Alex Edwards, Highly Skilled Volunteer (Citizen Science)

Our Accelerator Award encourages cross-institutional collaboration to develop tools which will accelerate translational research.

In partnership with AIRC and FC AECC, we invited research centres in Italy, Spain and the UK to submit outline proposals for Accelerator Awards of up to £1 million per year for up to 5 years. We have now shortlisted the proposals and invited 16 Principal Investigators to develop their ideas into full applications, backed by a suitable team of co-investigators and collaborators to deliver the proposals.

If you think you or your research team have the skills or expertise to contribute to any of the proposed research projects and would be interested in joining a team, please contact us for an informal, confidential discussion.

The deadline for full application submissions is 30 January 2018.

 

Contact the research funding team

Dr Alessia Errico  

Research Funding Manager  

acceleratoraward@cancer.org.uk

Tel: 0203 469 6799

Shortlisted proposals

  1. HUNTER: Hepatocellular Carcinoma Expediter Network

  2. Human Tumour Explants Collaborative (HUTEX-CO)

  3. Single-cell cancer evolution in the clinic

  4. Single Cell and Cell Free DNA Platforms To Study The Mechanistic Basis Of Therapy Resistance and Relapse in Cancer

  5. Shared platforms to accelerate biomarker and targeted therapeutic development in bone sarcomas

  6. Early detection and intervention: Understanding the mechanisms of transformation and resistance of incurable hematological malignancies

  7. Innovative CAR Therapy Platforms (INCAR)

  8. Precision-Panc Europe

  9. Low dose CT scan of lung cancer can shift the distribution of stages, but specificity is limited (suboptimal distinction of benign nodules from cancer). We aim to set up an infrastructure in London and Italy to develop innovative early detection tools to improve the performance of LDCT.

  10. Multi-modal clinical testing of prostate cancer patient plasma

  11. Acute promyelocytic leukemia network: A platform for research developments on long-term survivors

  12. ACRClerate: Colorectal Cancer Stratified Medicine Network

  13. Late effects in adolescent and young adult cancer survivors (Lea). A multicentre cohort in Europe

  14. Accelerating our ability to understand and target complexity and heterogeneity in cancer by developing an accessible, multi-scale microscopy pipeline from in vitro high content discovery to intravital imaging.

  15. Virtual BIopsy in OncoLogical ImagiNg – VIOLIN

  16. An open-access database of cell-free DNA dynamics and T-cell repertoires from 20-years of serial blood samples for identifying cancer-specific signatures in liquid biopsies.

HUNTER: Hepatocellular Carcinoma Expediter Network

Helen Reeves, Newcastle University

Primary liver cancer, predominantly hepatocellular carcinoma (HCC), is the 2nd commonest cause of cancer death globally. While mortality from other cancers is falling, HCC mortality is escalating –because incidence is rising, but also because many HCC are detected at advanced stages when surgical cure is not possible and medical treatments are limited.  Recent studies using immune checkpoint inhibitors have elicited remarkable responses in 20% of HCC patients. While not all patients are responders, these trials offer genuine hope that immunology-focused research may hold the key to better treatments for many more patients. The pressing scientific need is to understand how the diseased liver microenvironment and combined molecular cues determine immune cell phenotypes promoting HCC development or progression.

Patients with advanced HCC that are fit to treat presenting to any one Unit are scarce, as are the clinicians and scientists with the required research expertise for the analyses. HUNTER will bring together outstanding investigators from UK, Spain and Italy who will work together to deliver (1) the urgently needed fresh tissues resource, (2) a PhD training programme, (3) the immunogenomic and metabolomic characterisation of the immunosuppressive HCC microenvironment, and (4) the relevant pre-clinical animal and human models required for translation. These tools shared with the research community will accelerate research addressing the urgent medical needs – which are to identify (1) biomarkers predicting HCC response to existing immuno-modulators and (2) novel molecular targets for harnessing immune control of HCC.

