• PhD Projects for 2017

Training - PhD Projects for 2017


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Clinical Research Training Fellowships

Project title: Investigating the role of the epigenetic factor MOZ in normal haematopoiesis and leukaemia

  • Lead supervisor: Professor Georges Lacaud
  • Co-supervisor(s): Dr Tim Somervaille
  • Type: Clinical research training fellowship

Project summary: This project aims to deepen our knowledge on the global function and requirement of a histone modifying enzyme, the histone acetyl transferase (HAT) MOZ, in both healthy and pathological haematopoiesis. The gene encoding this epigenetic factor MOZ is altered in a subtype of leukaemia with a dismal prognosis. Previous studies have indicated that this protein is essential for the development of the blood system and this early defect has largely impeded further examination of the relevance of this protein in adult mice. A conditional genetically engineered mouse model will be used to determine the function and requirement for MOZ, and its epigenetic activity, in the normal adult blood system. Similarly the function of MOZ, and its HAT activity, in mouse models of leukaemia will be investigated and these findings correlated in human patient samples. We will also identify the sets of genes controlled by MOZ, or by the oncogenic MOZ fusion protein MOZ-TIF2, in these different contexts. The overarching aim of this study is to determine to what extent MOZ, its HAT activity, or MOZ/MOZ-TIF2 regulated genes, represent potential therapeutic targets and if there is a therapeutic window allowing the elimination of leukaemic cells with minimal impairment of normal haematopoiesis.

Please contact georges.lacaud@cruk.manchester.ac.uk for more information.

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Project title: Developing novel therapeutic approaches to enhance tumour-specific immunity in breast cancer

  • Lead supervisor: Dr Jamie Honeychurch
  • Co-supervisor(s): Dr Anne Armstrong
  • Type: Clinical research training fellowship

Project summary: Metastatic breast cancer remains a leading cause of death in women meaning that there is a clear demand for novel, more effective treatments. An exciting new possibility is to utilise the patient’s own immune system to eradicate malignant disease. Data suggests that infiltration by immune cells, including T-lymphocytes, correlates with better response to chemotherapy, and acts as an independent prognostic indicator in breast cancer patients. Preliminary data from early phase clinical trials targeting immune checkpoints which negatively regulate anti-cancer immune responses also show great promise. Thus, there is currently considerable interest in developing strategies to enhance the generation of anti-tumour immunity.

Histone deacetylase (HDAC) inhibitors are a novel class of compounds, known to induce tumour cell death. However, recent evidence also suggests that they are able to modulate the host immune system and enhance tumour immunogenicity. Pre-clinical evidence demonstrates that combination of HDACi with immuno-regulatory antibodies can enhance therapeutic responses in solid cancers such as melanoma. HDACi are now gaining approval for use in breast cancer, although it remains poorly understood as to how HDACi may modulate immune responses in this setting.

Thus, this project aims to assess whether treatment of breast cancer cells with HDACi can induce immunogenic cell death and immuno-phenotypic changes, which result in the generation of potent tumour-specific CD8+ T-cell responses and how this may be enhanced through targeting of immune checkpoints. The project will utilise pre-clinical orthotopic breast cancer models as well as human cell lines and primary breast tumour. Immunogenic cell death and immune response will be characterised using multi-parameter flow cytometry, immunoblot analysis and a range of immuno-assays. Ultimately, the data generated in this project will be used to guide the development of effective therapeutic regimen which may be translated to clinical application.

Please contact Jamie.Honeychurch@ics.manchester.ac.uk for more information.

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Project title: A bench to bedside workflow for repurposing drugs: Targeting the procoagulant systemic and tumour environment in breast cancer

  • Lead supervisor: Miss Cliona Kirwan
  • Co-supervisor(s): Dr Robert Clarke
  • Type: Clinical research training fellowship

Project summary: Cancer patients who develop venous thromboembolism (VTE) have a 3-fold lower cancer survival than those remaining VTE-free, irrespective of cancer stage. In breast cancer, hypercoagulability correlates with presence of circulating tumour cells (CTCs) and reduced survival, highlighting the role of coagulation in facilitating dissemination and survival of CTCs.

Tumour stroma resembles a non-healing wound. The primary phase of wound healing is leakage of extrinsic clotting factors and blood components to instigate clot formation. This procoagulant environment creates a permissive milieu for extravasation, extracellular remodelling, cell differentiation and angiogenesis. Tissue factor (TF, initiator of extrinsic clotting cascade) induces apoptosis resistance, tumour cell migration and invasion. Downstream of TF, thrombin induces angiogenesis, proliferation, invasion and induction of cancer associated fibroblasts (CAFs), which promote tumour growth and angiogenesis. In breast cancer, TF, thrombin and their receptors PAR2 and 1, have increased expression in CAFs compared to normal breast fibroblasts, with further increased expression in poor prognosis breast cancer phenotypes (ER-/Her2+/high Ki67).

