ga DOTATATE PET/CT for imaging of neuroblastoma, in comparison with the standard of 123I-mIBG, (2) to assess the relationship between the expression of somatostatin receptors measured by immunohistochemistry in archived neuroblastoma tissue from each patient with their imaging, and (3) to correlate tumour radiation dosimetry with response. This will be a Phase II clinical trial using a Simon Two Stage Minimax design. This requires 14 patients in Stage 1. If three or more responses are seen, another 10 patients will be recruited in Stage 2. If eight or more responses are seen in these 24 patients, then the treatment will be deemed worthy of further investigation in this patient group.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Molecular basis for control of cell processes by protein post-translational modification
Funder: Cancer Research UK

Abstract: The aims of our research are to elucidate the molecular mechanisms of control of cell signalling pathways and the cell cycle, by X-ray crystallographic and electron microscopic techniques, complemented by biochemical and other biophysical approaches. The focus is on pathways and systems that function to regulate cellular processes through post-translational modifications and small GTPases, and that are relevant to cancer. This information will provide insights into complex regulatory systems, in terms of control and specificity, and will inform structure-based drug design. Research will focus on three themes: 1. Anaphase promoting complex (APC/C). The APC/C is an unusually large multi-subunit complex that functions as an E3 ubiquitin ligase to regulate progression through the cell cycle via controlled degradation of cell cycle regulatory proteins by the ubiquitin proteasome system. Our aim is to determine a high-resolution structure of the APC/C to address questions of its assembly and molecular basis for substrate specificity, regulation and catalysis. To address these questions we will apply two complementary approaches. First, a hybrid approach of X-ray crystallography of individual APC/C subunits and sub-complexes and high-resolution (7-5 Å) cryo-electron microscopy of functional states of the APC/C. Second, we are intensifying efforts to crystallize the APC/C to obtain atomic resolution information of the complex. 2. Enzymes that post-translationally modify the RAS CAAX motif. The C-terminal CAAX motif of Ras, and numerous small GTPases undergo post-translational modification by a sequence of three enzymatic reactions that determines the ultimate localization of Ras to the cell membrane, and are required for Ras function. We will focus efforts on obtaining structural and mechanistic insights into two enzymes involved in post-prenyl processing, RCE1 and ICMT, two intrinsic membrane proteins localized to the endoplasmic reticulum. Specifically, we will develop inhibitors of ICMT and determine the crystal structures of eukaryotic ICMT and RCE1. 3. Guanine nucleotide exchange factors of the DOCK super-family. The DOCK guanine nucleotide exchange factors activate Rac and Cdc42 to control cell migration, morphogenesis and phagocytosis, and are important components of tumour cell movement and invasion. In humans, DOCK proteins are organized into four subfamilies, characterized by their differing specificities for Rac and Cdc42, and associated regulatory domains and subunits. DOCK2, a member of the DOCK A subfamily and specific for Rac, exists in a complex with ELMO and is activated by RhoG. To understand the basis for the regulation of DOCK2 activity, we will determine the crystal structure of this complex.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUKD/12/007: DEBIOC a Phase I dose-escalating study of EGFR inhibitor AZD8931 in combination with oxaliplatin and capecitabine chemotherapy in patients with oesophago-gastric adenocarcinoma
Funder: Cancer Research UK