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Human Tumour Explants Collaborative (HUTEX-CO)

Joaquin Arribas, Instituto de investigación Oncologica de Vall d´Hebron

Human cancers are currently classified as distinct genomic entities, not just based on the organ of origin (e.g. breast cancers are a constellation of 10 genome driver-based subtypes). We also recognise that tumours are communities of malignant cell clones and tumour micro-environment, constituting a complex ecosystem. Modelling this inter- and intra-tumour heterogeneity is one of the main challenges for developing predictive pre-clinical models, where drugs can be tested, and processes such as drug resistance and metastatic spread can be properly dissected.  Arguably, the best models to reproduce the complexity of human cancers are those directly derived from tumours in patients. These human tumour explant models (i.e. patient-derived tumour xenografts/PDTXs; PDTX-derived tumour cells/PDTCs, and tumour organoids) recapitulate the evolution of the complex tumour ecosystem during treatment.

Current limitations of these model systems include (i) lack of robust and reproducible protocols for use in pre-clinical therapeutic development (including drug dosing and scheduling, and defined criteria for imaging response assessment); (ii) a uniform platform to molecularly characterise models, and (iii) a system to ‘humanise’ the models with a patient-derived immune system. Our 3 centres, CRUK CCC, SRSI and VHIO, are coming together in a collaborative effort to tackle these challenges and use the Accelerator Award to create the required infrastructure, building on existing investment at each of the centres.

Our aim is to establish a Human Tumour Explants Collaborative (HUTEX-CO) with the overarching goal of establishing a top quality multi-centre infrastructure, that will provide the means to do transformative translational research on patient-derived tumour models.  

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Single-cell cancer evolution in the clinic

Giovanni Tonon, Fondazione Centre San Raffaele

Cancers adapt to therapy through a process of clonal evolution. Patients undergo multiple rounds of potentially highly toxic treatments, without a clear pre-emptive indication of efficacy. When the patient relapses, meaningful information to choose the most effective treatment is rarely available. There is therefore an unmet clinical need to develop tools, applicable to the clinic, to determine how cancer evolves under therapy.

Accumulating evidence indicates that resistance to specific treatments entails recurrent evolutionary mechanisms. We argue that these recurrent mechanisms do not just beset a formidable hurdle for cancer therapy, but also represent a major Achille’s heel for cancer cells that could be exploited for novel therapeutic approaches.

The recent introduction of single-cell genomics approaches has finally provided a mean for the comprehensive understanding of the evolutionary strategies exploited by cancer cells as a population. In particular, profiling rare, treatment-resistant subclones at single cell level is becoming feasible. In this proposal, we combine cancer evolution modelling, new single-cell approaches and novel microfluidic devices, as well as new data integration techniques, with the aim to provide a definitive single-cell portraits of tumor cells, before and after treatment.

We propose to deliver tools and devices that could be promptly implemented in a clinical setting, to pre-emptively intercept resistance in individual cancer patients.

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Single Cell and Cell Free DNA Platforms To Study The Mechanistic Basis Of Therapy Resistance and Relapse in Cancer

Claus Nerlov, University of Oxford

The primary cause of death in cancer patients is therapy failure. In Acute Myeloid Leukaemia (AML) 80% of patients are >60 years with cure rates of 5-10%. Younger patients tolerate cytotoxic therapy, but cure rates remain <40%. Similarly, cure rates are low in many solid cancers, including head-and-neck squamous cell carcinoma (HNSCC), where overall cure rate is ~50% and survival of patients with recurrent cancer <20%.

Emerging technologies, including single cell RNA-Seq, ExomeSeq and circulating tumour DNA (ctDNA) analysis, have dramatically enhanced diagnosis and molecular characterization of tumours, and monitoring of tumour evolution and recurrence. While this can potentially both improve diagnosis and inform molecularly tailored, less toxic or combination treatments, fully realizing the potential of these technologies will require concerted acquisition and integrated analysis of large-scale clinical and molecular data sets.

