NIHRDataInsights/HRCSData huggingface dataset:
Title: Genomics & Molecular Pathology of Pancreatic Cancer
Funder: Cancer Research UK

Abstract: Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer-related mortality in the western world, with a median survival time of 5-6 months and only 5% of individuals survive for more than 5 years. The outlook for patients with PDAC is therefore bleak, with 34,290 related deaths predicted this year in the US alone and approximately 6,500 in the UK in 2008. Relevance to cancer: Pancreatic cancer is now recognised by Cancer Research UK as one of the three tumour types with highest priority for strategic investment in clinical and translational research. A full understanding of the molecular basis of its initiation and progression is necessary for the development of new diagnostic markers and novel targets for therapy in order to change the outlook for patients with this disease. Aims: This programme focuses on the genomics and molecular pathology of pancreatic cancer, exploiting microarray technologies to profile the genetic abnormalities that characterize this tumour type. New bioinformatic tools will be developed to analyse and annotate the genomic, transcriptomic and proteomic data, developing a platform that allows integrated visualization for the wider pancreatic cancer research community. Almost all patients with pancreatic cancer present with metastases to the liver and lymph nodes that make curative surgery impossible, and with perineural invasion that causes excruciating pain. This programme will investigate the molecular mechanisms involved, using genomic and proteomic analysis of microdissected clinical material to identify candidate genes. New in vitro and in vivo models will be developed to test novel therapeutic approaches targeted against invasion and metastasis.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: New Approaches to Reverse Endocrine Resistance in Breast Cancer
Funder: Cancer Research UK

Abstract: Background Endocrine therapy, when given de novo to patients with primary breast cancer, reduces the death rate by around 30%. My hypothesis is that that overt relapse could be avoided by switching from one type of endocrine (or other) agent to another to combat resistance. The proposed programme focuses on defining the roles of four important targets: CDK7, LRH-1, FOXO/A and gamma secretase. Relevance to Cancer We already have prototype inhibitors for some of the four targets. If we can determine the mechanism of action of these as well as understanding when to apply them, we could use them clinically. In addition, if we could validate methods for detecting and characterising treatment-resistant micro-metastatic disease, we could use these treatments at a sufficiently early stage to prevent the development of life-threatening metastatic disease. Specific Aims (Hypotheses and Outcomes) CDK7 is required for ER phosphorylation at a residue associated with acquired tamoxifen resistance, and CDK7 levels are elevated in cancer cells, positioning CDK7 as a potentially important therapeutic target. We have recently discovered a specific inhibitor of CDK7 . Currently, inhibitors of aromatase are non-specific in that they inhibit the enzyme in all locations in the body, leading to side-effects. LRH-1 specifically regulates aromatase in breast tissue. We have now demonstrated that LRH-1 also regulates ER expression. Our findings highlight LRH-1 as a key target which acts by positively regulating both estrogen biosynthesis and ER expression. We hypothesise that the PI3K-FOXO signalling pathway plays a major role in resistance of breast cancer to endocrine therapy and is a candidate target. One possible mechanism may involve the interaction between FOXO3a and ER, as well as its interaction with FOXA which cooperate to regulate gene expression. Finally, the Notch pathway intersects with estrogen receptor signaling at several levels. It is de-regulated in cancer and inhibition of Notch signaling can be achieved through inhibiting an enzyme, gamma secretase, responsible for cleaving the precursor to the active form. We plan to determine whether inhibitors of this pathway can help reverse resistance. Outline Plan of Research (include methods) We propose to investigate these targets using a common approach: using gene expression arrays and RNA interference to study how they regulate cancer cells, examining expression in breast cancer tissues, as well as using molecular imaging to examine function in vivo. Together, these studies will pave the way for future clinical studies in patients with breast cancer.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: The role of kinesin motor proteins in MT1-MMP vesicle trafficking to the leading edge of invasive cancer cells
Funder: Cancer Research UK

Abstract: Cancer metastasis and invasion are the most life-threatening features of the disease, and membrane-type 1 matrix metalloproteinase (MT1-MMP) is thought to play a crucial role in this process. MT1-MMP is a membrane-anchored proteinase that promote cancer cell invasion. One of the crucial levels of regulations of the enzyme is its localisation to the leading edge of invading cells; i.e. lamellipodia and invadopodia, however, the precise mechanisms regulating this localisation are not clear. Recently we found that trafficking of MT1-MMP-containing vesicles along microtubules is one of the key mechanisms in localising MT1-MMP to the leading edge of cells, and we identified three kinesin motor proteins that are potential regulators of MT1-MMP vesicle transport to different parts of the plasma membrane. Therefore, in this grant proposal we propose to identify and characterise specific kinesin motor proteins responsible for transporting MT1-MMP vesicles to different membrane structures that include ECM attachment site in HT1080 fibrosarcoma cells, invadopodia in MDA-MB231 breast carcinoma cells, and lamellipodia in both HT1080 and MDA-MB231 cells. We will also identify the molecular interactions that determine incorporation of MT1-MMP into the specific vesicles transpoted by specific kinesins to the leading edge of cancer cells. There are not much studies done in the role of kinesins during cancer invasion and metastasis. This is a new area in cancer research and we believe it is important as it will open new avenues to combat against cancer invasion and metastasis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Cancer Research UK stress response laboratory
Funder: Cancer Research UK

