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Evaluation of combination therapies targeting DNA damage repair signalling pathways in acute myeloid leukaemia


   Institute of Cancer Sciences

  Dr Heather Jorgensen, Dr Helen Wheadon, Dr Xu Huang  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Acute myeloid leukaemia (AML) is an aggressive cancer affecting mostly adult and elderly patients. It has a very poor 5-year survival of <20% in the UK. Oncogene driven genomic instability leads to accumulation of DNA damage; this is a key and common phenomenon in AML cells, that could be therapeutically targeted. Targeted inhibitor efficacy as single agents in clinical trials has been limited, partly due to the activation of alternative compensatory DNA damage response (DDR) pathways therefore rational combination strategies may be more appropriate.

We previously established a family of histone demethylases as critical and selective oncogenic factors in AML. Genetic knockdown or pharmacological inhibition of family members was sufficient to induce apoptosis in a broad spectrum of human AML cell lines and primary patient blasts with no effect on normal haematopoiesis, indicating leukaemia cells are more sensitive to inhibition thereby offering a potential therapeutic window. We hypothesise that a combination treatment of DDRi with histone demethylase inhibitor may result in enhanced cytotoxic effects in human AML cells. Our preliminary data indeed show promising synergistic lethality activity with this combination in human AML cell line suspension culture. In this project we wish to further evaluate histone demethylase inhibitors as single agents or in combination with DDRi in primary patient blasts to inform future clinical trial design.

Methodology

We have a collection of individual primary AML patient samples and normal human bone marrow cells in our Glasgow biobank. An in vitro co-culture system has been established in our laboratory that mimics in vivo bone marrow microenvironment, that has been demonstrated to be a reproducible and reliable system for assessing clonal function and drug efficacy in primary AML cells. Functional assays including cell proliferation assay, cell apoptosis assay and colony formation assays will be performed. These data will be correlated with gene expression in each patient sample.

Aim 1 To validate the efficacy of histone demethylase inhibitor monotherapy or in combination with DDRi in stratified AML patient blasts.

Aim 2 To evaluate biomarker expression pattern in AML patient samples following single or combination treatment.

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References

1. ME Massett, et al (2021): A KDM4A-PAF-1-mediated epigenomic network is essential for acute myeloid leukemia cell self-renewal and survival. Cell Death Dis 12(6):573. doi: 10.1038/s41419-021-03738-0.
2. L Monaghan, et al (2019): The emerging role of H3K9me3 as a potential therapeutic target in acute myeloid leukaemia. Front Oncol doi.org/10.3389/fonc.2019.00705
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