We will, in parallel and at scale:

  • Systematically acquire patient tumour and -monitoring samples, and patient outcome data from AML and HNSCC cohorts treated with uniform, state-of-the-art therapies in clinical trials. Tumour samples will be collected at presentation, best response and recurrence.
  • Develop platforms to generate whole tumour genomic, epigenomic and transcriptomic data to systematically profile sequential patient samples.
  • Develop an integrated database, computational and statistical framework to mine diagnostic and prognostic markers, and molecular and cellular therapeutic targets.

Importantly, single cell-level tumour characterization will include malignant cells, immune cells, stromal cells and vasculature, allowing prognostic information and therapeutic targets to be independently extracted from all tumour components. 

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Shared platforms to accelerate biomarker and targeted therapeutic development in bone sarcomas

Katia Scotlandi, Rizzoli Institute

Despite intense multi-agent chemotherapy, and local therapy, outcome for patients with the most common bone cancers found in young people, Ewing sarcoma and osteosarcoma, remains poor.  For those with high-risk disease at diagnosis, only 1 in 5 survive for 5 years, and for those who relapse after treatment, outcome is equally poor. In addition, therapy frequently results in significant long-term morbidity.

Through this Accelerator Award we will build an innovative, sustainable, international pipeline to hasten the evaluation and prioritisation of targeted therapeutics to develop early phase risk-based trials, with the aim of improving outcomes. The project will focus on cross-cutting biomarker studies and preclinical experimental modelling exploiting extracellular vesicles (EVs) to design response-adaptive trials. The proposal builds on well-established international clinical and translational networks including the EURO EWING Consortium and the European Bone Sarcoma Network and major stakeholders such as established Patient Advocacy groups, the Spanish and Italian Sarcoma Groups and the National Cancer Research Institute Sarcoma Clinical Studies Group. This provides a unique opportunity to validate circulating biomarkers across multiple international clinical trials to accelerate their use to improve management of bone cancer patients and to exploit EVs to deliver novel targeted therapeutics. An EV- and tissue-biobank will be created, incorporating patient samples linked to clinical data, as well as samples collected from standardised preclinical models. The study findings will be translated into the clinic to treat patients with aggressive bone tumours, tailoring therapies for optimal efficacy and safety to improve quality of life and long-term survival.

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Early detection and intervention: Understanding the mechanisms of transformation and resistance of incurable hematological malignancies

Jesus San Miguel, Fundación para la Investigación Médica Aplicada

Although great strides have been made in the management of haematological malignancies in the last decade, our best opportunity to eradicate cancer lies in preventing progression at pre-malignant and minimal residual disease (MRD) states, and offers an under explored area for disease control and cure.  Our accelerator consists of national hubs focussing on 3 haematological disorders, Monoclonal Gammopathies (MG,Spain), Myelodysplastic syndromes & Acute Myeloid Leukaemia (MDS, AML- Italy), and Follicular Lymphoma (FL-UK), malignancies that represent singular models of cancer progression, from pre-malignant (clonal yet benign) into malignant disease (chemosensitive that ultimately become refractory due to persistent MRD). Each hub will work collectively with researchers in the partnering countries to realise the ambitions of the accelerator that set out to 

  • Identify precise biomarkers of early transformation and novel targets for pre-emptive treatment through comprehensive phenotypic and molecular analyses of single tumour cells vs their normal counterpart and corresponding immune cells from patients at different disease states.
  • Understand and overcome initial tumour resistance by investigating the molecular nature of MRD clones, develop biomarkers for precision treatment based on MRD-immune signatures, and define surrogates of cure based on depth of MRD response and immune signatures.