Abstract: The deregulation of signal transduction is a crucial event in the development of human cancers. Growth factors, cytokines and proto-oncogenes transduce signals, which promote growth or differentiation through the mitogen-activated protein kinase (MAPK) cascades and the abnormal activation of these pathways plays an important role in the genesis and progression of many human tumours including pancreas, breast, colon, lung, liver and melanoma. We have learned much about the mechanisms by which MAPK signalling pathways become activated in response to extracellular signals. In contrast, we know considerably less about the ways in which these signalling cascades are switched off and how negative regulatory controls may interact with the process of carcinogenesis. Our work on a family of dual-specificity MAP kinase phosphatases (MKPs) has established these proteins as key negative regulators of MAP kinase activity in mammalian cells. However, although there are numerous reports of either over-expression of MKPs during the early stages of tumour development or loss of expression as cancers become more aggressive or invasive, we do not know if or how these proteins may contribute to the development of cancer or modify tumour behaviour. We have generated mouse gene knockouts to facilitate the study of these proteins in the context of development and disease. These include several phosphatases, which regulate the Ras/ERK MAPK pathway such as DUSP6/MKP-3, DUSP5, DUSP7/MKP-X and DUSP4/MKP-4. Our research programme will focus on the use of these genetic models to probe the involvement of MKPs in cancer. We will intercross our knockout mice with animals in which oncogenes such as activated Kras can be expressed in a variety of specific tissues and give rise to tumours including pancreas, lung skin and intestine. This will allow us to assess the impact of MKP gene deletion on the incidence and progression of cancers and to study the mechanism by which MKPs might modulate the carcinogenic potential of oncogenes in terms of primary incidence and also invasion and metastasis. Tissues and cell lines derived from these animals and tumours will be used to study the underlying mechanisms by which MKP activity might either promote or restrain the transformed properties of cancer cells including signalling activities, proliferation, growth arrest/senescence, cell death and cell migration/motility. Our work will contribute to a greater understanding of the complex regulation of MAPK signalling in human cancer and may reveal new targets for anti-cancer therapy or lead to the improvement of existing treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Recurrence in DCIS: A study of clinico-pathological and molecular variables to identify prognostic and predictive factors
Funder: Cancer Research UK

Abstract: Background: Ductal carcinoma in situ (DCIS) is a pre-invasive breast cancer. Almost thirty percent of DCIS cases treated with Breast Conserving Surgery (BCS) either recur or progress to frank invasive breast cancer (IBC). Radiotherapy and Tamoxifen as adjuvant therapies reduce recurrences by half. However, since a large majority of patients do not recur, adjuvant therapy is clearly an overtreatment for them. Similarly, since some patients recur despite adjuvant therapy, their tumours are non-responsive to these treatments. This underscores the need for good prognostic and predictive markers since current prognostic factors are not sufficiently accurate. Relevance: Breast cancer is the most common cancer among women and DCIS comprises approximately 20% of screen detected breast cancers in the developed world. Good prognostic and predictive markers for DCIS will help to improve our management of this common disease. Specific aims: 1. To develop prognostic markers/models for DCIS treated with BCS. 2. To develop predictive markers/models for DCIS treated with BCS. Research plan outline: We propose to use data and pathology material from the UK/ANZ DCIS trial to investigate candidate molecular markers by immunohistochemistry and analyse this data with clinic-pathological variables to identify prognostic and predictive markers/models for management of DCIS.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Edinburgh Cancer Research UK Centre
Funder: Cancer Research UK

