Unravelling biological heterogeneity in neoplastic myeloproliferative stem cells
Lead Research Organisation:
University of Oxford
Department Name: Weatherall Inst of Molecular Medicine
Abstract
One of the key challenges in cancer biology is to better understand why patients with the same subtype of cancer show remarkably different responses to treatment. One emerging explanation for this observation is that not all cells within a specific cancer behave in the same way. This partly reflects variability in the types of DNA damage or mutation(s) carried within each cell but might also be related to the type of cell which carries the mutation(s) as only some cancer cells, known as cancer stem cells (CSCs), are able to propagate disease relapse in patients. Our ability to understand the biology underlieing this variability is limited as most methods of analysing cancer cells involve pooling large populations of cancer cells, often many millions of cells, and thus the variability within individual cells is lost. This is important as the cancer cell which ultimately cause relapse following treatment may in some cases only account for a small proportion of cancer cells at diagnosis; akin to "finding a needle in a haystack". One approach that can be used to overcome this is to analyse single cancer cells. Whilst single cell analysis is not a new approach, previous methods have been limited by issues of sensitivity and technical variation making it difficult to understand which of the findings are "real" and which simply reflect "noise" in the testing process. An exciting new technology, introduced to the WIMM by AJM, allows analysis of single cancer cells, thus overcoming the above limitations. This technology will allow both mutation testing and analysis of the expression of genes all from the same cell, thus allowing presence of specific mutations to be correlated with the biology of single cells and also, most importantly, outcome of the patient.
During this fellowship, AJM will develop and apply single cell analysis to a particular form of blood cancer known as myeloproliferative neoplams (MPN). Chronic myeloid leukaemia (CML) is a type of MPN which can now be highly effectively treated with a drug called imatinib. Whilst imatinib induces remissions in almost all patients with CML, the disease remains detectable in the large majority of patients due to the presence of imatinib resistant CML-CSCs. As these CML-CSCs are "hidden" amongst the normal bone marrow stem cells, single cell analysis is required to distinguish CML-CSCs form their normal counterparts in order to understand how these CSCs might be more effectively treated. A similar strategy will be used to investigate high-risk MPN patients receiving novel JAK2 inhibitor treatment, an exciting new treatment for patients with certain types of MPN. Whilst JAK2 inhibitor treatment induces symptomatic improvement in patients, it is also clear that MPN-CSCs are largely unaffected by the treatment and single cell analysis of MPN-CSCs will help to understand the reasons for this. Importantly, whilst these studies are specific to MPNs, as this is the area of clinical medicine in which AJM specialises, the findings of these studies will also be more broadly applicable across cancer biology.
In order to understand how different types of cells respond to the acquisition of specific cancer causing mutations, a complementary approach is required. AJM will develop a number of model systems allowing the selective targeting of combinations of different MPN causing mutations to different types of bone marrow stem cells. It is possible, for example, that the same mutation may behave very differently depending on the cell type which originally acquires the mutation, thus influencing influence the resulting disease type, even though the mutation might remain the same.
Through application of these state of the art cell and molecular biology techniques in humans and model systems, these studies will provide a substantial contribution to the understanding of MPN-CSCs and the findings will highlight the clinical applicability of single cell technology across cancer biology.
During this fellowship, AJM will develop and apply single cell analysis to a particular form of blood cancer known as myeloproliferative neoplams (MPN). Chronic myeloid leukaemia (CML) is a type of MPN which can now be highly effectively treated with a drug called imatinib. Whilst imatinib induces remissions in almost all patients with CML, the disease remains detectable in the large majority of patients due to the presence of imatinib resistant CML-CSCs. As these CML-CSCs are "hidden" amongst the normal bone marrow stem cells, single cell analysis is required to distinguish CML-CSCs form their normal counterparts in order to understand how these CSCs might be more effectively treated. A similar strategy will be used to investigate high-risk MPN patients receiving novel JAK2 inhibitor treatment, an exciting new treatment for patients with certain types of MPN. Whilst JAK2 inhibitor treatment induces symptomatic improvement in patients, it is also clear that MPN-CSCs are largely unaffected by the treatment and single cell analysis of MPN-CSCs will help to understand the reasons for this. Importantly, whilst these studies are specific to MPNs, as this is the area of clinical medicine in which AJM specialises, the findings of these studies will also be more broadly applicable across cancer biology.
In order to understand how different types of cells respond to the acquisition of specific cancer causing mutations, a complementary approach is required. AJM will develop a number of model systems allowing the selective targeting of combinations of different MPN causing mutations to different types of bone marrow stem cells. It is possible, for example, that the same mutation may behave very differently depending on the cell type which originally acquires the mutation, thus influencing influence the resulting disease type, even though the mutation might remain the same.
Through application of these state of the art cell and molecular biology techniques in humans and model systems, these studies will provide a substantial contribution to the understanding of MPN-CSCs and the findings will highlight the clinical applicability of single cell technology across cancer biology.
Technical Summary
In haematologic malignancies, and cancers in general, there is increasing appreciation of complex subclonal genetic structures in cancer stem cell populations which may intersect with the differentiation and quiescence state of the cells and dictate variability in self-renewal and chemoresistance. To unravel this complexity requires robust single cell analysis in a high throughput manner. The Fluidigm C1 mircofluidics Platform allows capture of single primary cells and the interrogation of RNA and DNA content by multiplex PCR or through whole transcriptome/genome analysis, all at the single cell level. The technology will be used to define single cell heterogeneity in human and mouse malignant stem and progenitor populations to allow us to better define, purify and therapeuticlaly target these critical populations of cells. Furthermore, the novel mouse models generated as part of the fellowship, allowing specific targeting of different stem cell subsets with oncogenic mutations, is a further major technical advance in the field.
Both these techniques are central to the aspiration to develop stratified medicine in the UK, using state of the art genomic approaches to dissect heterogeneity in patients and to understand this heterogeneity in model systems.
Both these techniques are central to the aspiration to develop stratified medicine in the UK, using state of the art genomic approaches to dissect heterogeneity in patients and to understand this heterogeneity in model systems.
Planned Impact
This research will have a clear beneficial impact well beyond the immediate professional circle carrying out similar research. For example:
1. Economic impact: It is estimated that tyrosine kinase inhibitor (TKI) therapy for patients with chronic myeloid leukaemia (CML) will cost the health service between £2-3 billion over the coming 10 years. Thus, it is of major economic importance to be able to identify which patients might be able to safely stop TKI treatment. In those patients with TKI resistant CML-SCs, it is important to identify the pathways propagating these cells in order that they might be eradicated allowing therapy discontinuation. This is a key part of the "pathway to cure" developed by Novartis, the pharmaceutical company which manufactures imatinib and nilotinib, two NICE approved TKIs.
2. People: As outlined in the communication plan, AJM has considerable experience of disseminating scientific research findings more broadly with the public including schools and also for inspiring young potential scientists.