The success of the accelerator program and our ability to unveil the regulatory networks responsible for maintaining ‘cells’ in a pre-malignant state will allow us to treat disease causation instead of symptomatology and to tailor and manage MRD clones instead of waiting for invariable clinical relapses, all in areas of unmet medical need.

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Innovative CAR Therapy Platforms (INCAR)

Andrea Biondi, Università degli Studi di Milano-Bicocca

The Innovative CAR Therapy Platform (INCAR) initiative aims to launch a novel consortium of European centres to support in-depth research into Chimeric Antigen Receptor (CAR) engineered cellular therapies. INCAR brings together world-class centres (University of Milano-Bicocca, Ospedale Pediatrico Bambino Gesù, ASST Papa Giovanni XXIII Bergamo, Cancer Research Center FICUS, and University College London) with established research programmes in CAR therapies for a range of malignancies, and with a number of phase I/II studies either open or in implementation.

The consortium will take advantage of differences in cellular platforms, CAR design, manufacturing methods, and methods of gene transfer being investigated in studies across the program to in turn dissect key biological factors, which influence the mechanism of action of CAR-engineered cellular therapies.

The common aim is rapidly enhancing our understanding of mechanisms responsible for biological efficacy and toxicity. This goal will be obtained through the complementary approaches of the participating teams in terms of clinical and academic expertise, skills and techniques, as well as of the core facilities underpinning the institutions in which the teams are placed. Emphasis will be placed on a collaborative scientific approach, establishing standardized protocols and a rigorous, constructive data-sharing to ensure the most rapid progress is achieved. A project management team will schedule collaborative meetings to maximize outputs. 

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Precision-Panc Europe

Aldo Scarpa, ARC-Net, University of Verona

Pancreatic ductal adenocarcinoma (PDAC) dismal outcome (5-year survival <5%) has remained almost unchanged for 50 years. PDAC high mortality requires a networked platform approach to accelerate advancement beyond incremental progress, which is a central goal of this proposal. We will establish a synergistic and dynamic “Precision-Panc Europe” platform, aligning discovery, pre-clinical and clinical therapeutic development by expanding the UK based Precision-Panc therapeutic development platform (www.precisionpanc.org, a CRUK Flagship Programme).

As part of a global collaborative effort with the International Cancer Genome Consortium the applicant team defined discrete subgroups of PDAC based on genomic and transcriptomic analysis. The goal is now to define subgroups, based on similarities in molecular mechanisms that can be targets for therapy. We will focus on emerging therapeutic opportunities based on our preliminary data and industry partnerships using combination therapies targeting these vulnerabilities. Although single agent immunotherapy has been disappointing in PDAC, we and others have shown that combinations based on an understanding of molecular mechanisms are showing efficacy, with some that we have advanced to clinical trials.

We will use our emerging data and novel experimental approaches to build robust preclinical platforms of evidence to advance combinations that target DNA maintenance deficiency (an actionable segment in PDAC) and immune evasion to define specific approaches for clinical testing. These will then be developed into clinical trials through the platform. The applicant team are leaders in pancreatic cancer research internationally, and between them harbour significant and complementary expertise in discovery, preclinical and clinical therapeutic development. 

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Low dose CT scan of lung cancer can shift the distribution of stages, but specificity is limited (suboptimal distinction of benign nodules from cancer). We aim to set up an infrastructure in London and Italy to develop innovative early detection tools to improve the performance of LDCT.

Paolo Vineis, Italian Institute for Genomic Medicine

In several countries governmental agencies are considering the implementation of low-dose CT-scan (LDCT) for lung cancer, based on the results of RCTs and single arm studies. However, specificity of LDCT is limited by the suboptimal distinction of benign nodules from lung cancers, with a high false positive rate. One way to increase the predictive ability of LDCT scans is to combine blood biomarkers with LDCT.

We will improve the performance of current prediction algorithms (mainly based on smoking habits) using a personalised risk profile, in order to select subjects at high risk who should undergo LDCT scans (eligibility to screening). Predictive models will incorporate methylation and proteomic measurements within an already (NIH) funded network.

