NIHRDataInsights/HRCSData huggingface dataset:
Title: SAFIR-ABC10: molecular screening for precision medicine in advanced biliary cancers
Funder: Cancer Research UK

Abstract: Background Despite the description of accepted treatment standards of care (SoC) in the last 10 years, survival for advanced biliary tract cancer (ABC) remains poor and is an area of significant unmet need. Genomic profiling has demonstrated actionable molecular alterations (AMA) in 40-60% of ABC and preliminary data have been promising. This study proposal was suggested following an MRC stratified medicine proposal 3 years ago. Aims We propose a study of maintenance therapy in ABC following 1st line SoC treatment (currently Cisplatin and Gemcitabine described in the ABC-02 study) directed by molecular profiling to determine the benefit of precision medicine in ABC. Methods Patients with ABC will be profiled whilst on 1st line SoC chemotherapy. If the patient has stable or responding disease and (1) has an AMA, they will be randomised to targeted therapy or to continue on SoC, (2) has a putative AMA, to targeted therapy only (3) has no AMA, to Regorafenib-Durvulumab vs SoC. If the patient progresses on SoC they will proceed to either AMA or Regorafenib-Durvulumab. The primary outcome will be progression free survival (PFS) in arm (1) and secondary endpoints include PFS in arm (3) and OS for the whole cohort. Cross over will be permitted in randomised sub-studies. Where infrastructure permits, patients will have pre and 8 week ABC-10 therapy biopsies for multiparameter flow cytometry of immune cell subsets, multiparameter immunofluorescence of immune cell subsets, whole genome and T cell repertoire studies. Additionally, peripheral blood will be taken for circulating tumour DNA as well as germline DNA analysis. The study has been developed and will be be run in collaboration with the sponsors, UNICANCER who aim to recruit 400 of 800 patients. A key collaborations is the Glasgow Precision Oncology Laboratories (GPOL) who will run the initial profiling using an Agilent SureSelect platform in addition to multiple collaborations that have been established with Pharma to provide drug and financial support. How the results of this research will be used The data, if positive, will be used to establish targeted therapies as SoC for ABC. There are multiple secondary outputs including the development of putative drug-target combinations (cohort 2) and the value of Regorafenib-Durvulumab and further translational outputs (cohort 3). ABC-10 will represent the single largest cohort of ABC patients molecularly profiled and prospectively treated with clinical trial quality data permitting multiple further outputs and collaborations.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Understanding the role of mediator and cohesin complexes during endocrine resistance in breast and prostate cancers
Funder: Cancer Research UK

Abstract: Background: Breast and prostate cancers are the commonest malignancies in women and men respectively. Estrogen receptor (ER) and Androgen Receptor (AR) are the classical markers of most of these cancers respectively, which are the nuclear receptors important for cancer progression. Even though survival rates of these cancer patients have increased in recent years due to the development of ER and AR targeting agents, drug resistance and metastasis to other organs are the major causes of cancer-related deaths. Understanding how specific gene mutations make cancer cells to relapse after treatment is essential to improve patient outcome. Preliminary analyses from genome-wide CRISPR screens identified a novel role of chromatin architectural proteins which mediate long range chromosomal interactions, Mediator and Cohesin, in promoting response to ER/AR targeting agents in breast and prostate cancer cell lines. Interestingly, these complexes are mostly inactivated by mutations in metastatic breast cancers and amplified in metastatic prostate cancers. This suggests an important and differential association of these proteins in breast and prostate cancers in endocrine treatment response. Aims: I aim to understand how Mediator and Cohesin complexes(MED12 and RAD21) regulate treatment resistance in breast and prostate cancer patients in a differential manner. My research team will investigate the transcriptional association of nuclear receptors with Mediator and Cohesin complexes regulating specific gene regulatory networks. We will identify the druggable chromatin-associated proteins, which are enriched in the context of Mediator and Cohesin alterations to overcome treatment resistance. Methods: We will utilise CRISPR-Cas9 edited knockout and lentiviral-based overexpression on breast and prostate cancer cells to investigate the impact of MED12/RAD21 alterations in drug resistance using cutting-edge technologies, including qPLEX RIME (Quantitative Rapid Immunoprecipitation and Mass-spectrometry of endogenous proteins), ChIP-sequencing and ChIA-Drop (chromatin architecture studies) to define the functional interplay of the Mediator, Cohesin and nuclear receptors. We will employ cell lines- and patient-derived xenografts with copy number changes on these genes to reflect the human disease. We will assess the efficacy of epigenetic inhibitors targeting alteration-specific enriched proteins to explore their effect in tumour growth. How the results of this research will be used: By utilising systematic appraoches and clinically relevant systems, we can systematically discover the role of frequently represented MED12 and RAD21 alterations and the potential impact of epigenetic inhibitors in overcoming resistance to the existing therapies in breast and prostate cancers. This study will provide mechanistic insights into tumour relapse and potential therapeutic strategies to target aggressive tumours.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Investigating the molecular basis of Heparan Sulfate biosynthesis
Funder: Wellcome Trust