Abstract: The Edinburgh Cancer Research UK Centre brings together scientists, doctors and nurses from across the city. It will harness the breadth of research expertise in Edinburgh, developing new ideas from the laboratory into improvements in treatment that will benefit patients in the city and beyond. The Centre is a partnership between Cancer Research UK, the University of Edinburgh and NHS Lothian, which will link state-of-the-art cancer research to the best possible patient care. Researchers at the Edinburgh Centre will focus on bowel, breast and ovarian cancers, but will also develop new research programs into other common cancers. They will study the genetics and biology of cancer, as well as researching and devising new ways to treat the disease. Scientists at the Centre are particularly interested in understanding how cancer spreads and becomes resistant to drugs. They aim to develop new imaging techniques to monitor cancer spread and, crucially, to find ways to slow or stop the process. This research will help to improve treatment for patients with advanced cancer. Researchers in Edinburgh are also uncovering the genetic changes involved in bowel cancer, making it possible to identify those people at greatest risk of the disease and offer them tailored advice, screening and treatment. Scientists and doctors will work in partnership to identify biomarkers that can be used to predict an individualÆs cancer risk or determine the best treatment. And unique imaging approaches will underpin efforts to detect cancer earlier and to monitor the effects of treatment. Edinburgh is also the location of one of our Experimental Cancer Medicine Centres and there is a well established network of clinical trials, involving local patients. Together with the excellent standard of patient care offered through NHS Lothian, these initiatives will ensure that people across Edinburgh and the surrounding area have the opportunity to benefit from the latest treatments. The new Edinburgh Cancer Research UK Centre will also provide an inspiring environment in which to train the next generation of cancer researchers, continuing to build the cityÆs already thriving research community. Last updated 02/07/2010


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Quantitative diffusion-weighted MR imaging of microcapillary perfusion and tissue diffusivity as biomarkers of response to sunitinib treatment in renal cell carcinoma
Funder: Cancer Research UK

Abstract: In renal cell carcinoma (RCC), targeted treatment using sunitinib improves disease outcome and survival. However, assessing RCC tumour response to treatment is challenging because there are no reliable biomarkers to assess response to novel therapeutics. Diffusion-weighted MR imaging (DW-MRI) is a non-invasive imaging technique that probes the mobility of water protons in tissues. Quantitative indices can be derived using DW-MRI which reflect microcapillary perfusion (f, D*) and tissue diffusivity (D, ADC). We hypothesize that DW-MRI can be an imaging biomarker for treatment response and disease prognostication in patients with metastatic RCC. The aim of this study is to evaluate changes in tissue diffusivity and microcapillary perfusion of metastatic RCC in response to the multi-kinase inhibitor (sunitinib); and to explore whether an increase in tissue diffusivity and decrease in microcapillary perfusion after 7 or 28 days of treatment or the baseline pre-treatment values may have any prognostic value. 34 patients with metastatic RCC will undergo DW-MRI before and at 7 and 28 days after sunitinib treatment. Quantitative DW-MRI indices will be compared before and after treatment, and changes in these indices will be correlated with response defined using conventional imaging criteria and clinical assessment at 12 weeks following treatment.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Transcriptional programs in melanoma metastasis
Funder: Cancer Research UK

Abstract: BACKGROUND TO THE PROPOSAL:_x000D_ To metastasise tumour cells must move through tissues and cross tissue boundaries, which requires cell migration, remodelling of cell-cell contacts and interactions with the extracellular matrix. Tumour cells can move as collective groups or as individual cells. Individual tumour cells have two modes of movement: an elongated mode requiring extracellular proteolysis at cellular protrusions and a rounded mode where cell movement is driven by high contractile forces. We and others have revealed how tumour cells can switch between those two different modes of movement. Efficient metastasis may require both elongated movement for rigid tissues that require extracellular proteolysis and rounded movement for rapid migration in deformable environments._x000D_ _x000D_ Rho GTPases are key regulators of cell movement. I have previously shown that elongated movement in melanoma cells is driven by Rac that promotes protrusions and suppresses rounded movement. In rounded movement Rho-ROCK drives high acto-myosin contractility that suppresses elongated movement. Cell migration in other tumour cells seems to operate in a similar way._x000D_ _x000D_ RELEVANCE TO CANCER:_x000D_ Metastatic melanoma accounts for 75% of skin cancer deaths. Melanoma cells are very invasive as the cell of origin - the melanocyte - is a neural crest derivative that has to migrate long distances during development. During melanoma progression oncogenes may cooperate with re-expression of developmental programs These studies will highlight key pathways for the spreading of other tumours._x000D_ _x000D_ SPECIFIC AIMS OF THE RESEARCH:_x000D_ The aim is to investigate the regulatory events underlying rounded versus elongated movement and how cancer cells interconvert between these two modes to efficiently metastasize._x000D_ _x000D_ OUTLINE PLAN OF RESEARCH:_x000D_ My preliminary data show that new gene expession is required to switch between the two modes. I will study how Rho GTPases control gene expression patterns that determine the different types of movement and we will:_x000D_ - Carry out mechanistic studies with RNAi and over-expression approaches to understand the roles of these genes in determining modes of movement_x000D_ - Characterise patterns of gene expression relating to tumour spread in patients with potential prognostic value_x000D_ - Set up organotypic co-cultures to investigate if genes controlling type of movement affect melanoma-stromal interactions._x000D_ _x000D_ We will provide new insights into how Rho GTPases control gene expression crucial for melanoma metastasis in order to find new therapeutic targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Dissecting the genetics of colorectal cancer
Funder: Cancer Research UK