Once the prediction model has been refined it will be applied in the EPIC-Italy cohort, that includes 47,000 subjects and a biobank. We plan to measure targeted DNA methylation, proteomics, mutations in circulating DNA, and miRNA. We will also test the new biomarkers within the on-going LDCT programs in Florence, Pisa and Milan.

The main aim of the proposal is to set up an infrastructure in London and Italy to allow biomarker research in the context of LDCT screening programs. Purposes are: guideline development and harmonisation of practices, including criteria for eligibility; procedures for LDCT; and biobanking. The algorithms produced in the previous steps will be tested for feasibility in an asymptomatic London population (heavy smokers) undergoing LDCT scans, and in the LDCT activities in Milan, Florence and Pisa.

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Multi-modal clinical testing of prostate cancer patient plasma

Francesca Demichelis, University of Trento

Precision medicine in oncology requires broadly-applicable molecular characterisation of tumours. In contrast to tissue, liquid biopsies are minimally disruptive and can be obtained repeatedly, providing real-time molecular data. We aim to broaden the clinical utility of plasma analyses for risk stratification and treatment selection, monitoring and characterisation of resistance by increasing the amount and quality of information obtained. We have assembled a team that includes prostate cancer specific expertise on all key components (molecular, clinical, genomics, epigenetics, vesicles, liquid biopsies) and extends to multiple hospitals and clinical trial cohorts with the dual aim of ensuring both prospective enrollment of advanced prostate cancer patients to answer specific clinical questions and to result in up-and-running liquid biopsy tests at multiple institutions by end of the project. Approaches established will also have utility in plasma analyses in other cancer types. Our team will i) implement novel computational approaches and targeted design strategies to accurately quantitate commonly recurring point mutations and copy number changes, including mono- and bi-allelic deletions at low tumour purities; ii) integrate these genomic data with readouts of methylation status and use clinically applicable approaches for exosome isolation and analyses to obtain information on mRNA and protein expression; iii) establish a cloud-based computational pipeline to enable standardized analysis across our network and with external collaborators; and iv) independently clinically qualify the multi-modal testing in plasma samples collected in multi-centre prostate cancer clinical trials representative of different stages in the disease spectrum.

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Acute promyelocytic leukemia network: A platform for research developments on long-term survivors

Francesco Lo-Coco, University of Rome "Tor Vergata"

Long-term outcome in adults cured from cancer is a growing area of investigation. Acute promyelocytic leukemia (APL), once regarded as the most rapidly fatal human leukemia, is now curable in 80-90% of patients using targeted agents alone or combined with chemotherapy. However, there is still scarce information on complications occurring in long-term survivors from this tumour. The scope of this project is to create a network of UK, Spanish and Italian scientists working on a shared platform on APL survivors and addressing multiple aspects related to disease- and treatment-related side effects. The project will build upon a pre-existing collaboration among the three teams in this area, implementing an international scientific partnership that contributed important advances in APL diagnosis, classification and therapy. The available national databases will be gathered into a common digital platform that will be integrated by an inventory of biologic specimens. The network including experts on long-term cancer-related complications will focus on: i) cardiovascular, neurologic and metabolic disorders; ii) patient reported quality of life; iii) male and female fertility; iv) development of secondary malignancies (t-MN and solid tumours). The platform will be instrumental in defining and comparing long-term effects of conventional cytotoxic vs. targeted therapies, allowing improvements in healthcare delivery by indicating approaches for continued surveillance and prevention. It will be accessible to external investigators and a patient website will give voice to patient perspectives. Finally, insights generated from this project may have broad relevance to the increasingly growing population of long-term survivors from cancer.