Abstract: Heparan sulfates (HS) are complex polysaccharides that mediate diverse structural and signalling interactions between cells and their extracellular matrix neighbours. They are essential for myriad physiological processes, ranging from glomerular filtration to developmental morphogenesis. HS biosynthesis is currently very poorly understood. At least 26 different enzymes are involved, but many of these remain poorly characterized, and almost nothing is known about how they functionally co-operate. My project aims to establish a molecular understanding of HS biosynthesis. I will investigate the mechanisms of individual HS biosynthesis enzymes in vitro, using both biochemical and structural (crystallography, cryo-EM) approaches. These in vitro studies will complement tomographic imaging of HS biosynthesis events inside cells, allowing insights for individual enzymes to be synthesised into a unified understanding of how HS biosynthesis occurs within its native environments. HS is intimately connected to human health. Aberrations in its regulation cause developmental disorders and can promote cancer growth. A molecular understanding of HS biosynthesis may provide insights into how such aberrations can be corrected to treat HS related disorders. HS and its derivatives also have considerable potential as therapeutically useful molecules. Characterizing the HS biosynthesis machinery will facilitate improved methods to produce defined HS molecules for such applications.

Lay abstract: Heparan sulfates are complex chain-like sugar molecules found around all cells of the body. They are essential for life, mediating diverse processes ranging from kidney filtration to cell differentiation. Abnormal production of heparan sulfate can cause congenital diseases, and contribute to cancer growth. At least 26 enzymes are involved in producing heparan sulfate. My project aims to understand how these enzymes function and co-operate. I will investigate the molecular mechanisms of individual heparan sulfate producing enzymes through structural characterization by crystallography and cryo-EM, alongside biochemical studies of their activities. I will also image heparan sulfate production directly inside cells, which will shed light on how the many enzymes involved in producing heparan sulfate work together in their native environments. My research will provide insights into how cells produce heparan sulfate, allowing us to better understand myriad heparan sulfate dependent biological processes, and to address diseases where these processes go wrong.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: CRUK/19/013 VICTOR: Venetoclax or Intensive Chemotherapy for Treatment Of Favourable Risk Acute Myeloid Leukaemia: A Molecularly Guided Phase 2 Study
Funder: Cancer Research UK

Abstract: Background Acute myeloid leukaemia (AML) is an aggressive haematological malignancy diagnosed in ~3000 patients annually in the UK, of whom fewer than half survive. Most deaths are attributable either to disease relapse or side effects of treatment. For patients treated with curative intent, intensive chemotherapy protocols have not changed significantly for many years and are associated with high levels of treatment related mortality and severe short and long term morbidity. Recently, phase II trials with the BCL2 inhibitor venetoclax combined with low-intensity chemotherapy have shown remarkable efficacy in elderly patients with AML who are unfit for intensive therapy. These responses are most striking in patients who harbour mutations in the gene encoding nucleophosmin (NPM1, present in 30-40% of all AML) where complete responses are achieved in 90-100% of patients. This raises the possibility that this novel low intensity combination could be equivalent to intensive chemotherapy in this subgroup of patients, potentially sparing them from the very significant toxicity, prolonged hospitalisation, economic cost and impact on quality of life associated with intensive chemotherapy. Aims To compare the outcome of patients with NPM1 mutated AML treated with venetoclax and low dose cytarabine (VEN+LDAC) with those treated with intensive chemotherapy aiming to gather sufficient evidence of non-inferiority to proceeed to a phase III trial. Methods VICTOR is a randomised phase 2 study for previously untreated patients with AML who are considered fit for induction therapy (n=156). The study will initially enroll adults aged over 60y and employs an adaptive, staged design allowing younger patients to enroll as evidence of non-inferiority in the older patients grows. Patients will undergo rapid molecular screening to identify those with the genotype NPM1mut FLT3 ITDneg. Eligible patients will be randomly allocated to receive standard of care intensive chemotherapy (using the DAGO regimen) or VEN+LDAC. All patients will receive stringent molecular monitoring. Patients with evidence of molecular failure in the experimental group will be switched to standard salvage chemotherapy, providing a molecular safety net. The primary end point is molecular event free survival. How the results of this research will be used The results from this study will inform a larger phase 3 study embedded in NCRI AML20 which we anticipate will study an expanded population with respect to age and genotype. VICTOR may also be informative for optimal treatment of older patients with NPM1 mutated AML.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: APPROACH: Using a mobile application to promote physical activity after cancer
Funder: Yorkshire Cancer Research

Abstract: People affected by cancer who take part in physical activity (PA) are more likely to live longer, less likely to get cancer again and experience fewer side effects from treatment. Our previous work suggests smartphone applications (apps) are an acceptable way to promote PA to cancer patients. The first, smaller study will explore whether it is realistic and possible to test an existing PA app (Active 10) in people diagnosed with breast, prostate or bowel cancer within South Yorkshire. If so, the second, larger study will explore whether the app increase participants PA, improves quality-of-life and reduces cancer related side effects.

Lay abstract: People affected by cancer who take part in physical activity (PA) are more likely to live longer, less likely to get cancer again and experience fewer side effects from treatment. Our previous work suggests smartphone applications (apps) are an acceptable way to promote PA to cancer patients. The first, smaller study will explore whether it is realistic and possible to test an existing PA app (Active 10) in people diagnosed with breast, prostate or bowel cancer within South Yorkshire. If so, the second, larger study will explore whether the app increase participants PA, improves quality-of-life and reduces cancer related side effects.

Research activity codes: 6.7 PHYSICAL
Health categories: CANCER AND NEOPLASMS
Title: CRUK/11/049: PNET5: An international prospective study on clinically standard-risk medulloblastoma in children older than 3 to 5 years with low-risk biological profile or average-risk biological profile (jointly funded by The Brain Tumour Charity)
Funder: Cancer Research UK

Abstract: Background Medulloblastoma is a highly cellular malignant embryonal neoplasm classified as a Primitive Neuro-ectodermal Tumour (PNET). It is the most common malignant brain tumour in children. As with other PNETs, medulloblastomas have a marked propensity to metastasize via CSF pathways, and evidence of such metastatic spread is present in up to 35% of cases at diagnosis. Medulloblastoma remains incurable in approximately one-third of patients and 20-25% of standard risk patients. Moreover, survivors suffer from long-term toxic side effects related to therapy that often seriously affect their quality of life. It would be of benefit if the population of clinically standard risk medulloblastoma patients could be divided into those with a good outcome who may be cured with less therapy, and those with a less good outcome whose survival may be improved with extra treatment. Assessing quality of survival and long term neurological and endocrine function is important to determine the impact of the disease and its treatment on these patients. Aims PNET5MB:A single arm to confirm that the 3-year event-free survival (EFS) in children and adolescents with standard-risk medulloblastoma having a low-risk biological profile remains in excess of 80% when patients are treated with 23.4 Gy neuraxis irradiation plus boost and reduced-intensity chemotherapy. A randomised arm will test whether the EFS in children and adolescents with standard-risk medulloblastoma having an average-risk biological profile is different for those patients treated with or without carboplatin concomitantly with radiotherapy (23.4 Gy neuraxis irradiation plus boost) followed by a modified maintenance chemotherapy. Methods This is an international trial for patients with standard-risk medulloblastoma from 3 to 21 years old. The ß-catenin nuclear immune status of all patients will be tested prior to the commencement of treatment. Patients found to be ß-catenin nuclear immunopositive are considered to be of a low-risk biological profile and are eligible for the single arm phase II study. These patients will receive radiotherapy followed by reduced intensity maintenance chemotherapy. Patients found to be ß-catenin nuclear immunonegative are considered to be of an average risk biological profile and are eligible for the randomised phase III study. These patients will receive radiotherapy ± carboplatin followed by maintenance chemotherapy. In both studies quality of survival, neurological, kidney and hearing function will be followed and reported. Results The results of the trial will be used to inform standard practice worldwide and provide the standard arms for future PNET trials.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Evaluating the role of fast MRI and image-fusion for detection of prostate cancer
Funder: Cancer Research UK

