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 52,000 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.

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 available for: Honours / Mphil / PhD
Location: SAHMRI
Research project start: Semester 1

Special requirements: Police Clearance

 

Research 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.

Project available for: Honours / Mphil / PhD
Location: SAHMRI
Research project start: Semester 1

Special requirements: Police Clearance

 

Research Project 3 - Dr David Yeung, Dr Liu Lu and Dr Ilaria Pagani

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

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.

Project available for: Honours / Mphil / PhD
Location: SAHMRI
Research project start: Semester 1

Special requirements: Police Clearance

 

Research Project 4 - Dr Chung Kok

Title: Developing an artificial intelligence-based algorithm to enable a risk-adapted approach to frontline therapy in chronic myeloid leukaemia (CML).

Chronic myeloid leukaemia (CML) is a model cancer for targeted therapy, driven by an activated mutant kinase. BCR-ABL1 is both necessary and sufficient to cause CML, through the expression of the constitutively active tyrosine kinase Bcr-Abl, targetable using tyrosine kinase inhibitors (TKIs). Despite the excellent progress we have made, major challenges remain. Even with our current choice of 5 TKIs, 15-20% respond poorly to TKI therapy and half of these patients will die from CML-related causes. Approximately 10% patients still fail to respond despite receiving second generation TKIs frontline, which are more potent than the first generation TKI imatinib. This very high-risk (VHR) group would likely be more effectively managed with a “dual targeted” approach from the start of therapy. For this reason, we have focused on developing baseline predictors of treatment failure to first and second generation TKIs, so that subsequent adverse outcomes can be minimized in high-risk cases by using a more intensive approach upfront. However, this approach would not be beneficial for most patients - adding toxicity without clinical benefit in the low-risk (LR) setting. Predictors that are capable of identifying the patients most likely to benefit from the use of a more potent TKI (high-risk (HR)) and the patients who will do poorly with any of the currently available TKIs (VHR) are urgently needed. We have previously published several bioassays that are predictive of response to frontline therapy in CML, however no single assay allows a sufficiently precise classification of patient risk groups to be clinically actionable.

We propose that the most effective approach will be to utilise all of these biomarkers to develop an artificial intelligence (AI) based algorithm to guide front-line therapy. This will enable up-front triaging of CML patients, tailoring therapy to the most appropriate risk-adapted approach. The theme of this proposal, therefore, is maximising the clinical effectiveness of rationally targeted therapies in CML.

HYPOTHESES

High-risk and very high-risk patients can be identified using an artificial-intelligence derived predictive algorithm based on informative biomarkers to

  1. enable optimal risk-adapted treatment decisions and
  2. maximise the clinical effectiveness of rationally targeted therapies.

SPECIFIC AIMS

Aim 1. Develop and validate an artificial intelligence (AI) based algorithm by integrating clinical and laboratory information to predict therapy-specific risk of failure in CML

Aim 2. Design interventions in patients identified as very high-risk based on pathways identified as potential actionable targets

Aim 3. Explore the potential use of the AI algorithm in a dynamic setting to enhance clinical utility

Project available for: Honours / Mphil / PhD
Location: SAHMRI
Research project start: Semester 1

Special requirements: Police Clearance

 

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  • Appointments

    Date Position Institution name
    2019 Precision Medicine Theme Leader South Australian Health and Medical Research Institute (SAHMRI)
    2015 - 2020 Chair SA Comprehensive Cancer Collaborative (SACCC)
    2015 - 2018 Cancer Theme Leader South Australian Health and Medical Research Institute
    2013 Cancer Council Professor SAHMRI
    2013 Chair International CML Foundation (iCMLf)
    2008 Co-founder International CML Foundation (iCMLf)
    2008 - 2014 Head, Department of Haematology SA Pathology
    1993 Consultant Haematologist, , Division of Haematology Royal Adelaide Hospital & SA Pathology
    1991 - 1993 Post-Doctoral Fellow Howard Hughes Medical Institute, UCLA, California USA
    1989 - 1991 Leukaemia Research Fellow Adult Leukaemia Research Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London UK
    1987 - 1988 Haematology Registrar Prince Henry Hospital, Sydney
  • Awards and Achievements

    Date Type Title Institution Name Country Amount
    2019 Award Ramaciotti Medal for Excellence in Biomedical Research Ramaciotti Australia
    2018 Achievement Clarivate top 1% of cited scientists in their field internationally Clarivate Australia
    2017 Award GSK Award for Research Excellence, Research Australia Health & Medical Research Awards Research Australia Health & Medical Research Australia
    2017 Award Goldman Prize, International CML Foundation (iCMLf) – outstanding lifetime contribution to the management of CML International CML Foundation (iCMLf) Australia
    2015 Research Award CIC on Top Ranked NHMRC Program Grant assessed in 2013 NHMRC Australia
    2015 Fellowship Inaugural Fellow of the Australian Academy of Health and Medical Sciences (AAHMS) Australian Academy of Health and Medical Sciences (AAHMS) Australia
    2015 Achievement Carl De Gruchy Award, HSANZ for lifetime achievements HSANZ Australia
    2015 Award The World’s Most Influential Scientific Minds 2015, “Clinical Medicine” Thomson Reuters Australia
    2014 Award Top 1% of highly cited Scientists in 2014 Thomson Reuters Australia
    2011 Research Award NHMRC Ten of the Best Research Projects NHMRC Australia
  • Education

    Date Institution name Country Title
    1993 University of New South Wales Australia Doctor of Medicine
    1988 Fellowship of the Royal Australasian College of Physicians Australia FRACP
    1988 Fellowship of the Royal College of Pathologists of Australia Australia FRCPA
    1981 The University of New South Wales Australia MBBS Hons
  • Research Interests

2021 - 2026  Medical Research Future Fund (MRFF) - Research Grants - Precision Medicine for Chronic Myelomonocytic Leukaemia: Phase II Trial Studying the Efficacy of Lenzilumab or High Dose Ascorbate plus Azacitidine Based on Molecular Profiling Compared to Risk-matched Historical Cohort.

2020   Cancer Council SA Beat Cancer Research Project Grant. Developing an artificial intelligence-based algorithm to enable a risk-adapted approach to frontline therapy in chronic myeloid leukaemia (CML)

2018  Australian Cancer Research Fund (ACRF) – Infrastructure: ACRF Centre for Integrated Cancer Systems Biology (ACRFCICSB).

2018 - 2021   NHMRC Project Grant. Chronic Myeloid Leukaemia: Changing the treatment paradigm

2018 - 2022   NHMRC. Principal Research Fellowship. Improving Leukaemia Outcomes

2016 – 2018  Leukemia & Lymphoma Society (US). Translational Research Program Grant

2015 - 2019  NHMRC Program Grant: Cytokine dysregulation in leukaemia      

2015  Bristol Meyer Squibb Australia. Correlative Science Proposal Associated with the DIRECT study.  

2014 - 2017  Determining the prerequisites for the achievement of treatment-free remission in chronic myeloid leukaemia to facilitate the development of new therapeutic approaches with curative intent.   

2014  Bristol Meyer Squibb Australia. Correlative Science Proposal Associated with the REGALLIA clinical trial registry.   

2014  Bristol Meyer Squibb Australia. Correlative Science Proposal Associated with the REGALLIA clinical trial registry.  

2014  Novartis Australia. Correlative Science Proposal Associated with the ENESTxtnd clinical trial.    

2013 - 2015  Screening for recently defined genetic lesions in poor risk adult and childhood ALL, and developing treatment approaches to target causative pathways

2013 - 2017  NHMRC. Practitioner Fellowship   

2012 - 2014  NHMRC. Assessment of markers of genomic instability for the prediction of treatment response of chronic myeloid leukaemia    

2012 – 2014 NHMRC.  Characterisation of a new poor-risk sub-category of chronic phase chronic myeloid leukaemia    

2012 – 2014  NHMRC.  Development of a treatment algorithm for kinase inhibitor therapy in CML   

2011 - 2012  Leukaemia Foundation of Australia. Developing a gene signature to predict the optimal front-line kinase inhibitor for CP-CML patients

2011 - 2013  Novartis Pharmaceuticals Australia. Correlative Science Proposal Associated with the ENESTxtnd clinical trial.     

2011  Novartis Pharmaceuticals Australia. Correlative Science Associated with TIDELII Clinical Trial – expansion of patient numbers.         

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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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