3. New processes: Single cell technology is likely to develop rapidly over the coming years. This will potentially have a key role in stratified medicine particularly in cancer biology and this fellowship will place AJM and the MRC at the forefront of these developments. As an example, AJM introduced the Fluidigm BioMark system to the WIMM and HSCB laboratory in 2011. We were the first to use this technology in Europe for low cell number analysis. We are now the reference center for BioMark in Europe and AJM regularly receives requests for information on our experience of using this platform and requests for collaboration, as illustrated by the research outputs listed on AJM's CV. As a direct result of these interactions, a number of other research groups (at least 4) have introduced the Fluidigm BioMark system in their center. The Fluidigm C1 microfluidics Platform allows capture of single primary cells and the interrogation of RNA and DNA content by multiplex PCR or through whole transcriptome/genome analysis, all at the single cell level. The technology will be used to define single cell heterogeneity in human and mouse malignant stem and progenitor populations to allow us to better define, purify and therapeutically target these critical populations of cells. It is anticipated that this will generate much more interest even than the BioMark system, with benefits for many other groups interested in working with genomics at the single cell level in the UK and further afield. This fruitful interaction with Fluidigm (the manufacturer of the BioMark and C1-prep systems) has clear and mutual beneficial impact.
4. New products: The access to serial samples from patients treated on innovate clinical trials, for example the MAJIC study assessing the role of ruxolitinib therapy (made by Novartis) in high-risk patients with myeloproliferative neoplasms will help identify specific patients/groups of patients who are likely to benefit from these new treatments, accelrating introduction of these new treatments with benefits for patients, the health service and industry alike. A number of other pharmaceutical companies have JAK2 inhibitor treatments in development (Sanofi Aventis, Cellular Therapeutics, Gilead) and AJM is already in the process of developing fruitful collaborations with these industry partners which will be further facilitated by the pioneering work outlined in this fellowship proposal.
5. Inward investment: AJM has developed a number of collaborations with industry on related but distinct projects. Industry stakeholders are extremely interested in single cell technology but do not have the skills or expertise to analyse, interpret or apply this emerging new technology. Thus, it is anticipated that a number of collaborations with industry will arise as a result of developing single cell expertise in the WIMM led by AJM
1. Economic impact: It is estimated that tyrosine kinase inhibitor (TKI) therapy for patients with chronic myeloid leukaemia (CML) will cost the health service between £2-3 billion over the coming 10 years. Thus, it is of major economic importance to be able to identify which patients might be able to safely stop TKI treatment. In those patients with TKI resistant CML-SCs, it is important to identify the pathways propagating these cells in order that they might be eradicated allowing therapy discontinuation. This is a key part of the "pathway to cure" developed by Novartis, the pharmaceutical company which manufactures imatinib and nilotinib, two NICE approved TKIs.
2. People: As outlined in the communication plan, AJM has considerable experience of disseminating scientific research findings more broadly with the public including schools and also for inspiring young potential scientists.
3. New processes: Single cell technology is likely to develop rapidly over the coming years. This will potentially have a key role in stratified medicine particularly in cancer biology and this fellowship will place AJM and the MRC at the forefront of these developments. As an example, AJM introduced the Fluidigm BioMark system to the WIMM and HSCB laboratory in 2011. We were the first to use this technology in Europe for low cell number analysis. We are now the reference center for BioMark in Europe and AJM regularly receives requests for information on our experience of using this platform and requests for collaboration, as illustrated by the research outputs listed on AJM's CV. As a direct result of these interactions, a number of other research groups (at least 4) have introduced the Fluidigm BioMark system in their center. The Fluidigm C1 microfluidics Platform allows capture of single primary cells and the interrogation of RNA and DNA content by multiplex PCR or through whole transcriptome/genome analysis, all at the single cell level. The technology will be used to define single cell heterogeneity in human and mouse malignant stem and progenitor populations to allow us to better define, purify and therapeutically target these critical populations of cells. It is anticipated that this will generate much more interest even than the BioMark system, with benefits for many other groups interested in working with genomics at the single cell level in the UK and further afield. This fruitful interaction with Fluidigm (the manufacturer of the BioMark and C1-prep systems) has clear and mutual beneficial impact.
4. New products: The access to serial samples from patients treated on innovate clinical trials, for example the MAJIC study assessing the role of ruxolitinib therapy (made by Novartis) in high-risk patients with myeloproliferative neoplasms will help identify specific patients/groups of patients who are likely to benefit from these new treatments, accelrating introduction of these new treatments with benefits for patients, the health service and industry alike. A number of other pharmaceutical companies have JAK2 inhibitor treatments in development (Sanofi Aventis, Cellular Therapeutics, Gilead) and AJM is already in the process of developing fruitful collaborations with these industry partners which will be further facilitated by the pioneering work outlined in this fellowship proposal.
5. Inward investment: AJM has developed a number of collaborations with industry on related but distinct projects. Industry stakeholders are extremely interested in single cell technology but do not have the skills or expertise to analyse, interpret or apply this emerging new technology. Thus, it is anticipated that a number of collaborations with industry will arise as a result of developing single cell expertise in the WIMM led by AJM
People |
ORCID iD |
Adam Mead (Principal Investigator / Fellow) |
Publications
Ahern D
(2022)
A blood atlas of COVID-19 defines hallmarks of disease severity and specificity
in Cell
Aulicino A
(2018)
Invasive Salmonella exploits divergent immune evasion strategies in infected and bystander dendritic cell subsets
in Nature Communications
Booth CAG
(2018)
Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors.
in Cancer cell
Brierley CK
(2020)
Single-cell sequencing in hematology.
in Current opinion in oncology
Buono M
(2016)
A dynamic niche provides Kit ligand in a stage-specific manner to the earliest thymocyte progenitors.
in Nature cell biology
Butt NM
(2017)
Guideline for the investigation and management of eosinophilia.
in British journal of haematology
Chowdhury O
(2021)
Impaired antibody response to COVID-19 vaccination in patients with chronic myeloid neoplasms.
in British journal of haematology
Cross NCP
(2018)
Consensus on BCR-ABL1 reporting in chronic myeloid leukaemia in the UK.
in British journal of haematology
Description | BCSH Myeloproliferative Disease National Guidelines for Essential Thrombocythaemia and Myelofibrosis |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | I am a member of the national clinical study groups for chronic myeloid leukaemia and myeloproliferative neoplasms and have helped formulate national guidelines in the research areas relevant to this grant. |
Description | Member of the NCRI clinical study group in Chronic Myeloid Leukaemia (CML) |
Geographic Reach | National |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | The clinical study group for CML provides a national leadership for trials run in the UK. |
Description | Member of the NCRI clinical study groups in myeloproliferative neoplasms (MPNs) |
Geographic Reach | National |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | The clinical study group for MPNs provides national leadership for trials run in the UK. |
Description | NICE technology appraisal for ruxolitinib in myelofibrosis and polycythaemia vera |
Geographic Reach | National |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | Helped advise on NICE technology appraisal |
Description | Application of single cell genomics for precision medicine in myelodyspastic syndromes |
Amount | £319,053 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2019 |
End | 09/2022 |
Description | CRUK Combinations Alliance |
Amount | £532,057 (GBP) |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2019 |
End | 04/2022 |
Description | CRUK Infrastucture Award |
Amount | £228,917 (GBP) |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 11/2019 |
End | 03/2022 |
Description | CRUK Senior Cancer Research Fellowship |
Amount | £2,426,011 (GBP) |
Organisation | Hub at the MRC/CRUK/BHF Clinical Trial Service Unit |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2019 |
End | 05/2025 |
Description | Clinical Research Training Fellowship (Nicholas Fordham): The Role of EZH2 mutation in paediatric myelodysplasia |
Amount | £276,509 (GBP) |
Organisation | The Kay Kendall Leukaemia Fund |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2017 |
End | 03/2020 |
Description | Clinical Research Training Fellowship (Nicholas Fordham): The Role of EZH2 mutation in paediatric myelodysplasia |
Amount | £276,500 (GBP) |
Organisation | The Kay Kendall Leukaemia Fund |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2017 |
End | 03/2020 |
Description | Combinatorial targeting of Chemokines using EVASINs in Myelofibrosis |
Amount | £50,000 (GBP) |
Organisation | University of Oxford |
Department | Radcliffe Department of Medicine |
Sector | Academic/University |
Country | United Kingdom |
Start | 06/2015 |
End | 06/2016 |
Description | ELSTAR Small Scale |
Amount | £7,980 (GBP) |
Organisation | Elstar Therapeutics Inc. |
Sector | Private |
Country | United States |
Start | 01/2018 |
End | 12/2018 |
Description | ELSTAR: Large Scale |
Amount | £777,818 (GBP) |
Organisation | Elstar Therapeutics Inc. |
Sector | Private |
Country | United States |
Start | 01/2019 |
End | 01/2022 |
Description | Genome and Transcriptome analysis of patients with rare stem and Myeloid disorders |
Amount | £65,000 (GBP) |
Organisation | University of Oxford |
Department | John Fell Fund |
Sector | Academic/University |
Country | United Kingdom |
Start | 06/2017 |
End | 06/2019 |
Description | Identification and therapeutic targeting of the abnormal bone marrow stromal cells underlying bone marrow fibrosis in myelofibrosis |
Amount | £216,000 (GBP) |
Organisation | The Kay Kendall Leukaemia Fund |
Sector | Academic/University |
Country | United Kingdom |
Start | 11/2018 |
End | 10/2021 |
Description | Impact of Leukaemia-Associated Loss of Function of Epigenetic Regulators on Distinct Haematopoietic Stem Cells (Co-applicant with Sten Eirik Jacobsen) |
Amount | £266 (GBP) |
Organisation | The Kay Kendall Leukaemia Fund |
Sector | Academic/University |
Country | United Kingdom |
Start | 01/2017 |
End | 12/2019 |
Description | Improving cardiovascular outcomes in polycythaemia by risk stratification and targeted therapy |
Amount | £304,015 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 02/2020 |
End | 01/2023 |
Description | Investigating the molecular mechanism of thrombocytopenia and neutropenia using in vitro models and in multiple myeloma patients during therapy with IMiDs and CelMoDs |
Amount | £401,995 (GBP) |
Organisation | Bristol-Myers Squibb |
Department | Celgene |
Sector | Private |
Country | United States |
Start | 03/2020 |
End | 03/2022 |
Description | Kay Kendall Leukaemia Fund Project Grant |
Amount | £232,919 (GBP) |
Organisation | The Kay Kendall Leukaemia Fund |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2014 |
End | 04/2017 |
Description | LAB282 Large Scale Award |
Amount | £499,817 (GBP) |
Organisation | LAB 282 |
Sector | Charity/Non Profit |
Start | 01/2019 |
End | 06/2020 |
Description | Late Phase Haematology Research Team |
Amount | £85,242 (GBP) |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 03/2015 |
End | 03/2016 |
Description | MRC CRI: The Oxford Single Cell Biology Consortium (co-investigator) |
Amount | £4,975,434 (GBP) |
Funding ID | MR/M00919X/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2015 |
End | 04/2016 |
Description | MRC Confidence in Concept Scheme |
Amount | £50,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Department | MRC Confidence in Concept Scheme |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2014 |
End | 11/2015 |
Description | MRC Discovery Award - Identification and characterisation of cellular targets for genome editing of foetal haematopoietic stem/progenitor cells |
Amount | £56,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2016 |
End | 08/2017 |
Description | MRC Proximity to discovery Industry Engagement Fund |
Amount | £10,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 02/2016 |
End | 07/2016 |
Description | Measuring DNA damage in Single Cells Using a Novel High Throughput Genomic Assay |
Amount | £15,000 (GBP) |
Organisation | University of Oxford |
Department | John Fell Fund |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2017 |
End | 03/2018 |
Description | Megakaryocytes as novel cellular targets for myelofibrosis, a severe bone marrow disorder |
Amount | £54,166 (GBP) |
Organisation | LAB 282 |
Sector | Charity/Non Profit |
Start | 02/2018 |
End | 09/2018 |
Description | NIHR Rare Disease TRC Fellowship Scheme PhD Studentship (Co-lead supervisor with Irene Roberts) |
Amount | £221,439 (GBP) |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 09/2014 |
End | 10/2017 |
Description | PROMise: Investigation into the combination of a Plexxikon BETi with ruxolitinib in patients with high or intermediate-2 risk myelofibrosis not receiving an adequate response with ruxolitinib alone |
Amount | £532,057 (GBP) |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2019 |
End | 04/2022 |
Description | Rosetrees Trust |
Amount | £40,000 (GBP) |
Organisation | Rosetrees Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2015 |
End | 01/2017 |
Description | Testing the validity of novel cell surface markers expressed on the JAK2-mutant HSPC's as useful biomarkers and as therapeutic targets in Myelofibrosis, a severe bone marrow disorder |
Amount | £777,818 (GBP) |
Organisation | Elstar Therapeutics Inc. |
Sector | Private |
Country | United States |
Start | 03/2019 |
End | 03/2022 |
Description | The cellular and genetic landscape of transformed myeloproliferative neoplasms |
Amount | £25,000 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2019 |
End | 09/2022 |
Description | The single cell immunological landscape of Juvenile Myelomonocytic Leukaemia |
Amount | £36,000 (GBP) |
Organisation | University of Oxford |
Sector | Academic/University |
Country | United Kingdom |
Start | 06/2018 |
End | 07/2019 |
Description | The single cell immunological landscape of Juvenile Myelomonocytic Leukaemia |
Amount | £12,000 (GBP) |
Organisation | University of Oxford |
Sector | Academic/University |
Country | United Kingdom |
Start | 06/2018 |
End | 07/2019 |
Description | Tracking the origins of post-transplant myelofibrosis relapse at single cell level |
Amount | £240,000 (GBP) |
Organisation | Hub at the MRC/CRUK/BHF Clinical Trial Service Unit |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2018 |
End | 03/2021 |
Description | Unraveling cancer stem cell heterogeneity in myeoproliferative neoplasms |
Amount | £2,426,001 (GBP) |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2019 |
End | 03/2025 |
Description | Unravelling signatures of clonal response, resistance and evolution of high-risk essential thrombocythaemia at single-cell resolution |
Amount | £261,848 (GBP) |
Funding ID | MR/S001190/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2018 |
End | 08/2021 |
Description | WIMM - Galecto - Mead 21 |
Amount | £60,290 (GBP) |
Organisation | Gedea Biotech AB |
Sector | Private |
Country | Sweden |
Start | 03/2021 |
End | 12/2021 |
Description | WIMM - PRM-151 (Roche) |
Amount | £204,908 (GBP) |
Organisation | F. Hoffmann-La Roche AG |
Sector | Private |
Country | Global |
Start | 11/2020 |
End | 04/2022 |
Description | WIMM - PROMise Plexxikon 21 |
Amount | £178,571 (GBP) |
Organisation | Plexxikon |
Sector | Private |
Country | United States |
Start | 03/2021 |
End | 01/2025 |
Description | WIMM-Mead-BSH Cohort Study |
Amount | £149,760 (GBP) |
Organisation | British Society for Haematology |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2021 |
End | 01/2025 |
Description | Wellcome Trust ISSF |
Amount | £150,135 (GBP) |
Organisation | Wellcome Trust |
Department | Wellcome Trust Institutional Strategic Support Fund |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 11/2014 |
End | 11/2017 |
Description | Wellcome Trust Postdoctoral Research Training Fellowship for Clinician |
Amount | £248,107 (GBP) |
Organisation | Wellcome Trust |
Department | Wellcome Trust Research Training Fellowship |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 07/2016 |
End | 07/2019 |
Title | Single Cell Biology Techniques and Infrastructure |
Description | I have established the infrastructure and techniques for state of the art single cell genomics in the WIMM in Oxford. This has proven to be instrumental in obtaining a large infrastructure grant from the MRC to support single cell research in Oxford. |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2014 |
Provided To Others? | Yes |
Impact | Multiple publications and grants. |
Description | Investigating the impact of Nilotinib on Imatinib-Resistant Chronic Myeloid Leukaemia Stem Cells |
Organisation | University of Oxford |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This is an educational award from Novartis UK (approx £250K) for a research project focused on leukaemia stem cells in patients with chronic myeloid leukaemia and how these might be better eradicated. Details of the research proposal are below: Chronic myeloid leukaemia (CML) is a stem-cell driven chronic leukaemia propagated by a population of therapy-resistant cancer stem cells (CSCs) that, over time, are capable of causing disease relapse and progression, making this an ideal disease for the study of the cellular and molecular biology of CSCs. Current evidence supports that imatinib does not effectively eradicate CML-CSCs. The high proportion of patients in cytogenetic remission on imatinib therapy allows for ready availability of biological material for the study of these therapy-resistant CML-CSCs. It is perhaps surprising, therefore, that the phenotype and, in particular, the biology of CML-CSCs remains poorly characterized. Whilst second generation tyrosine kinase inhibitors such as nilotinib have shown considerable efficacy in CML, with a higher frequency of deeper molecular remissions than seen with imatinib, the optimal indication and timing of a change in therapy to second generation tyrosine kinase inhibitors such as nilotinib also remains unclear. Furthermore, whether patients in complete molecular remission can safely discontinue nilotinib is largely dependent on the presence or absence of residual CML-CSCs. Thus, understanding the response of the CML-CSC population to first or second line nilotinib therapy in pre-clinical studies is a key hurdle to help inform strategies towards the "path to cure" of patients with CML. |
Collaborator Contribution | The aims of this research, which is still underway, were: 1. Establish the cell population(s) with CSC properties in patients with CML at diagnosis using state of the art FACS, molecular biology and xenograft techniques. 2. To determine the CML-CSC burden in patients with suboptimal response to imatinib and in patients on 1st or 2nd line nilotinib therapy 3. To further characterise the biology of these residual CML-CSCs functionally and at the molecular level throughout the course of the disease in a series of patients on imatinib and nilotinib to: a. Compare and contrast mechanisms mediating resistance of CML-CSCs to imatinib and 1st or 2nd line nilotinib b. To understand whether 2nd line nilotinib can effectively eradicate residual CML-CSCs in imatinib suboptimal responders c. Most importantly, to directly compare the biology of normal stem cells with CML-CSCs in patients on imatinib and 1st or 2nd line nilotinib to understand how these cells might be selectively targeted with novel agents. |
Impact | This work has been presented at an international meeting (American Society of Hematology) as an oral presentation and is currently under review at Nature Medicine. Cost of tyrosine kinase inhibitor (TKI) treatment is the UK over the next few years will be £billions with tens of thousands of patients living with CML; so any treatments that might allow patients to discontinue TKI will have a major economic and societal impact. |
Start Year | 2015 |
Description | Medical Research Council Proximity to Discovery Fund |
Organisation | Fluidigm Corporation |
Country | United States |
Sector | Private |
PI Contribution | The award "Senior Visiting Fellowship in Integrative SingleCell Genomics and Genome Editing" provided funding for a visiting fellow from Fluidigm. My group has long had strong links with Fluidigm and have interacted with the company on a number of projects focused on single cell gene expression analysis. I was a co-applicant on the grant and helped with the scientific proposal. |
Collaborator Contribution | Dave Ruff is the fellow visiting from Fluidigm and a number of members of my group and the single cell facilities as part of the Oxford consortium are interacting with Dave during his visit. |
Impact | The award is currently active and as yet there are no outputs |
Start Year | 2016 |
Description | Stem Cell Biology Research with Professor Sten Eirik Jacobsen |
Organisation | University of Oxford |
Department | Weatherall Institute of Molecular Medicine (WIMM) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Longstanding research collaboration |
Collaborator Contribution | Multiple publications and joint grant applications |
Impact | See publications |
Start Year | 2008 |
Description | The Genetic Landscape in Transfusion Dependent Myelofibrosis |
Organisation | Bristol-Myers Squibb |
Department | Celgene |
Country | United States |
Sector | Private |
PI Contribution | This is a research collaboration with Celgene. Detail of the original research proposal are below. This research is currently underway and still active. Myelofibrosis is a clinically and genetically heterogeneous BCR-ABL-negative myeloproliferative neoplasm (MPN) with reported mutations in a number of genes primarily affecting signalling pathways, epigenetic regulators and splicing machinery e.g. JAK2, CALR, MPL, TET2, ASXL1, EZH2, DNMT3A, IDH1/2, CBL, IKZF1, U2AF1, CHEK2, TP53, SF3B1, SRSF2 and LNK.1-3 The most frequent reported genetic event is a gain of function recurrent mutation in JAK2 (V617F) causing constitutive activation of the kinase with consequent activation of downstream signalling. Furthermore, many patients show activation of the JAK2 signalling pathway in the absence of the JAK2 mutation, likely caused by mutations indirectly activating the JAK2 pathway e.g. MPL. Recently, somatic mutation of CALR has been reported in MPN patients without the JAK2V617F mutation.4,5 These mutations are mutually exclusive of JAK2V617F and MPL mutations, suggesting that they might activate similar pathways. Severe anaemia with RBC-transfusion-dependence is common in patients with advanced MPN-associated myelofibrosis. The above signalling pathway mutations are associated with high as well as low blood counts and rather mutations affecting splicing (SRSF2) and epigenetic regulation (ASXL1) are associated with development of anaemia in myelofibrosis. Pomalidomide, an immune-modulating drug with pleiotrophic bone marrow effects, resulted in improvements in the level of anaemia in several phase 2 studies, however, preliminary results in a phase 3 study are disappointing. Nevertheless, in this phase 3 study, 16% of patients showed an anaemia response (16% also in placebo arm) and 22% a platelet response suggesting that some response does occur in a subgroup of patients. There also were some possible differences in clinical parameters between patients achieving transfusion independence on placebo versus pomalidomide. Together, these findings suggest that a there might be a subgroup of transfusion-dependent or thrombocytopenic patients who would benefit from pomalidomide therapy, although this subgroup is relatively small and lost within the context of heterogeneous patients included in this large phase 3 trial. With the advent of next generation sequencing and personalised medicine it is possible that molecular features might better define a subgroup of patients predicted to respond to pomalidomide. |
Collaborator Contribution | Samples are available from 250 patients with high/intermediate risk myelofibrosis enrolled on a phase III trial of pomalidomide (2:1 randomisation pomalidomide:placebo). All samples will be analysed by targeted resequencing using a gene panel developed in our institution (TruSeq™ target enrichment kit) followed by sequencing using MiSeq. This assay will require minimum of 1µg gDNA using PicoGreen quantification. The panel will include all the genes listed above. For this project it is important that deep coverage is obtained to gain insights into clonal architecture and evolution in myelofibrosis patients during response to pomalidomide therapy, during prolonged follow-up, and at the point of any disease progression events. Thus, we will aim to achieve 100x coverage for each of the above gene targets. Any patients not carrying any of the above mutations (likely to be a small minority (<5%) will be subject to exome sequencing. Using algorithms well established in Oxford by the computational biology research group housed at the WIMM (http://www.molbiol.ox.ac.uk/CBRG_home.shtml) we will carry out state of the art bioinformatics analysis to identify likely somatic driver mutations in this large cohort. Through the interaction with Celgene, these data will be correlated with the robust clinical information collected as part of the trial to understand the relationship between somatic mutations, clinical characteristics and response to pomalidomide. For such a large and well annotated cohort of patients with carefully defined transfusion dependent myelofibrosis, this will also provide unique insights into genetic heterogeneity in this disorder and the relationship to clinical phenotype and disease course. Recurrent, previously undescribed mutations predicted to be functionally relevant will all be validated using sanger sequencing and tracked through serial samples. Importantly, we are also well placed in the HSCB laboratory to follow-up findings from the sequencing with biological studies to understand how any novel candidate genes/pathways might modulate response to pomalidomide. In addition to state of the art cell culture and molecular platforms, we also have a number of highly relevant mouse models available (JAK2 V617F conditional knock-in, EZH2 conditional knockout) providing powerful platforms for understanding the in vivo consequence of different mutations for development of anaemia and response to pomalidomide. Any candidate genes will initially be studied in cell lines by lentiviral transduction of the relevant mutation or shRNA mediated knockdown if genes are inactivated/deleted to understand if the candidate gene(s) affects the response to pomalidomide in vitro. Once validated in cell lines, candidate genes will be further studied using the above in vivo models, including in vivo treatment of mice with pomalidomide, to understand how different mutations may interact to modulate response to this treatment. Finally, using our extensive cell bank of samples from patients with myelofibrosis, we will then validate possible candidate genes using human myelofibrosis patient samples using either lentiviral transduction as above or by using targeted agents if available, both with and without pomalidomide treatment. |
Impact | AJM is a newly established group leader and MRC Senior Clinical Fellow in the WIMM working in the field of myeloid malignancies. The intention for initiating this collaboration is to generate substantial information with regards to the genomic architecture in myelofibrosis that will result in a strong publication. Thus, it would be expected that AJM would "own" the genomic data arising from this research and will have the right to publish these data following an appropriate review period by Celgene. |
Start Year | 2015 |
Description | The Oxford SIngle Cell Consortium |
Organisation | University of Oxford |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Abstract of the grant application: Limitations in our ability to study the biology of individual cells has historically been a major obstacle, inhibiting our understanding of some fundamental problems in biomedical research such as the onset of cancer, the immunological determination of 'self', and the ability to purify tissue-specific stem cells. Recent developments in the field of single cell genomics is now opening up unprecedented opportunities to uncover individual cell differences within such complex tissues. The objective of the proposed research is to establish a Centre of Single Cell Biology (CSCB) in Oxford that will take advantage of this pioneering technology in order to improve the diagnosis, stratification and treatment of a wide variety of human diseases. The CSCB will be coordinated by the Weatherall Institute of Molecular Medicine (WIMM) which has a long-standing technical and strategic expertise in single cell research. The capital development will be used to enhance single-cell research capabilities across the campus in a number of key areas: Data analysis: Single cell genomics studies generate an enormous amount of data, with consequent challenges for the analysis and correct interpretation of these complex data sets. We propose to establish an entirely new research group devoted to the development of novel approaches for the statistical and computational analysis of single cell biology data and its application to medicine. This group will be located in new space to be developed at the WIMM, but jointly led by leading scientists across the campus. This new initiative will provide a clear pathway to integrate multidisciplinary, scientific and technical innovation in single cell biology research across the Oxford University Campus and to provide ground-breaking applications of this approach to medicine in the UK. State of the art facilities: We will develop single cell biology research laboratories to allow practical access for research groups conducting these studies across the campus. These facilities will house cutting edge technology platforms and, importantly, will create "ultra clean" environments to carry out single cell experiments. This is necessary as very low levels of background "contamination" make the interpretation of single cell experiments challenging. Projects: As a specific example of how this technology will be applied to address fundamental problems in human disease, the lead programme of research in the CSCB will be focused on inherited disorders of red blood cells. These disorders are amongst the most common of all human genetic diseases worldwide with an estimated 300,000 affected babies born each year and a total number of affected UK patients of ~16,000. Currently, severely affected individuals are treated with supportive care, including lifelong blood transfusion and treatment to prevent accumulation of iron in the body, which is costly, burdensome, and gives rise to serious, long-term clinical complications. Here we propose to "genetically repair" the damaged genes in the patient's own blood stem cells. Single cell biology will be central to this project: First, single cell genomic approaches will be used to identify the blood stem cells which are the best target for this therapy. Second, single-cell analysis will be used to assess the safety and efficiency of this approach. This programme, focussed on developing an entirely new approach to treating the haemoglobinopathies, has the potential to transform the treatment of all human genetic diseases that can be cured by stem cell transplantation. This is one example of many projects in development across the campus which will be greatly facilitated by the development of improved single cell research capabilities. Oxford is in a very strong position to take a world-leading role in the up-and-coming area of Single Cell Biology and application of these technologies to important clinical and basic biology questions across the University and beyond. |
Collaborator Contribution | Abstract of the grant application: Limitations in our ability to study the biology of individual cells has historically been a major obstacle, inhibiting our understanding of some fundamental problems in biomedical research such as the onset of cancer, the immunological determination of 'self', and the ability to purify tissue-specific stem cells. Recent developments in the field of single cell genomics is now opening up unprecedented opportunities to uncover individual cell differences within such complex tissues. The objective of the proposed research is to establish a Centre of Single Cell Biology (CSCB) in Oxford that will take advantage of this pioneering technology in order to improve the diagnosis, stratification and treatment of a wide variety of human diseases. The CSCB will be coordinated by the Weatherall Institute of Molecular Medicine (WIMM) which has a long-standing technical and strategic expertise in single cell research. The capital development will be used to enhance single-cell research capabilities across the campus in a number of key areas: Data analysis: Single cell genomics studies generate an enormous amount of data, with consequent challenges for the analysis and correct interpretation of these complex data sets. We propose to establish an entirely new research group devoted to the development of novel approaches for the statistical and computational analysis of single cell biology data and its application to medicine. This group will be located in new space to be developed at the WIMM, but jointly led by leading scientists across the campus. This new initiative will provide a clear pathway to integrate multidisciplinary, scientific and technical innovation in single cell biology research across the Oxford University Campus and to provide ground-breaking applications of this approach to medicine in the UK. State of the art facilities: We will develop single cell biology research laboratories to allow practical access for research groups conducting these studies across the campus. These facilities will house cutting edge technology platforms and, importantly, will create "ultra clean" environments to carry out single cell experiments. This is necessary as very low levels of background "contamination" make the interpretation of single cell experiments challenging. Projects: As a specific example of how this technology will be applied to address fundamental problems in human disease, the lead programme of research in the CSCB will be focused on inherited disorders of red blood cells. These disorders are amongst the most common of all human genetic diseases worldwide with an estimated 300,000 affected babies born each year and a total number of affected UK patients of ~16,000. Currently, severely affected individuals are treated with supportive care, including lifelong blood transfusion and treatment to prevent accumulation of iron in the body, which is costly, burdensome, and gives rise to serious, long-term clinical complications. Here we propose to "genetically repair" the damaged genes in the patient's own blood stem cells. Single cell biology will be central to this project: First, single cell genomic approaches will be used to identify the blood stem cells which are the best target for this therapy. Second, single-cell analysis will be used to assess the safety and efficiency of this approach. This programme, focussed on developing an entirely new approach to treating the haemoglobinopathies, has the potential to transform the treatment of all human genetic diseases that can be cured by stem cell transplantation. This is one example of many projects in development across the campus which will be greatly facilitated by the development of improved single cell research capabilities. Oxford is in a very strong position to take a world-leading role in the up-and-coming area of Single Cell Biology and application of these technologies to important clinical and basic biology questions across the University and beyond. |
Impact | The Oxford Single Cell Consortium was established in 2014 followed by successful application for MRC CRI funding (£5 million) led by Professors Doug Higgs and Kay Davies, I am a coauthor on this grant application. The consortium has established 2 single cell facilities across the Oxford campus and I have led the development of protocols and infrastructure required for single cell experiments. We held the official consortium launch in October 2014, supported by a press release and webinars from international experts. |
Start Year | 2014 |
Title | A Randomized, Single Blind, Multicenter, Phase 2 Study to Evaluate the Activity of 2 Dose Levels of Imetelstat (GRN163L) in Subjects with Intermediate-2 or High-Risk Myelofibrosis (MF)Relapsed / Refractory to Janus Kinase Inhibitor |
Description | A Randomized, Single Blind, Multicenter, Phase 2 Study to Evaluate the Activity of 2 Dose Levels of Imetelstat (GRN163L) in Subjects with Intermediate-2 or High-Risk Myelofibrosis (MF)Relapsed / Refractory to Janus Kinase Inhibitor |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | N/A - trial still in recruitment |
URL | https://clinicaltrials.gov/show/NCT02426086 |
Title | BFORE. A Multicenter Phase 3 Randomized, Open-Label Study of Bosutinib versus Imatinib |
Description | Principal Investigator - BFORE. A Multicenter Phase 3 Randomized, Open-Label Study of Bosutinib versus Imatinib in Adult Patients with Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia. Open to recruitment |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
UKCRN/ISCTN Identifier | DRKS00007133 |
Impact | Currently in follow up. |
URL | https://clinicaltrials.gov/show/NCT02130557 |
Title | DESTINY. A trial of de-escalation and stopping treatment |
Description | Principal Investigator - DESTINY. A trial of de-escalation and stopping treatment in chronic myeloid leukaemia patients with excellent responses to tyrosine kinase inhibitor therapy. In follow-up. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Currently in follow up. Preliminary results to be presented at the European Haematology Association meeting in 2016. |
URL | https://clinicaltrials.gov/show/NCT01804985 |
Title | ENEST1st; A phase IIIb, multicentre, open-label study |
Description | Local Principal investigator - ENEST1st; A phase IIIb, multicentre, open-label study of nilotinib in adult patients with newly diagnosed Philadelphia chromosome and/ or bcr-abl positive CML in chronic phase, ENEST1st, CAMN107EIC01. Closed to recruitment. Lead UK recruiter. Closed. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2014 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | This was a phase 3b study using nilotinib as first line therapy in CML. Oxford was the lead recruiter with AJM as the principal investigator. Nilotinib is now NICE approved for first line use in the UK. Results have been presented at international meetings. |
URL | https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-017775-19 |
Title | ENESTfreedom. A single-arm, multicenter, nilotinib treatment-free remission study |
Description | 12. Chief Investigator - ENESTfreedom. A single-arm, multicenter, nilotinib treatment-free remission study in patients with BCR-ABL1 positive Chronic Myelogenous Leukemia in chronic phase who have achieved durable minimal residual disease (MRD) status on first line nilotinib treatment. In follow up. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Currently in follow up. Results will be reported in 2016. |
URL | https://clinicaltrials.gov/show/NCT01784068 |
Title | ENESToberve. An observational, open-label, multi-center, prospective follow-up study |
Description | UK Chief Investigator - ENESToberve. An observational, open-label, multi-center, prospective follow-up study of patients with chronic phase CML treated with Nilotinib in the ENEST1st (CAMN107EIC01) study. In follow up. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Currently in follow up. |
Title | EPIC - A Phase 3 Randomized, OpenLabel Study of Ponatinib versus Imatinib |
Description | Principal investigator - EPIC - A Phase 3 Randomized, OpenLabel Study of Ponatinib versus Imatinib in Adult Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase. Closed. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2015 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Results presented in abstract form. |
Title | INForMeD Study |