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ACRClerate: Colorectal Cancer Stratified Medicine Network

Owen Sansom, University of Glasgow

Colorectal cancer (CRC) remains the second most common cause of cancer death, and patients with stage 3/4 cancers at diagnosis only have a 10% survival rate at 5 years. Chemotherapy relies on the use of combination cytotoxics against the proliferating tumour epithelium, with novel targeted therapies having disappointing trial results to date.  CRC presents an opportunity for precision medicine as it is common, has known and established driver molecular pathways and pre-treatment molecular stratification is achievable.  Recent advances in sequencing technology and biological models have resulted in paradigm shifts in our understanding of CRC biology, but have failed to significantly impact upon patient care. Indeed, stratified medicine clinical trials such as FOCUS4 have been hampered by the lack of robust preclinical prediction, which have left many therapeutic arms of the trial unfilled.

This Accelerator application brings together a European-wide consortium at the forefront of CRC research to align and interrogate a suite of state-of-the art preclinical models (GEMMs, organoids and PDXs). Our platform will accelerate therapeutic target identification and preclinical validation of new and repurposed drugs, to accomplish rapid clinical translation. Our focus will be to generate and share models of CRC that correlate with human CRC molecular subtypes, to enhance testing of CRC therapeutics in functionally relevant microenvironments. By placing molecular phenotyping and stratification at the heart of this programme we will target biologically plausible pathways known to be dysregulated in CRC, and design molecularly stratified clinical trials to test them, to ensure that no therapeutic opportunities are overlooked.

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Late effects in adolescent and young adult cancer survivors (Lea). A multicentre cohort in Europe

Andrea Ferrari, Fondazione IRCCS - Istituto Nazionale dei Tumori

We aim to develop a research infrastructure to study etiopathogenesis and subsequent outcomes of late effects (second malignant neoplasms, major chronic diseases, health-related (HR) QoL) in adolescents and young adults (AYAs) cancer survivors. AYAs include patients aged 15-29 years at diagnosis. Survivors are those alive > 5 years after diagnosis.

AYAs have different cancer types from children and adults, and the biology of AYA cancers is distinct. AYAs may handle treatment differently and have different late effects. We cannot extrapolate to AYA cancer survivors the late effects reported for childhood or adult cancer survivors.

Late affects might be due to cytotoxic treatment and radiotherapy, but may also reflect shared etiological influences (lifestyle, mental and socio-economic status, host factors, genetic predisposition).

Given their rarity, we will establish a multicentre cohort of AYA cancer survivors from UK, Italian and Spanish expert centres to:

  1. describe multiple late effects,
  2. identify the relative contribution and interac­tion of lifestyle, host genetics and treatment on the development of late effects, and their impact on QoL
  3. develop clinical follow-up guidelines and identify preventive strategies to reduce patients’ morbidity and suffering

We will collect demographics, information on lifestyle, treatment, HRQoL and biological samples. The latter will be essential to evaluate genetic susceptibility and possible biological causes that could enhance the development of late effects. Our cohort will include all cancers diagnosed at AYA age. We will involve cross-disciplinary expert teams and survivors. The infrastructure will facilitate skills transfer between centres and the wider community.

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Accelerating our ability to understand and target complexity and heterogeneity in cancer by developing an accessible, multi-scale microscopy pipeline from in vitro high content discovery to intravital imaging.

Paul French, Imperial College London

Drug resistance and metastasis are major challenges in cancer therapy arising from heterogeneous cellular behaviours within tumours, where initially genetically identical cells can mutate and adapt to diverse microenvironments. This complexity is rarely addressed in standard phenotypic assays that typically measure the average response of cell populations in highly artificial contexts.

We propose to develop and share a new, modular fluorescence imaging pipeline from 2D high content analysis through automated 3D organoid and cell co-culture imaging to intravital microscopy. Utilising advanced capabilities including FLIM/FRET, light sheet microscopy, intravital microscopy and endoscopy, this will enable individual cell behaviours (e.g. signalling processes, metabolic changes, tumour-stroma interactions and invasion) to be mapped in space and time with the potential for bidirectional translation between higher throughput studies in cell culture, amenable to systematic manipulation, and longitudinal in vivo studies. Reverse engineering of in vivo studies towards predictive in vitro assays for screening and mechanistic interrogation would accelerate the identification of new targets and therapeutic approaches by enabling assays to more reproducibly recapitulate the complexity of cancer in situ.

With development based at Imperial and the Crick, this new modular imaging technology would be validated with CRUK centres of excellence in phenotypic screening, organoid culture and assays, and intravital imaging. To widen access, it would be developed with open source software, providing customisable experimentation and integrated data analysis across the pipeline. A PhD cohort would be trained in these technologies to help establish robust and reproducible methodologies and introduce them to the cancer biology community. 

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Virtual BIopsy in OncoLogical ImagiNg – VIOLIN

Andrea Laghi, University of Rome La Sapienza

Purpose: To integrate multimodality, multiparametric imaging biomarkers in a radiomic, feature-based model together with molecular biology and clinical data in order to generate a virtual biopsy system for phenotyping individual tumours.

Materials and Methods: This international multicentre project will involve multidisciplinary expertise. Initially, using rectal, breast and prostate cancer as exemplars, specific imaging features, including radiomic features, from primary and secondary lesions on CT, MRI and PET images, will be retrospectively extracted, analyzed and integrated with clinical and serum biomarker data into an information-rich diagnostic model that will enable the derivation of a tumour “phenotype” that is predictive of treatment response and outcome. Tumour phenotyping in this way also should allow characterization of regional signatures within a tumour, known as tumour “habitats”. Habitat imaging will provide detailed information on tumour heterogeneity, a known poor prognostic indicator for metastasis and recurrence. Multivariate analysis by several machine learning and artificial intelligence approaches will be implemented to develop the nosological maps that will serve as predictive, prognostic and treatment response biomarkers. Subsequently, we will validate this model prospectively in new cohorts of patients. Prospective data collection also will allow documentation of genomic signatures which will be added to the model to increase its performance.

Expected Results: to generate a structural radiogenomic model that will serve as a tumoral virtual biopsy system. This should improve prediction of tumour behaviour, its response to therapy, and patient outcomes, ultimately facilitating a cost-effective and personalized management approach for individual patients.

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An open-access database of cell-free DNA dynamics and T-cell repertoires from 20-years of serial blood samples for identifying cancer-specific signatures in liquid biopsies.

Douglas Easton, University of Cambridge

Liquid biopsies offer potential to diagnose cancer at its earliest stages, when it is most treatable. Two of the most promising blood based biomarkers for early detection are circulating tumour DNA (ctDNA) and T-cell receptor (TCR) repertoire profiling. However, if the potential of ctDNA and TCR biomarkers are to be translated into clinical outcomes, we must identify signals that are highly specific to cancer. This calls for the development of a large-scale resource characterizing the baseline dynamics of somatic variants of cell-free DNA and TCR repertoires from thousands people who do, and crucially who do not, develop cancer. This resource should be openly available to the wider scientific community to accelerate the development of robust ctDNA and TCR repertoire-based tests.

We propose to develop such a resource by using ultra-deep sequencing to track the dynamics of somatic alterations and TCR repertoires from an existing “fossil record” from blood samples banked regularly over a 20-year period from thousands of BRCA1 and BRCA2 mutation carriers at high-risk of cancer and, in addition, to generate a large prospective sample resource from the same individuals. These data will be linked to detailed epidemiological and tumour phenotype data. The rich data resource and analysis tools developed by the assembled team will be hosted on a dedicated “predicting malignancy” website (in a similar manner to NextStrain: http://www.nextstrain.org/) whereby all data, code and prediction metrics will be openly accessible to other researchers. We expect this resource will accelerate the development of robust liquid biopsy based diagnostic tests.

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