Rivaroxaban is a rapidly-acting, targeted (anti-Factor Xa) oral anticoagulant prescribed for thromboprophylaxis and for stroke prevention in atrial fibrillation. In vitro, the stimulatory effect of exogenous procoagulants and procoagulant CAFs on breast cancer growth is abrogated by Rivaroxaban. The effects of Rivaroxaban on early breast cancer are currently being investigated in a short-term pre-operative randomised clinical trial (TIP, ISRCTN14785273).

This PhD investigates the effects of the extrinsic clotting system and Rivaroxaban on breast cancer in a comprehensive bench-to-bedside workflow. In vitro studies will determine the effects of procoagulant CAFs on cancer cell proliferation, migration and invasion. In vivo studies will use cell lines and patient derived samples (PDX) in mouse models to investigate tumour growth and identify novel biomarkers of tumour response, in a procoagulant and anticoagulant (Rivaroxaban) setting. These biomarkers will be validated in archived clinical specimens from the TIP trial.

Please contact cliona.kirwan@manchester.ac.uk for more information.

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Project title: Personalised Chemoprevention of Breast Cancer

  • Lead supervisor: Dr Sacha Howell
  • Co-supervisor(s): Dr Robert Clarke and Dr Michael Sherratt
  • Type: Clinical research training fellowship

Project summary: Tamoxifen (TAM) reduce the incidence of breast cancer (BC) by approximately 40%. However, all of the reduction in risk is seen in women who experience a reduction in mammographic density during the first year of treatment. Mammographic density is thus a powerful predictive biomarker of resistance to chemoprevention with TAM. We have recently shown that mammographic density is primarily associated with collagen organisation rather than abundance. Such periductal fibrillar collagen increases tissue stiffness and is a key mediator of mammary carcinogenesis in rodents. In this project we seek to identify the molecular mechanisms underlying mammographic density and to investigate how they change in response to TAM. By examining the patterns of response in responding vs resistant breast tissue we hope to identify novel agents that will reverse resistance and thus prevent more cases of BC in the future.

Women commencing tamoxifen chemoprevention will have biopsies of the breast prior to and after 1 month of treatment. RNA-Seq bioinformatic analysis will identify the gene networks differentially expressed in resistant vs sensitive breasts. In collaboration with the CRUK MI Drug Discovery Unit chemo-informatic screening of the FDA panel of drugs will identify lead compounds for repurposing into prevention. Proteomic analysis will identify differential protein composition and the relationship between TAM sensitivity and tissue micro-structural and mechanical stiffness will be characterised by atomic force microscopy and micro-computed tomography (microCT). An architecturally intact whole tissue in vitro culture model of normal breast tissue will be developed that faithfully recapitulates in vitro the changes in gene expression seen in response to TAM in vivo. The candidate chemoprevention agents will then be tested in this model with the aim of identifying a lead candidate for translation in to a pilot prevention trial.

Please contact sacha.howell@manchester.ac.uk or Sacha.Howell@christie.nhs.uk for more information.

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Project title: Aged skin homeostasis and skin cancer prevention

  • Lead supervisor: Dr Amaya Viros
  • Co-supervisor(s): Dr Claus Jorgensen
  • Type: Clinical Research Training Fellow – Molecular Pathology post

Project summary: The skin is a complex microenvironment divided into the epidermis, which defends humans from the environment, and the dermis and hypodermis, connective and adipose tissue below the epidermal basement membrane. In the epidermis, different cell types interplay generating a cooperative physiology. The predominant cell types are keratinocytes and melanocytes, which are physically connected; and there is a well-established bidirectional communication between melanocytes and keratinocytes in homeostasis1.

Recent work has revealed that aged, sun-exposed skin accrues DNA damage in cancer-driving genes2 despite the skin retaining normal morphology. Importantly, some of the more prevalent, selected and clonally expanded mutations present in aged skin affect TP53 and NOTCH1, genes that are critical to cutaneous function and homeostasis1,3. When skin is exposed to ultraviolet radiation (UVR), TP53 is expressed in keratinocytes, which signals to adjacent melanocytes to produce melanin, which is then transferred back to keratinocytes to afford further protection from UVR1. Thus, the TP53-dependent tanning response depends on correct communication between different cell types. By contrast, Notch signaling regulates keratinocyte stem cell differentiation and the replenishment of the upper layers of the epidermis that offer a skin barrier from the environment.

The elderly population has the highest incidence and mortality of melanoma and non-melanoma skin cancers, and old patients with cutaneous squamous cell carcinoma are at highest risk for melanoma and vice versa. We aim to understand how abnormal cellular communication in the aged, damaged epidermis impacts cutaneous function and the early stages of skin cancer development, studying the disruption to the keratinocyte and melanocyte communication in old skin using in vitro, proteomic and in vivo validation studies. We seek to gain insight that will provide new rationales for skin cancer prevention strategies and follow up care in the elderly population.

Please contact Amaya.Viros@cruk.manchester.ac.uk for more information.

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