Abstract: Every year, 150,000 men at risk of prostate cancer (PCa) are referred to UK hospitals wit this set to rise to 250,000 per year by 2030. Recently, UK and international guidelines have recommended that men have an multi-parametric MRI (moMRI) before biopsy. Since biopsies can cause side-effects such as pain, bleeding and infection, a non-suspicious mpMRI can allow some men to avoid an invasive biopsy because there is a low probability of clinically-important prostate cancer. In those with a suspicious mpMRI, targeted biopsies to areas of suspicious can improve detection of clinically-important PCa compared to the previous diagnostic pathway. We want to further improve this new pathway. First, mpMRI takes 40-minutes due to injection of intravenous gadolinium contrast which requires medical supervision due to risk of allergic reactions. Many hospitals do not have enough scanner time or expert radiologists to look at the images. There has also been concern about brain tissue deposition of gadolinium. mpMRI costs £450 in the UK NHS. A 15-minute biparametric MRI (bpMRI), without gadolinium, and at a cost of £250 might be as accurate as mpMRI. Second, once a man needs a biopsy the doctor has to estimate where to aim the biopsy needle. This so-called visual-estimation targeting requires expertise which is not readily available everywhere. New image-fusion technology that overlays MRI with ultrasound images to guide the biopsy needle might be better. Aims We want to test if a bpMRI, compared to mpMRI, is as accurate in diagnosing clinically-important PCa. We also want to test whether image-fusion is better than visual-estimation biopsies. Methods We want to answer both questions in one trial - this will provide economies of scale and scope compared to running two separate RCTs. Men who need a prostate MRI and agree to participate will first be randomised to mpMRI or bpMRI. If the mpMRI or bpMRI is suspicious, these men will then be randomised to visual-estimation or image-fusion targeted biopsy as well as systematic biopsies. We will look at the proportion of clinically-important and unimportant PCa detected, the proportion of men biopsied and value for money in the UK NHS. How the results will be used We will present our findings at conferences and publish in high impact journals. We will share results with trial participants and key stakeholders like patient support groups, charities, policy makers, professional medical, nursing and radiography bodies. Our findings will inform clinical guidelines.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: DECONSTRUCTION, RECONSTRUCTION AND FUNCTIONALIZATION OF PROSTATE CANCER HETEROGENEITY
Funder: Cancer Research UK

Abstract: It is becoming increasingly apparent that cancers are constantly evolving eco-systems where heterogeneous populations of malignant cells interact with a variety of normal cells. Such ecosystem depends on the constant communication among multiple components that can change over time, and it can be described as open, complex and adaptive. Nevertheless, the vast majority of cancer research relies on close, simple and static models, and the fact that the transition “from bench to bedside” has been halted by frequent failures should come as no surprise. The high level of inter-patient and intra-patient tumour heterogeneity is still at the core of relapse to cancer therapies and availability of appropriate models of tumor heterogeneity represents a major hurdle. I here propose work packages that integrate a rapid “off-the-shelf” mouse modeling approach based on prostate cancer organoids with innovative tracking technologies for the in vivo characterization of distinct cancer cell populations. Focusing on prostate cancer, I aim to uncover cancer vulnerabilities by studying mechanisms of adaptive evolution upon therapy and co-operation between cancer cells and their microenvironment. The goal of this proposal is to understand cancer trajectories of drug resistance and to rationally design dynamic therapies to act towards cancer’s next evolutionary move.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Glasgow ECMC
Funder: Cancer Research UK

Abstract: The overall aim of the Glasgow ECMC is to improve the quality and output of experimental medicine projects and clinical trials for patient benefit. The scientific and clinical themes of our experimental medicine programmes include: drug development (early phase clinical trials); biological markers; DNA damage response; leukaemia stem cells; invasion & metastasis; chemokine biology & immunotherapy; cancer cell metabolism; epigenetics; cellular senescence; precision medicine; pancreatic cancer; ovarian cancer; urological cancers (prostate, bladder); leukaemias; neuro-oncology & radiotherapy. Specifically, the Glasgow ECMC's Translational Pharmacology Laboratory (TPL) leads and performs biomarker studies including pharmacokinetic (PK) and pharmacodynamic (PD) studies within clinical trials and biomarker studies applied to clinical questions; we provide research nurse support to our clinical investigators for early phase clinical trials when these involve translational components with complex and intensive patient sampling schedules; and contribute support for the collection of patient samples, including tumour tissues, for specific clinical and / or biomarker studies. We will continue to collaborate effectively with the ECMC network and with industry, and will aim to be a leading example of engagement, increasing awareness of the ECMC and its relevance to the treatment of cancer patients.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS