Timothy Hughes

Timothy Hughes

Adelaide Medical School

Faculty of Health and Medical Sciences

Eligible to supervise Masters and PhD - email supervisor to discuss availability.


Professor Timothy P. Hughes, MD, FRACP, FRCPA, MBBS, FAAHMS - TITLEHOLDER.
Professor Timothy Hughes is Precision Medicine Theme Leader at SAHMRI
Professor Timothy Hughes is the Precision Medicine Theme Leader at SAHMRI; Beat Cancer Professor at the University of Adelaide and Consultant Haematologist at the RAH. He is also Chair of the International Chronic Myeloid Leukemia Foundation (iCMLf); an inaugural Fellow of the Australian Academy of Health and Medical Sciences (AAHMS)

Professor Hughes had a significant leadership role in the establishment of the molecular response criteria and kinase domain mutation screening guidelines that are used world-wide to monitor response and resistance in chronic myeloid leukaemia (CML). He has been a principal investigator on many of the key Global and Australian CML trials that have shaped the way tyrosine-kinase inhibitors (TKI's) are selected and sequenced. He has been a leader in the area of treatment-free remission (TFR) and influential in the recent recommendations to make TFR a mainstream goal of therapy. He has published over 300 papers with over 46,000 citations.

Chronic Myeloid Leukaemia (CML) - Precision Medicine Theme, SAHMRI

Lead: Professor Tim Hughes.

Brief description of research area:

The treatment of chronic myeloid leukaemia (CML) has been one of the most remarkable cancer success stories this century, heralding the widespread application of small molecules to target oncogenic kinases. Insights from CML research in this era have provided guidance for the targeted therapy programs in many other cancers. The improvement in 10-year survival for CML patients from 20% in the 1990s to over 80% today has been achieved with the clinical application of tyrosine kinase inhibitor (TKI) therapy targeting Bcr­Abl. Despite the improvements in outcomes achieved with TKI therapy, major challenges still confront the CML clinician. Transformation to blast crisis is still seen in -10%, similar numbers are resistant to all TKls and only -50% overall achieve deep molecular responses (DMR). Furtherme>re most CML patients will remain dependent on TKI therapy for life with current approaches. As well as the massive cost burden, this long­term dependence on TKI therapy often leads to impaired quality of life and, in some cases, significant organ damage. Pioneering work from the Bordeaux and Adelaide trial groups has shown that around half of the patients who achieve stable DMR can cease TKI therapy without evidence of molecular relapse, even with long-term follow-up ( defined as achieving treatment-free remission -TFR). By contrast the other half have molecular evidence of recurrence, usually within 6 months of stopping, and have to restart TKI therapy. We have made excellent progress in understanding some of the key drivers of DMR and TFR and are already translating some of these findings into clinical trials to expand opportunity for these optimal outcomes. This emerging knowledge will provide urgently needed criterio for safe TKI cessation and guide the design of future trials to maximise TFR with consequent major benefits for many CML patients. CML is projected to become the most prevalent leukaemia by 2040, so for f'he thousands of CML patients in Australia who are facing lifelong dependence on expensive and debilitating therapy, support for this work is critical.

Research Project 1 – Dr Ilaria Pagani

Title: Identifying and exploiting metabolic dependencies for improved therapeutic outcomes in chronic myeloid leukaemia.

Project description:

While the treatment of BCR-ABL1 driven chronic myeloid leukaemia (CML) with tyrosine kinase inhibitors (TKI) has been a success story of modern medicine, not all patients respond optimally, with a small but significant minority progressing to fatal blast crisis.

The inability of TKIs to eradicate leukaemic stem and progenitor cells (LSPC) provides a potential pool for subsequent relapse. This is exemplified by the dependence of most CML patients on lifelong TKI treatment, even in patients who achieve molecular responses. Universally, the presence of an activated tyrosine kinase drives metabolic changes, and the perturbation of these metabolic pathways provides potential avenues for exploration of therapeutic interventions. Targeting metabolic pathways may potentiate the effect of TKI therapies particularly in the LSPC compartment.