Abstract: Background Around 35% of the variance of colorectal cancer (CRC) is attributable to genetic factors, but only ~3% of cases are due to known high-penetrance susceptibility genes. Using a genome-wide association approach, we recently identified 10 new common genetic variants associated with CRC risk. These account for ~6% of the excess familial risk. The aim of this 5-year programme is to build on these discoveries and move towards full elucidation of the genetic basis of CRC to i) shed new light on mechanisms of disease causation; ii) provide tangible clinical and public health benefits in the foreseeable future. Relevance to cancer CRC is a common fatal cancer (37,500 new cases annually in UK, survival 50%) but much evidence indicates it is eminently preventable. Understanding the genetic basis of CRC will lead to new understanding of cancer causation, informing development of new anti-cancer drugs and offering the potential of risk prediction to target screening to those most at risk. Specific aims •Extend our genome-wide association studies in CRC to fully elucidate the contribution of common genetic variation •Study entire genome for interactions between pairs of common genetic variants affecting CRC risk. •Determine the functional consequences of heritable genetic risk variants. •Identify genes conferring high risk of CRC by discovering new, low-frequency, alleles of major/moderate effect through sequencing all coding DNA in highly selected CRC cases. •Investigate genetic interactions between common variants and dominant mutations responsible for Lynch Syndrome. •Explore heritable genetic influences on tumour survival/prognosis. Research plan We will interrogate the wealth of genome-wide data we have amassed, conducting replication genotyping in case-control sets to confirm new associations with CRC risk. We will search for interactions between common genetic variants by study of genomewide data. We will identify causal variants at respective loci and analyse genotypic influences on expression/function of nearby genes in cell and tissue experiments. To identify new genes conferring high CRC risk, we will use massive parallel sequencing of coding DNA (exomes) to study extreme phenotype CRC where all known susceptibility genes have been excluded. Effect on CRC risk in the general population will be determined for newly identified genes. Using large sample sets of Lynch Syndrome patients, we will search for common genetic variants interacting with high-penetrance mutations in DNA mismatch repair genes. We will undertake genome-wide studies to identify heritable genetic factors influencing survival after a diagnosis of CRC.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Deconstructing Myc oncogenesis
Funder: Cancer Research UK

Abstract: Myc is a highly pleiotropic transcription factor that coordinates multiple, diverse aspects of cell proliferation and whose expression is frequently deregulated and/or elevated in human cancers. Our studies indicate that Myc orchestrates not only the wide variety of intracellular programs necessary for orderly cell expansion – cell metabolism, cell growth, cell cycle progression, de-differentiation and apoptosis – but also a suite of extracellular programs that reorganize the local somatic microenvironment and prepare it for the cell expanding in its midst. Oncogenic activation of Myc hijacks all of these diverse processes, allowing oncogenic Myc to instruct and maintain multiple aspects of the neoplastic phenotype. The unique manner in which coordinates and integrates the diverse intra and extracellular regenerative programs that drive and maintain cancers suggests make it, and its immediate upstream affectors and downstream effectors, attractive candidates for therapeutic targets in the treatment of multiple, perhaps all, cancers. In this proposal, we will address three pivotal questions in Myc cancer biology. First, how does Myc activation in somatic cells in vivo instruct and maintain widespread tumorigenic changes in the immediate somatic microenvironment. Second, how is Myc oncogenic action determined by the cell/tissue type in which Myc is activated? Third, to what extent is endogenous Myc activity required for the evolution and maintenance of the vast majority of cancers in which it is not the driving oncogene but an obligate downstream effector of upstream oncogenic pathways? We will address these questions in three aims In Aim 1 we will use our well-established and kinetically defined reversibly switchable pancreatic ß cell mouse model of Myc-induced tumorigenesis to ascertain how Myc precipitates the causal chain of events that reorganize the islet tumor microenvironment. Focusing specifically on Myc-induced tumor angiogenesis, we will ascertain the role of inflammatory cytokines and infiltrating cells in initiating and maintaining tumor vasculature and the role this plays in tumor maintenance. In Aim 2 we will address the consequences of Myc action in different tissues using a novel transgenic mouse model that allows sporadic and reversible activation of Myc in any target tissue. Using this same model, we will then specifically focus on Myc oncogenic mechanism in lung. In Aim 3 we will use a unique mouse model that allows for reversible inhibition of endogenous Myc function in multiple tissues in vivo to model the efficacy of a Myc inhibitory drug in the treatment of diverse cancer types.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS