NIHRDataInsights/HRCSData huggingface dataset:
Title: Mammographic density in breast cancer risk prediction: implications for personalised breast screening and clinical management
Funder: Cancer Research UK

Abstract: Background Mammographic density (MD) is the strongest intermediate marker of breast cancer (BC) risk. It has potential to be incorporated into personalized breast cancer screening strategies, risk prediction and monitoring and clinically to aid decisions on implementing prophylactic or treatment measures. The purpose of the proposed study is to further elucidate features of the MD–BC association relevant to risk prediction, screening and clinical utility. Aims (i) Investigate which measure(s) of MD are most predictive of BC risk, screen-detected and interval BC, when multiple measures are available across a woman’s repeat screens, including an assessment of the impact of changes in MD over time on risk. (ii) Examine whether between-woman variability in the distribution of radio-dense tissue within the breast provides additional information on BC risk prediction beyond that conveyed by whole-breast MD. (iii) Among women in the general population, investigate whether localised radio-dense areas within the breast are at greater risk of becoming the tumour location several years later. (iv) Assess the clinical utility of baseline and between-screen changes in localised MD in predicting subsequent tumour location within the breast. Methods A case-control study will be conducted within the intervention arm of the Age Trial to benefit from a large population-based cohort of women with annual mammograms at young ages, and established long-term follow-up. A total of about 1,500 BC cases and randomly selected tightly matched controls will be investigated. Their completed serial screening and diagnostic films will be retrieved, digitised and MD readings performed. This is a unique resource at young ages which needs to be exploited before films are routinely destroyed. How the results of this research will be used Information on MD (alone or with clinical data) would allow stratification of women according to their BC risk to improve screening outcomes. Such knowledge is needed (i) to improve early detection and risk prediction by establishing which or whether multiple time-specific MD (e.g. baseline, latest, average) is the best predictor of risk, (ii) to optimize screening strategies (e.g. low-risk women could be screened less intensively whereas high-risk women could be screened more often or with alternative modalities) and (iii) to perform preliminary investigations of potentially less aggressive alternatives to management of high-risk women (e.g. local excision of radio-dense tissue vs. prophylactic mastectomy). The significance of this research is imperative due to the limited primary prevention avenues for this most common female cancer.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Targeting the ALK-F1174L tyrosine-kinase mutation in treatment refractory neuroblastoma.
Funder: Cancer Research UK

Abstract: Neuroblastoma is a common and frequently lethal cancer of young children, and is a major cause of death from treatment-resistant cancer recurrence. The intensified use of conventional chemotherapeutics has not significantly improved the survival of patients with poor-outcome neuroblastoma in the last decade, and in fact has contributed to worsened long-term disability. _x000D_ _x000D_ We are seeking to develop novel drugs to treat neuroblastoma by targeting the two most common genetic abnormalities that are responsible for aggressive, poor-outcome tumours—increased copies of the MYCN gene and mutations in the ALK gene. Clinical evidence suggests that neuroblastoma patients with simultaneous abnormalities in both of these genes develop particularly aggressive, treatment-resistant disease that has a uniquely poor outcome._x000D_ _x000D_ We have developed genetic cancer models in which tumours mirror the behaviour of human neuroblastomas, including their resistance to treatment with conventional chemotherapeutics. We recently used these models to study the MYCN cancer-causing protein and to develop the first drugs that eliminate MYCN from neuroblastoma tumours. These drugs should be useful to treat all cancers (including adult cancers) that have mutations in these proteins. We are now using the same approaches to develop more effective drugs to target the ALK protein. We have developed a neuroblastoma cancer model in which tumours carry simultaneous alterations of both MYCN and ALK proteins. Like tumours in neuroblastoma patients, these tumours are highly aggressive and are resistant to treatment with ALK-inhibiting drugs._x000D_ _x000D_ Clinical trials of the first-generation, ALK-targeted drug crizotinib indicate that the most common ALK gene mutation found in high-risk neuroblastoma (ALK-F1174L) causes treatment resistance in both neuroblastoma and adult cancer patients. We will use our neuroblastoma cancer models to examine whether new-generation, improved ALK-targeted drugs are more effective against neuroblastoma tumours with ALK mutations. We have identified a specific molecular interaction between mutated ALK proteins and MYCN protein that could explain why tumours carrying both mutations resist treatment. Our ultimate goal is to discover whether neuroblastoma patients with these mutations can be more effectively treated using combinations of MYCN- and ALK-targeted drugs. We will use the results of our research to guide the continued development and clinical introduction of ALK- and MYCN-targeted drugs into the paediatric cancer clinic._x000D_


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/11/058: Neo-SCOPE: Neo-adjuvant Study of Chemoradiotherapy in OesoPhageal Cancer
Funder: Cancer Research UK

Abstract: Background The cornerstone of curative treatment of oesophageal cancer in the UK remains surgery. The standard treatment strategy in the UK is neo-adjuvant chemotherapy (CT) in the form of 2 cycles of cisplatin and 5-fluorouracil (CF), prior to surgery. However, the overall survival is still poor, just 23% of patients surviving 5 years from treatment. Currently patients are being recruited to the MRC OE05 trial, comparing 2 cycles of CF with 4 cycles ECX chemotherapy, but this trial will soon close to recruitment. The first analysis of survival for this trial will not occur for 2 years which is an opportunity to prepare for the next UK Phase III trial. Pre-operative CRT has been shown this approach increases R0 resection rates, reduces loco-regional recurrence and improves survival compared with surgery alone but previously with increased post operative morbidity. In recent years there has been a significant reduction in post-operative mortality. Additionally, the SCOPE1 trial has ensured that UK investigators now have significant experience in delivering quality assured CRT. Cisplatin, together with 5-fluorouracil or capecitabine, has been used most commonly as the platinum component of the CRT regimens in the UK. Oxaliplatin is at least equivalent to cisplatin, is more convenient, and has a more favourable toxicity profile compared to cisplatin. A recent trial by van der Gaast demonstrated that pre-operative CRT with paclitaxel and carboplatin was not associated with increased morbidity but an improved survival over surgery alone. Aims Neo-SCOPE will test the safety (post-operative morbidity/mortality), efficacy (pathological complete response (pCR)) as well as the feasibility of recruiting to a randomised multi-centre trial of pre-operative CRT in the UK and select the pre-op CRT regimen to take towards a Phase III trial of pre-op CT with pre-op CRT. Methods Neo-SCOPE is designed as a single stage, non-blinded, randomised, “pick a winner” Phase II study of two pre-operative chemoradiotherapy regimes for resectable oesophageal cancer. All patients will receive 2 cycles of oxaliplatin and capecitabine followed by radiotherapy with either oxaliplatin and capecitabine or paclitaxel and carboplatin before surgery. Pathological response, the primary endpoint, will be assessed by central histopathological review. How the results of this research will be used It is planned that the ‘best’ experimental arm will be taken forward to a future Phase III trial where neo-adjuvant CRT will be compared with pre-operative chemotherapy in patients with locally advanced oesophageal cancer at high risk of R1 disease at surgery.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Exploring and Exploiting C. elegans as a model to better understand apoptosis induction; combined cytological, genetic and proteomics based approaches
Funder: Cancer Research UK

Abstract: BACKGROUND: Cancer progression correlates with reduced apoptosis and chemotherapeutic agents largely act by inducing the apoptotic demise of cancer cells. Improved molecular diagnostics and treatments rely on a better understanding of how apoptosis is regulated. Seminal studies on C. elegans lead to the discovery of the conserved core apoptosis pathway that includes the anti-apoptotic Bcl-2-like protein CED-9 and the pro-apoptotic CED-4 Apaf1 homolog. According to the current model the ‘decision’ between cellular life and death is mediated by the direct interaction between CED-4 and CED-9. To better understand the function of Bcl-2 and Apaf-1 like molecules we will follow up on our compelling evidence (recently accepted for publication) suggesting that apoptosis induction in worms is more closely related to mammalian apoptosis where Bcl-2 and Apaf-1 do not directly interact. AIMS AND OBJECTIVES We wish (aim 1) to further advance our cytological studies to study the dynamic behaviour of CED-4 complexes to assess if and how changes in CED-4 turnover or oligomerization state correlate with apoptosis induction in vivo. We (aim 2) want to determine the molecular nature of the proteins that interact with CED-4 and CED-9, and we aim to test whether these are required for normal levels of apoptosis induction. We also wish to determine if the nature and composition of CED-4 and CED-9 complexes changes during apoptosis induction, and what the genetic requirements for those changes are. We will (aim-3) continue a complementary genetic screen to find genes that link the function of CED-9 localized to the mitochondria with perinuclear CED-4, and which act to either prevent apoptosis in cells that are to survive or to trigger apoptosis in cells destined to die. We will further validate candidate genes we already found and we will focus on most promising candidates. METHODS We will combine our proven expertise in C. elegans genetics, functional genomics and imaging with advanced cytological, biochemical and proteomics approaches we recently established. HOW RESULTS OF THIS RESEARCH WILL BE USED The core apoptosis pathway components Bcl-2 and Apaf-1 are required for apoptosis induction in cancer cells. Apaf-1 deficiency does not fully abolish apoptosis induction and we expect to find conserved genes that are required for this residual apoptosis. A better understanding of these components will allow for better and more specifically targeting cancer cells. Studying model organisms like C. elegans will make an important contribution towards these goals.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: CRUK/12/055: HYBRID - A multicentre randomised phase II study of HYpofractionated Bladder Radiotherapy with or without Image guided aDaptive-predictive planning
Funder: Cancer Research UK

Abstract: Background Localised muscle invasive bladder cancer (MIBC) is life-threatening and can cause significant symptoms Around 50% of patients with MIBC who are referred for radiotherapy are unfit for standard radical treatment (cystectomy or daily radiotherapy+/-chemotherapy), but would have a normal life expectancy if their cancer were adequately controlled. Defining an effective standard of care for this patient group would fulfil an unmet clinical need. Retrospective studies suggest that hypofractionated radiotherapy, given weekly using fewer fractions and higher doses, may be a well-tolerated alternative where daily radiotherapy is not an option. The bladder can vary in size and position, therefore large margins are required to avoid “geographical miss” whereby parts of the tumour lie outside the radiotherapy field. Despite this addition of margins, misses still occur, and large margins increase the risk of toxicity by exposing normal tissue surrounding the bladder to high doses. Technological advances mean that pre-treatment imaging is now possible, allowing the selection of the most appropriate plan for each treatment (adaptive planning). This technique has the potential to reduce safety margins whilst avoiding geographical miss, with predicted improvements in toxicity over a standard planned regime. Aims In patients with MIBC not suitable for cystectomy or daily radiotherapy we aim to assess 1) whether treatment using adaptive planning can be successfully delivered at multiple sites across the UK and results in acceptable levels of toxicity 2) the local tumour control rate achieved by hypofractionated weekly radiotherapy; 3) requirement to treat with adaptive planning. Methods HYBRID is a multicentre phase 2 trial. Sixty-two patients will be randomised to standard planning or adaptive planning (selecting the ‘best plan’ on each treatment day) and will receive up to six 6Gy fractions of radiotherapy given once a week for 6 weeks. The primary endpoint will be acute toxicity. Key secondary endpoints will be local control at 3 months and overall survival. Radiotherapy related endpoints include the proportion of fractions benefiting from adaptive planning. How results will be used Results will provide prospective toxicity data and evidence for use of hypofractionated radiotherapy and assess whether this is a plausible and worthwhile treatment in this patient population. The randomised element of the trial will support the implementation of image-guided adaptive radiotherapy for bladder cancer in the UK. It will provide evidence on the benefits or otherwise of this methodology and inform the development of further trials in this and other patient groups.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Optimisation of telomerase expression repressors
Funder: Cancer Research UK

Abstract: Cell immortality is essential in cancer and is directly controlled by telomerase. Pre-clinical testing of diverse telomerase targeting approaches has clearly demonstrated target validity, though no therapeutic candidate small molecule inhibitors exist. The only current clinical approach is a modified oligonucleotide. A huge number of studies support the concept that targeting the signal transduction pathways which contribute to telomerase overexpression in cancer cells is an attractive approach. Telomerase expression is well known as a focus of oncogenic/growth promoting pathways which activate its expression, while pathways controlling growth suppression have the opposite effect. There is agreement in the field that these effects are clearly controlled at the level of signalling pathways that regulate the telomerase promoters. We have exploited our extensive knowledge in this area to develop a cell based assay and perform a diversity screen for inhibitors of telomerase expression, leading to the identification of a series of highly promising compounds which suppress endogenous telomerase expression and activity with good specificity and without off-target effects.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Identifying and characterizing deubiquitylating enzymes that control cellular responses to DNA double-strand breaks.
Funder: Cancer Research UK

Abstract: Background Genomic DNA is constantly exposed to various DNA-damaging agents. Of the various types of DNA lesions produced, the most difficult-to-repair are DNA double-strand breaks (DSBs). DSBs are the prime cytotoxic lesions caused by IR and radiomimetic agents, and also arise when other DNA lesions are processed or are encountered by the DNA-replication apparatus. To avoid the deleterious effects of DSBs, two principle repair pathways operate: non-homologous end joining and homologous recombination. Because of its complexity, DSB repair can take many minutes and sometimes several hours to complete. During this time, the DNA-damage response (DDR) signaling system slows down or arrests cell-cycle progression at the G1-S, intra-S or G2-M cell-cycle transitions. Aims It is becoming increasingly clear that cellular responses to DNA damage are heavily influenced by protein ubiquitylation: the reversible, covalent attachment of the 76 amino-acid residue protein, Ubiquitin, to target proteins. The work described in this proposal aims to identify and characterize deubiquitylating enzymes (DUBs) that control cellular responses to DSBs by removing Ubiquitin adducts from DDR-protein targets. Methods Specifically, the proposed work will build on recent work carried out in this laboratory by the co-applicant, dr Ryotaro Nishi, who has systematically screened all 95 human DUBs for DDR functions. Specifically, the proposed work will further characterize DUBs identified by these screens to verify and then further explore their functions in response to DSB induction. For instance, we will define which DSB repair or DDR-signaling events are controlled by specific DUBs, and we will carry out experiments to identify the target proteins and interaction partners of these DUBs that allow them to execute their functions. How the results of this research will be used While being academic in nature, it is possible that this work will identify opportunities for therapeutic intervention via DUB inhibition.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: FULL STUDY International Cancer Genome Consortium: The Prostate Cancer Initiative: a UK-North American-French- Asian-Partnership (ICGC-PROSTATE CANCER)
Funder: Cancer Research UK

Abstract: Background and Relevance to Cancer: In Europe and North America over 500,000 cases of prostate cancer are diagnosed annually. However, prostate cancer is difficult to manage clinically, due to a poor current understanding of what dictates its highly variable natural history, and of what underlies the development of castration-resistant disease. The aetiology of this disease and in particular the reasons for ethnic differences in incidence are not understood. There is an urgent requirement to execute a large-scale and highly integrated research programme that will achieve breakthrough advances in understanding the molecular and cellular basis of this disease, including the identification of new biomarkers and drug targets. Specific Aims of Research: We [International Cancer Genome Consortium (ICGC)-Prostate Cancer] are a group of French, Canadian, US, Asian, and UK investigators. This is an application to fund the UK, Asian, and US members of the consortium. The proposed project consists of a Pilot Study and a Full Study. The aim of the Pilot Study is to set up and test a multi-centre structure that complies with ICGC standards. The aim of the Full Study is to determine the full genome DNA sequence for 250 prostate specimens, mostly cancers. The overall scientific aims are: (i) to understand molecular basis of the clinical heterogeneity of prostate cancer; (ii) to understand the large variation in incidences that occur in different populations and ethnic groups; (iii) to understand the molecular basis of development of castration-resistant and metastatic disease; (iv) to determine whether driving genetic alterations are unique to cancer epithelium or may also occur in morphological ‘normal’ epithelium and stroma; and (v) to subsequently collect genome wide transcriptomics and epigenetic data to provide integrated models of cancer development.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: The role of the microenvironment in regulating the therapeutic response in childhood ALL as a model for other cancers.
Funder: Cancer Research UK

Abstract: Success in childhood acute lymphoblastic leukaemia (ALL), has come from the progressive intensification of therapy. Despite the attendant therapeutic toxicity disease still recurs in 15% of patients [1]. The rationale for why, therapeutic intensification is required to eradicate a highly chemosensitive tumour and recurrent disease retains chemosensitivity remains unclear. Genome wide mutation analyses do not provide an explanation for therapeutic failure [2, 3]. Our clinical investigations suggest chemosensitive ALL blast cells are protected by microenvironmental niches during therapy. Cessation of therapy results in recurrence of a chemosensitive disease. Intensification or prolonged continuous therapy damages the niche(s) and their protective ability. This eradicates disease at the expense of toxicity. The balance of cure and toxicity is therefore regulated by the trifecta of tumour, host and drugs applied. We speculate that chemoprotective niches, composed of mesenchymal (MSC’s) and other cells [4], are located within select marrow (osteoblastic and vascular) and extramedullary microenvironments [5]. Our laboratory has evidence that direct contact between tumour and host cells, is chemoprotective and selects for a clonal population with an invasive phenotype responsible for extramedullary disease [6]. Implicit in this is the stromal: haematopoietic cell dynamic, now known to involve communication, asinothersystems, vialipid and protease enriched vesicles that regulate the niches. We have identified key adhesion molecules expressed by invasive leukaemic blast cells. Sophisticated animal models developed by us will be used to (i) identify niche sites (ii) the mechanisms by which niche cells (NC’s) protect and in turn are modulated by lymphoblasts, and (iii) the effect of targeting leukaemic cell specific adhesion molecules on preventing extramedullary recurrence. Soluble factors produced by NC’s also produce chemoresistance. Biochemical changes occur in leukaemic cells exposed to these soluble factors. These factors regulate glycolysis – a downstream effect of signalling pathways (RAS/MAPK/JAK-STAT) implicated in disease recurrence [3]. In part, the effects appear to be due to exosomal miRNA mediated transcriptional regulation and lipids produced by NC’s. We will identify lipids and key miRNA that regulate glycolysis. Our in vitro data suggest that relatively non-toxic drugs targeting aerobic glycolysis used in conjunction with chemotherapy kills resistant cells. We will extend these observations to our in vivo models. Our studies suggest mechanisms of chemoresistance relevant to other cancers yet also of specific importance in ALL. These are mediated by the tumour microenvironment, and suggest solutions with the potential of both improving outcome and decreasing toxicity for patients.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS