Vyas Group: Biology and Treatment of Human Myeloid Cancers
We aim to understand the fundamental biological processes underlying normal and malignant haematopoiesis and translate this to improve patient outcomes through new rational therapies.
Our group focuses on understanding the biological process of normal haematopoietic stem and progenitor cell differentiation and how this is disrupted during the development of blood malignancies. The ultimate goal of our work is to translate research findings into improved clinical outcomes through better use of existing treatments and the discovery of new and personalised therapies.
Trajectory of Myeloid Malignancy
Can we predict who will develop leukaemia later in life? Why do some abnormal cells develop into aggressive malignancies and others don’t? How does the microenvironment influence the emergence of cancerous cells in older age? We are interested in the molecular mechanisms that lead to malignant transformation of preleukemic progenitor cells and the evolution of established leukaemia resulting in therapy resistance or relapse.
For this reason, our lab studies clonal architecture and heterogeneity of myeloid malignancies and preleukemic conditions such as transient abnormal myelopoiesis (TAM) in children with Down syndrome or clonal haematopoiesis of indeterminate potential (CHIP) in older people. We are also interested in the contribution of the bone marrow microenvironment to disease initiation and progression in such conditions.
The application of multi-omics strategies (targeted and whole genome sequencing, single cell genomics and transcriptomics, flow cytometry and imaging) allows us to unravel evolutionary patterns within clonal trajectories and to identify cell-autonomous and non-cell-autonomous cues that influence the behaviour of individual clones. Using a wide array of techniques including gene editing and in vivo models we then can investigate the involvement of cell-intrinsic drivers such as epigenetic or transcriptional regulators as well as cell-extrinsic cues exerted by the microenvironment in the evolution of myeloid malignancies.
T cell Responses to Myeloid Cancer
Immune therapies offer the next frontier of targeted cancer treatments. Our lab has three interests in this area.
First, we are studying the immunological basis of alloreactivity in allogeneic stem cell transplantation, the most established cancer cellular immunotherapy used to treat the highest risk blood cancers. We are using state-of-the-art integrated unbiased genomic and functional immunological assays to identify novel alloreactive antigens and the adaptive immune responses to these antigens to improve the outcomes for cancer patients.
Second, we are studying the autologous immune response in patients treated for acute myeloid leukaemia (AML) to understand what role it plays in disease control.
Third, we are investigating the changes in diversity and function of the T cell compartment through ageing.
All three projects are linked and involve collaborative working with a number of immunology groups around Oxford and abroad.
Drug Resistance and Response
A central question in modern medicine is why most drugs fail to cure cancer patients. We are addressing this question in the context of AML. Patients diagnosed with this aggressive blood cancer have a poor clinical outcome mainly due to high relapse rates following treatment. Relapse is driven by therapy-resistant cells that are able to escape the therapy, remodel and dominate the blood ecosystem. In our lab we aim to understand the cellular and molecular basis of resistance by using state-of-the-art single cell methods (single-cell transcriptome, genotyping, ATAC-seq and multiparameter flow cytometry) to study patient AML samples. This highly translational work may provide novel tailored treatment options for patients.
The group’s research work is supported by the well-established Haematopoietic Cell Biobank, one of the largest haematological sample biobanks in the UK (around 14,000 samples), which is coordinated and managed by our lab.
We perform high quality processing of blood, bone marrow and biopsy samples from patients with haematological malignancies and healthy volunteers, and securely store the samples on-site alongside relevant anonymised clinical data. All of our Biobank procedures are performed in compliance with Good Clinical Practice (GCP) and Human Tissue Act (HTA) regulations.
The Biobank is a powerful resource providing national and international collaborators access to samples for ethically approved research projects. Through this collection of invaluable patient specimens, the Biobank ultimately aims to facilitate better understanding of the biology of blood cancers and to improve patient outcomes through improved use of existing therapy and discovery of new therapies.
1. Persephone Borrow https://www.ndm.ox.ac.uk/team/persephone-borrow
2. Ronjon Chakraverty https://www.rdm.ox.ac.uk/people/ronjon-chakraverty
3. Irene Roberts https://www.imm.ox.ac.uk/people/irene-roberts
4. Courtney DiNardo https://faculty.mdanderson.org/profiles/courtney_dinardo.html
5. Marina Konopleva https://faculty.mdanderson.org/profiles/marina_konopleva.html
6. Charles Craddock https://www.birmingham.ac.uk/staff/profiles/cancer-genomic/craddock-charles.aspx
7. Claus Nerlov https://www.imm.ox.ac.uk/people/claus-nerlov
8. Supat Thongjuea https://www.imm.ox.ac.uk/people/supat-thongjuea
9. Thomas Höfer https://www.dkfz.de/en/modellierung-biologischer-systeme/
Clinical Studies and trials
Chief Investigator: Prof Paresh Vyas
Celgene AML 004 and AML005 – International Phase III trials of a first-in-class oral enasidenib, an IDH2 inhibitor in Acute Myeloid Leukaemia. Sponsored by Celgene.
Celgene MDS003 - International Phase III trial of a first-in-class oral DNA and RNA demethylation inhibitor in Acute Myeloid Leukaemia. Sponsored by Celgene.
Celgene AML 005 - Azacitidine +/- IDH2 inhibitor AG221 inpatients with newly diagnosed, previously untreatd AML patients.
Chief Investigator: Dr Lynn Quek
AGILE - Azacitidine +/- IDH1 inhibitor (AG120/ Ivosidenib) in newly diagnosed, previously untreatd AML patients.
We regularly host both work experience students and visiting biomedical/medical science students.
Professor Vyas has given short talks about AML and the importance of single-cell approaches to study a heterogeneous disease.