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Macrophage driven therapy resistance in AML: from macrophage subset characterisation to therapeutic targeting.


   School of Health and Life Sciences


About the Project

Reference: SHLS20065

Background

Acute Myeloid Leukaemia (AML) is a common blood cancer in adults; with its incidence increasing with age, AML cases are predicted to double by 2030. Survival rates for the majority of adult AML patients are poor (<20%): remaining largely unchanged over the last 20 years (https://www.hmrn.org/statistics/survival). Resistance to cancer drugs (therapy resistance) is a major factor contributing towards low survival rates in adult AML, and is strongly influenced by the cellular elements residing within the bone marrow (BM) microenvironment. AML cells interact with these BM resident cells; including fibroblasts (supportive cells), and potentially macrophages (immune cells). Cancer-supporting macrophages are present in high numbers in the BM of blood cancer patients (e.g. Multiple Myeloma), and contribute towards therapy resistance. Our initial study findings show that cancer-supporting (M2-like CD163+CD206+) macrophages are increased in the BM of AML patients compared to healthy individuals. Direct culture of AML cell lines together with M2-like macrophages, as well as macrophage secreted factors, protects AML cells from cell death (apoptosis) induced by standard cancer drugs (Williams et al. 2020). However, whether these macrophages are capable of conferring protection to primary AML cells (harvested directly from AML patients), and the underlying molecular mechanisms responsible for this therapy resistance, have still to be elucidated. 

Aims

The purpose of this study is to ascertain the involvement of macrophages in therapy resistance in AML, and identify and target novel therapy protective mechanisms in AML, via the use a unique 3D model system, and clinically applicable agents, accessed via academia/pharma (Cornell University/AstraZeneca) links. This will be achieved by:

1. Establishing 2D and 3D co-culture model systems to determine if macrophages protect AML cell lines from therapy induced apoptosis, and validate these findings using primary AML cells.

2. Using various molecular biology techniques to investigate and identify the molecular mechanisms that are responsible for macrophage induced therapy protection of AML cells.

3. To use clinically applicable inhibitors to target the above identified molecular mechanisms, with the aim of re-sensitising AML cells to therapeutics in the context of therapy protective macrophages.

Specific requirements of the project:  

The successful applicant will have a strong interest in exploring therapeutic strategies for the treatment of Leukaemia/Acute Myeloid Leukaemia, and hold a minimum of a first degree (2:1) or above, ideally in Cell Biology, Biochemistry or Molecular Biology or combinations thereof. Experience in molecular biology (e.g. immunoblotting, qPCR and flow cytometry) or cell culture techniques (e.g. culturing adherent and/ suspension cell lines/ primary cells), would be an advantage.  

This project is available as a 3 years full-time PhD

Applicants should apply for their preferred intake date using the Biological Sciences links via the Application Process page 


Funding Notes

Applicants are expected to find external funding sources to cover the tuition fees and living expenses. Alumni and International students new to GCU who are self-funding are eligible for fee discounts.

References

Burnett, A. K. Treatment of acute myeloid leukemia: are we making progress? Hematology Am Soc Hematol Educ Program 2012, 1–6 (2012).
Williams M.T.; Duncan J.; Corradini S.; Wheadon H.; Barry, S; Guzman, M; Investigating the role of the anti-cell death protein myeloid cell leukaemia 1 in macrophage mediated chemoresistance in acute myeloid leukaemia. Br J Pharmacol. 2020:177:2576-2577.

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