The aim of the project will be to investigate the metabolic pathways that exists within normal haematopoietic cells (important knowledge to avoid toxicity), and in LSPC including cases sensitive and resistant to TKIs to enable a clear understanding of whether the metabolome of LSPC can be targeted to sensitise this pool to TKI therapy.

This novel and innovative approach will likely provide a combinational treatment strategy with greater efficacy than current approaches, specifically in CML blast crisis.

 

Project 2 – Dr Ilaria Pagani

Title: Monitoring of minimal residual disease on chronic myeloid leukaemia patients in a setting of treatment free remission.

For patients who have achieved deep molecular responses and have minimal residual disease after treatment, the new goal for clinicians today is to identify candidate patients that can safely cease TKI therapy achieving treatment free remission (TFR). It is estimated that approximately 50% of CML patients may be eligible to stop TKIs, however half of them experience molecular relapse, usually within 6 months, and have to restart therapy. CML is projected to become the most prevalent leukaemia  by 2040, therefore is critical to maximise the number of patients achieving TFR. However, unravelling the critical mediators of TFR is a major challenge.

The aim of the project will be to characterise the residual leukaemia population in TFR patients, and understand why some patients relapse and others don’t. One possible line of inquiry involves identifying the lineage of residual CML cells, through a highly sensitive DNA approach. This will involve a characterization of the genomic breakpoint and the development of a patient-specific assay to monitor residual leukaemia on sorted cell populations.

 

Projects available for:

Third Year / Honours / Mphil / PhD

Location:

SAHMRI

Research project start:

Semester 1

Semester 2

Semester 1 and 2

 

Special requirements:

Police Clearance

 

Chronic Myeloid Leukaemia (CML) - Precision Medicine Theme, SAHMRI

Lead: Professor Tim Hughes.

Team: Dr David Yeung, Dr Liu Lu and Dr Ilaria Pagani.

Brief description of research area.

The treatment of chronic myeloid leukaemia (CML) has been one of the most remarkable cancer success stories this century. The improvement in 10 year survival for CML patients from 20% in 1990s to over 80% today has been achieved through the clinical application of tyrosine kinase inhibitors (TKI) therapy targeting the oncoprotein BCR-ABL1. However, despite the improvements in outcomes, around 30% of CML patients respond poorly to TKI therapy. Even among those patients who respond well, many will remain dependent on TKI therapy for life, leading to a massive cost burden, organ damage, and impairment of quality of life. The current focus of research in CML centres on the following issues:

  1. Identification of patients at risk of failing frontline therapy and working out whether these patients may benefit from novel anti-CML therapy. An inter-related question concerns patients who have suboptimal responses – can adding novel agents to TKI therapy further improve disease response?
  2. Patients who have responded well to TKIs usually have undetectable circulating disease. Some patients in this groups can stop therapy without disease recurrence, whilst others experience rapid relapse. Identifying differences between these patients may hold the key to minimising the proportion of patients who need life long therapy.

Research Project 1

Title: Investigating the efficacy of a combination of TKI and a novel allosteric inhibitor asciminib in chronic myeloid leukaemia
 

Project description:

Clinical trials for the treatment of CML are currently underway using asciminib (ABL001), an allosteric inhibitor, alone and in combination with ATP-competitive tyrosine kinase inhibitors (TKIs: imatinib, nilotinib or dasatinib), to inhibit the constitutively active tyrosine kinase Bcr-Abl. The aims of this project are:

  1. Investigation of the synergistic effect of the combination of TKI and asciminib.
  2. Understand the signalling pathway changes in BCR-ABL+ cell lines and CML patient cells when combination therapy is given.
  3. Generation of resistant cell lines in the laboratory setting. This provides a useful tool for predicting and studying patient responses in vivo.

Understanding how these drugs work in synergy will enhance our ability to predict whether patients are likely to respond to combination therapy, and clarify ways to maximise synergism between these agents. In this project, BCR-ABL1+ cell lines will be exposed long term to gradually increasing concentrations of asciminib in combination with TKI. Mechanisms of resistance will be interrogated during resistance development and once overt resistance is observed. We will then examine mechanisms of treatment resistance in vitro, in an attempt to predict emergent disease resistance mechanisms that may arise.