Description | INvestigating the genetic and cellular basis of sporadic & Familial Myeloid Disorders |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Initial development |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Impact | This study provides the ethical framework for all the translational research in my research group. |
Title | JAKARTA; A Phase 3, RandomiSed, Double-Blinded, Placebo Controlled 3 arm Study |
Description | Principal investigator - JAKARTA; A Phase 3, RandomiSed, Double-Blinded, Placebo Controlled 3 arm Study of SAR302503 in Patients with Intermediate-2 or High Risk Primary (PMF), Post-Polycythemia Vera (PPVM), or Post-Essential Thrombocythemia Myelofibrosis (PTM) with Splenomegaly. Closed. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2014 |
Development Status | Closed |
Clinical Trial? | Yes |
Impact | The clinical development of fedratinib was put on hold due to an excess of encephalopathy (adverse events). |
URL | https://clinicaltrials.gov/show/NCT01437787 |
Title | JakaviPASS. A Non-Interventional Long-term Safety Study of Ruxolitinib in Myelofibrosis. |
Description | Principal investigator - JakaviPASS. A Non-Interventional Long-term Safety Study of Ruxolitinib in Myelofibrosis. In follow up. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Currently in follow up. |
Title | MAJIC; A RandoMised study of best Available therapy versus JAK Inhibition in patients with high risk Polycythaemia Vera or Essential Thrombocythaemia |
Description | Co-invesigator - MAJIC; A RandoMised study of best Available therapy versus JAK Inhibition in patients with high risk Polycythaemia Vera or Essential Thrombocythaemia who are resistant or intolerant to HydroxyCarbamide. Planned to open Spring 2012. First study to be run through the LLR Trial Acceleration Program. Open to recruitment. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | I am co-investigator of this trial which is the first investigator led study assessing JAK2 inhibitor treatments in the world and also the first Bloodwise Trial Acceleration Programme trial. Preliminary results will be presented in 2016 and I expect multiple publications to folow. |
URL | https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-005279-18 |
Title | MEASURES |
Description | Principal Investigator: The MPN Experimental Assessment of Symptoms by Utilizing Repetitive Evaluation (MEASURES) Trial: Serial Assessment of Symptomatic Response to Non Experimental Medical Therapies and/or Phlebotomy in Patients with Myeloproliferative Neoplasms. In set up. |
Type | Management of Diseases and Conditions |
Year Development Stage Completed | 2017 |
Development Status | Under active development/distribution |
Impact | None as yet, trial still recruiting |
Title | Myeloproliferative Disorders-Research Consortium (MPD-RC) MPD-RC 112 Randomized Trial of Pegylated Interferon Alfa-2a versus Hydroxyurea Therapy in the Treatment of High Risk Polycythemia Vera and High Risk Essential Thrombocythemia |
Description | Myeloproliferative Disorders-Research Consortium (MPD-RC) MPD-RC 112 Randomized Trial of Pegylated Interferon Alfa-2a versus Hydroxyurea Therapy in the Treatment of High Risk Polycythemia Vera and High Risk Essential Thrombocythemia |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | N/A - trial still in follow up. |
URL | https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2010-019501-41 |
Title | Myeloproliferative Disorders-Research Consortium (MPD-RC) MPD-RC Protocol 114. |
Description | 18. Co-Chair: Myeloproliferative Disorders-Research Consortium (MPD-RC) MPD-RC Protocol 114. Exploring the Potential of Dual Kinase JAK 1/2 Inhibitor Ruxolitinib (INC424) with Reduced Intensity Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis. |
Type | Management of Diseases and Conditions |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2015 |
Development Status | Under active development/distribution |
Impact | I am the chief Investigator of this NIH-funded investigator-led, international, multicentre phase 2 clinical study testing JAK2 inhibitor therapy before allogeneic transplantation in myelofibrosis. Preliminary results will be presented at the American Society of Hematology meeting in 2016 |
Title | NCRN-3257 - A Phase 3, Randomized Study To Evaluate the Efficacy of Momelotinib |
Description | Principal Investigator: NCRN-3257 - A Phase 3, Randomized Study To Evaluate the Efficacy of Momelotinib Versus Best Available Therapy in Anemic or Thrombocytopenic Subjects with Primary Myelofibrosis, Postpolycythemia Vera Myelofibrosis, or Post-essential Thrombocythemia Myelofibrosis who were Treated with Ruxolitinib (protocol ID: GS-US-352-1214). Due to open Q3 2015. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2015 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
UKCRN/ISCTN Identifier | DRKS00006320 |
Impact | Trial currently in follow up, no outputs as yet. |
URL | https://clinicaltrials.gov/show/NCT02101268 |
Title | OPTIC study |
Description | A Randomized, Open-label, Phase 2 Trial of Ponatinib in Patients with Resistant Chronic Phase Chronic Myeloid Leukemia to Characterise the Efficacy and Safety of a Range of Doses. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Initial development |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Impact | Trial in set-up phase |
Title | PAC203 |
Description | UK Chief Investigator: PAC203 Protocol Pacritinib An Open-Label, Randomized, Phase 2 Dose-Finding Study of Pacritinib in Patients with Thrombocytopenia and Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis Previously Treated with Ruxolitinib. In set up. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2017 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Trial still recruiting |
URL | https://clinicaltrials.gov/show/NCT03165734 |
Title | PERSIST-1 - A Randomized Controlled Phase 3 Study of Oral Pacritinib versus |
Description | UK Chief investigator - PERSIST-1 - A Randomized Controlled Phase 3 Study of Oral Pacritinib versus Best Available Therapy in Patients with Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis. In follow up. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
UKCRN/ISCTN Identifier | DRKS00005202 |
Impact | A number of abstracts have been presented at ASCO, ASH and EHA, including the late breaking abstract which I presented in 2015 at EHA. |
URL | https://clinicaltrials.gov/show/NCT01773187 |
Title | PERSIST-2 - A Randomized Controlled Phase 3 Study of Oral Pacritinib versus Best Available Therapy |
Description | Chief investigator - PERSIST-2 - A Randomized Controlled Phase 3 Study of Oral Pacritinib versus Best Available Therapy in Patients with Thrombocytopenia and Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis (PAC326). Open to recruitment. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
UKCRN/ISCTN Identifier | ACTRN12614000740695 |
Impact | Currently in follow up. |
URL | https://clinicaltrials.gov/show/NCT02055781 |
Title | PHAZAR study |
Description | A phase Ib study to assess the safety and tolerability of oral Ruxolitinib in combination with 5-azacitidine in patients with advanced phase myeloproliferative neoplasms (MPN), including myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) arising from MPN. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | N/A - trial still recruiting |
URL | https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-002563-16 |
Title | PT1; A randomised trial to compare aspirin vs hydroxyurea/aspirin |
Description | Local Principal investigator - PT1; A randomised trial to compare aspirin vs hydroxyurea/aspirin in intermediate risk primary thrombocythaemia and aspirin only with observation in low risk primary thrombocythaemia. Phase 3 trial. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Multiple high profile publications. |
URL | https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2004-000245-38 |
Title | Phase II study of INC424 for patients with primary myelofibrosis (PMF) or post polycythaemia myelofibrosis (PPV MF) |
Description | Chief investigator - A UK open-label, multicentre, exploratory Phase II study of INC424 for patients with primary myelofibrosis (PMF) or post polycythaemia myelofibrosis (PPV MF) or post-essential thrombocythaemia myelofibrosis (PET-MF). Closed and published in The British Journal of Haematology. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2015 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Mead, A.J., Milojkovic, M., Knapper, S., Garg, M., Chacko, J., Farquharson, M., Yin, J., Ali, S., Clark, R.E., Andrews, C., Ktiouet-Dawson, M., Harrison, C. Response to ruxolitinib in patients with intermediate-1-, intermediate-2-, and high-risk myelofibrosis: results of the UK ROBUST Trial. British Journal of Haematology, 2015;170(1):29-39. |
URL | https://clinicaltrials.gov/show/NCT01558739 |
Title | RESUME; A phase-3, multi-center, randomized, doubleblind, placebo-controlled, parallel-group study to compare efficacy and safety of pomalidomide in subjects with myeloproliferative neoplasm -associated myelofibrosis and red blood cell-transfusiondependence. |
Description | Local Principal investigator - RESUME; A phase-3, multi-center, randomized, doubleblind, placebo-controlled, parallel-group study to compare efficacy and safety of pomalidomide in subjects with myeloproliferative neoplasm -associated myelofibrosis and red blood cell-transfusiondependence. Closed to recruitment. In follow-up. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Currently in follow up. Results presented at international meetings. I also have a research collaboration with Celgene using samples collected as part of this trial. |
URL | https://clinicaltrials.gov/show/NCT01178281 |
Title | RETHINK study |
Description | A randomized, double blind, placebo-controlled, multicenter, Phase III study investigating the efficacy and safety of ruxolitinib in Early Myelofibrosis patients with high molecular risk mutations. Open to Recruitment |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | N/A - trial still recruiting |
URL | https://clinicaltrials.gov/show/NCT02598297 |
Title | Randomized Trial of Pegylated Interferon Alfa-2a versus Hydroxyurea Therapy |
Description | Local Principal Investigator - Myeloproliferative Disorders-Research Consortium (MPD-RC) MPD-RC 112. Randomized Trial of Pegylated Interferon Alfa-2a versus Hydroxyurea Therapy in the Treatment of High Risk Polycythemia Vera and High Risk Essential Thrombocythemia. Mandatory Companion Protocol MPD-RC 107. EudraCT #2010-019501-41. Open to recruitment. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2014 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | The trial is actively recruiting. |
URL | https://clinicaltrials.gov/show/NCT01259856 |
Title | SPIRIT2; STI571 Prospective International Randomised Trial 2. |
Description | Local Principal investigator - SPIRIT2; STI571 Prospective International Randomised Trial 2. Closed to recruitment, in follow-up. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Results presented as at international meetings. |
URL | https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-006185-15 |
Title | TAMARIN study |
Description | Effects of TAMoxifen on he Mutant Allele Burden and Disease Course in Patients with MyeloprolifeRatIve Neoplasms |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | N/A - trial still recruiting. |
URL | https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-005497-38 |
Title | UK TARGET - CML Study : Real World UK use of Tyrosine Kinase Inhibitors (TKIs) |
Description | Chief Investigator: Real World UK use of Tyrosine Kinase Inhibitors (TKIs): A Retrospective description of management pathways, clinical responses and compliance with 2013 European LeukemiaNeT (ELN) recommendations for Chronic Myeloid Leukaemia (CML) - the UK TARGET-CML study. Due to open Q4 2015. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2015 |
Development Status | Under active development/distribution |
Impact | Trial currently recruiting. No impact yet. |
Description | CML Patient Conference |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | CML Patient Conference |
Year(s) Of Engagement Activity | 2020 |
Description | Cancer immunotherapy stand - Michela Colombo & Guanlin Wang |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Re-run of the cancer immunotherapy stand, part of the Westgate Wonderlab at the IF Oxford 2028 |
Year(s) Of Engagement Activity | 2019,2020 |
Description | Cristina Di Genua - Science Roadshow |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | As part of the MRC Festival for Medical Research 2016, three MRC Units within Oxford collaborated to pool funds and resources to develop the 'Science in the Supermarket' roadshow. The team travelled to supermarkets and shopping centres all over Oxfordshire over the course of the Festival week, describing to the general public how the immune system fights cancer using three activities representing research currently ongoing in each of the three units. |
Year(s) Of Engagement Activity | 2016 |
Description | MPN Advances |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | I regularly talk at the national myeloproliferative neoplasms patients and carers day, updating patients about scientific advances in the field. Usually about 200 patients/carers attend this annual meeting. |
Year(s) Of Engagement Activity | 2014,2015 |
Description | MPN Advances Patient Group |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | MPN Advances Patient Group meeting. Whee patients and carers can ask questions/for help etc. |
Year(s) Of Engagement Activity | 2019 |
Description | MPN Voice Virtual Forum |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Talked ar MPN voice virtual forum |
Year(s) Of Engagement Activity | 2020 |
Description | MPN Voices Forum - Alba Rodriguez Meria |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | Talk at MPN voices forum. |
Year(s) Of Engagement Activity | 2019 |
Description | Museum of Natural History - Lucy Field |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | Hands on activities about blood (The Blood Factory). |
Year(s) Of Engagement Activity | 2017 |
Description | National CML patient and carers day |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Very liverly discussions. Very positive feedback formally collected from participants |
Year(s) Of Engagement Activity | 2013 |
Description | Nguyen Tran - Science Roadshow |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | As part of the MRC Festival for Medical Research 2016, three MRC Units within Oxford collaborated to pool funds and resources to develop the 'Science in the Supermarket' roadshow. The team travelled to supermarkets and shopping centres all over Oxfordshire over the course of the Festival week, describing to the general public how the immune system fights cancer using three activities representing research currently ongoing in each of the three units. |
Year(s) Of Engagement Activity | 2016 |
Description | Part of working group - Alba Rodriguez Meria |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Part of working group that developed activities for MRC Festival 2019 on Cancer immunotherapy |
Year(s) Of Engagement Activity | 2019 |
Description | Patient forum for chronic myeloid malignancies |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | We have established a regular patient forum in Oxford led by our advanced nurse practitioner and involving patients with chronic myeloid malignancies. Positive feedback from participants |
Year(s) Of Engagement Activity | 2014 |
Description | Public lecture at the Oxford BRC open day |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | The BRC regularly holds open days and I gave the lecture focused on Blood diseases. |
Year(s) Of Engagement Activity | 2013 |
Description | Q+A at the CML support group |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Q+A at the CML support group |
Year(s) Of Engagement Activity | 2019 |
Description | Royal Society Summer Science Exhibition - Lucy Field |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | Hands-on activities, including virtual reality tour of DNA.Huge amount of positive feedback at the time from visitors, engagement with social media posts, collaborative working across department and WIMM |
Year(s) Of Engagement Activity | 2017 |
Description | Science in the supermarket, MRC Festival 2019 - Alba & Lucy |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Science in the supermarket, MRC Festival 2019 |
Year(s) Of Engagement Activity | 2019 |
Description | Session on haematology for students - Lucy Field & Lauren Murphy |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Other audiences |
Results and Impact | Run a session on haematology for students in the MRC WIMM work experience programme. Included go fish game, activities on gene expression using legos and microscopy and leukaemia diagnosis |
Year(s) Of Engagement Activity | 2019 |
Description | Wrote article on how drug trials are designed with patient safety at heart - For charity MPN Voice |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Wrote an article on how drug trials are designed with patient safety at their heart for the charity MPN Voice (patient charity for patients with myeloproliferative neoplasms). |
Year(s) Of Engagement Activity | 2016 |