Abstract: A Phase I dose-escalating study of AZD8931 in combination with Oxaliplatin and Capecitabine chemotherapy in patients with oesophago-gastric adenocarcinoma Background In metastatic gastro-oesophageal cancer the role of ErbB2 inhibition has been established. Trastuzumab, in combination with cisplatin and capecitabine (CX) chemotherapy, resulted in a significant improvement in overall survival in HER2+ patients, compared with chemotherapy alone. Combining Erb inhibition with neo-adjuvant chemotherapy should improve the outcomes for patients undergoing surgery for oesophago-gastric adenocarcinoma. AZD8931 is a pan-Erb inhibitor with a wider Erb-inhibitory profile than trastuzumab. Since only approximately 20% patients with oesophago-gastric adenocarcinoma have high expression of ErbB2, it is anticipated that the broader activity of AZ8931 will make it effective in more patients than would be the case with trastuzumab or lapatinib. Aims 1. To establish MTD of AZD8931 in combination with Xelox chemotherapy. 2. To define the safety of the combination and safety of post-operative AZD8931 maintenance therapy 3. To assess early efficacy data as determined by progression free survival (PFS) at 6 months, and complete resection rate (R0) 4. To explore pharmacodynamic biomarkers including blood, tissue and imaging to help select a patient population for further studies Methods This is an open label phase I study with a dose-escalation phase recruiting up to 3 cohorts of patients with advanced oesophago-gastric adenocarcinoma, who will receive AZD8931 in combination with Xelox. Once the MTD of the combination has been defined, 30 patients with potentially operable oesophago-gastric adenocarcinoma will be recruited. They will undergo two cycles of the combination (dose as determined in the first phase) prior to oesophago-gastric resection. Patients will be allowed to continue AZD8931 after surgery for up to 12 months or until unacceptable toxicity or progression of disease. Primary study endpoint is MTD of AZD8931 in combination with Xelox and secondary endpoints include R0 resection rate, PFS at 6 months, overall survival, and metabolic response as measured by FDG-PET. How the results of this research will be used This is an early signal searching study paving the way for randomized phase II/III studies. If the addition of AZD8931 to neoadjuvant Xelox chemotherapy is tolerable we have defined hurdles in terms of progression free survival and R0 resection rates to make a go/no go decision for a neo-adjuvant randomized study of Xelox chemotherapy +/- AZD8931 with a second randomized component for the maintenance phase.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/11/036: CONSERVE - A feasibility study for a multicentre randomised controlled trial to COmpare Surgery (partial Nephrectomy) with needle ablation techniques (Radiofrequency ablation / cryotherapy) for the treatment of people with small renal masses ( 4 cm)
Funder: Cancer Research UK

Abstract: Background: The number of people diagnosed with kidney cancer has doubled over the past 20 years; making it the eighth most common cancer in the UK. Most tumours are less than 4 cm in size, but over 80% of these are malignant and if left untreated, will grow and spread. Current standard treatment for small kidney cancers is to remove the diseased part of the kidney (partial nephrectomy) which is quite a difficult operation. Because of the small tumour size and difficulties with surgery, less invasive treatments have been developed to destroy the tumours. These include radio frequency ablation (RFA) which kills the cancer by heat generation and cryoablation which kills the cancer by freezing. The partial nephrectomy is tried and tested to effectively treat the renal cancer but does have risks of complication including bleeding. The newer, less invasive treatments may have slightly lower complication rates but may not be as effective in eradicating the cancer and patients may require additional treatments and close surveillance. In order to decide which treatment is best we need to carry out a clinical trial comparing the outcomes of each. Before we do this we need to carry out initial pilot work to see if a trial is possible and feasible. Aims and objectives: CONSERVE study will primarily determine the feasibility of carrying out a randomised trial comparing the effectiveness of minimally invasive techniques of radiofrequency ablation and cryoablation with the standard treatment of partial nephrectomy for patients with small kidney cancers. This will involve exploring whether or not they would be willing to be randomised, ensuring that sufficient numbers of participants to a full trial are likely to be recruited in an appropriate time period and also deciding what aspects of the conduct and outcome of each treatment should be recorded to compare their effectiveness. Methods: Eligible participants identified through Multi-Disciplinary Team MDT meetings and would be invited to take part in the study; patients would be consented to trial registration. They would receive information about surgery and one of the ablative techniques (cryoablation/RFA) in the participating hospital and would be asked to consent to randomisation. Factors influencing willingness to be randomised will be determined in a qualitative study. How the results would be used: The results would be used to inform a decision to proceed to a multicentre randomised trial to compare clinical and cost effectiveness of the treatment options available.


Research activity codes: 6.4 SURGERY
Health categories: CANCER AND NEOPLASMS