 Projects available for: This project can be adapted for Hons, Mphil and PhD.

Location:

SAHMRI

Research project start:

Semester 1 and 2

Special requirements:

Police Clearance

 

 

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  • Current Higher Degree by Research Supervision (University of Adelaide)

    Date Role Research Topic Program Degree Type Student Load Student Name
    2019 Principal Supervisor Evaluating the mechanism of resistance in Bcr-Abl positive leukemia cells Doctor of Philosophy Doctorate Full Time Mr Govinda Poudel
  • Past Higher Degree by Research Supervision (University of Adelaide)

    Date Role Research Topic Program Degree Type Student Load Student Name
    2012 - 2014 Principal Supervisor The role of cytokines in governing the expansion of the T315I mutation in Chronic myeloid leukaemia Master of Philosophy (Medical Science) Master Full Time Dr Oi-Lin Lee
    2012 - 2016 Co-Supervisor In Vitro Investigation of Intracellular Ponatinib Transport and Modeling Ponatinib Resistence in BCR-ABL1+ Cell Lines: Implications for Therapeutic Strategies Doctor of Philosophy Doctorate Full Time Miss Liu Lu
    2012 - 2016 Co-Supervisor Prognostic Markers Associated With Tyrosine Kinase Inhibitor Treatment Response and Maintenance of Treatment Free Remission in Chronic Myeloid Leukaemia Doctor of Philosophy Doctorate Full Time Dr David Yeung
    2010 - 2014 Principal Supervisor Assessment of Critical Survival Mechanisms Exploited by BCR-ABL1+ Cells to Evade Tyrosine Kinase Inhibitor-Induced Death; Determination of Novel Therapeutic Targets in Chronic Myeloid Leukaemia Doctor of Philosophy Doctorate Full Time Miss Lisa Schafranek
    2010 - 2014 Co-Supervisor Defining CP-CML patient subsets associated with poor imatinib uptake and response Doctor of Philosophy Doctorate Full Time Mr Dale Benjamin Watkins
    2009 - 2013 Principal Supervisor Nilotinib Efflux and Resistance Development: The Effects of Combination and Concomitant Therapies on the Transport and Efficacy of Nilotinib Doctor of Philosophy Doctorate Full Time Ms Laura Eadie
    2008 - 2013 Principal Supervisor Investigating Drugs that Enhance Imatinib Uptake and Factors which Contribute to the Functional Activity of OCT-1 in CML Cells Doctor of Philosophy Doctorate Full Time Miss Jueqiong Wang
    2008 - 2012 Principal Supervisor TKI Resistance in CML Cell Lines: Investigating Resistance Pathways Doctor of Philosophy Doctorate Full Time Mrs Carine Tang
    2007 - 2011 Principal Supervisor Cell Lineage, Cell Maturity and BCR-ABL: Factors Which Influence Imatinib Uptake in Chronic Myeloid Leukaemia Doctor of Philosophy Doctorate Full Time Ms Jane Engler
    2006 - 2009 Principal Supervisor Minimal Residual Disease in Chronic Myeloid Leukaemia after Imatinib Treatment Doctor of Philosophy Doctorate Full Time Dr David Ross
    2005 - 2009 Co-Supervisor Investigating the Effects of ABL Kinase Inhibitors on the Signalling and Function of Normal Leukocytes and Leukemic Cells Doctor of Philosophy Doctorate Full Time Mr Stephen Blake
    2004 - 2008 Principal Supervisor Factors which Impact on the Response of CML Patients to ABL Kinase Inhibitor Therapy: A Study of Imatinib and Nilotinib Doctor of Philosophy Doctorate Part Time Prof Deborah Lee White
    2001 - 2006 Co-Supervisor GM-CSF Protection of CML CD34+ Cells from the Inhibitory Effect of Imatinib Doctor of Philosophy Doctorate Full Time Mr Pongtep Viboonjuntra

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