Project ID iCASE2026_08_CM-HD

ThemeCM-HD

Co Supervisor 1A Professor James Arnold Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer CentreEmail

Co Supervisor 1B Professor Miraz Rahman Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, Institute of Pharmaceutical ScienceEmail

Partner Supervisor Professor James Spicer

Partner Aethox Therapeutics

Enhancing antibody-drug conjugate efficacy in solid tumours via modulating macrophage function

This project aims to improve cancer treatment by enhancing the effectiveness of antibody-drug conjugates (ADCs), targeted therapies that deliver chemotherapy directly to cancer cells. While ADCs have shown success in some cancers, they are often less effective in solid tumours. This is partly due to the tumour microenvironment, a complex network of cells and signals that can protect tumours and reduce drug effectiveness. A key contributor to this resistance is the tumour-associated macrophage (TAM), an immune cell that supports tumour growth and limits therapeutic response.

The project will explore how TAMs influence ADC activity and test strategies to overcome this resistance, particularly by combining ADCs with agents that modulate macrophage behaviour. The aim is to improve treatment outcomes by addressing both the cancer cells and their surrounding environment.

The student will be trained in ADC synthesis, linker-payload chemistry, cell culture, and in vitro pharmacology. They will use in vivo models to assess treatment efficacy and study resistance. Techniques such as flow cytometry, immunofluorescence, and RNA sequencing will be used to analyse tumour responses.

Project Aims:
• To create and optimise an ADC targeting a solid tumour-specific antigen to improve therapeutic efficacy.
• To investigate how tumour-associated macrophages drive resistance to ADCs using laboratory and animal models.
• To apply advanced immune profiling to uncover resistance mechanisms, identify combination strategies, and discover biomarkers predictive of treatment success.

PhD Outline:
Year 1:
The student will be trained in ADC synthesis, solid- and solution-phase chemistry, and linker-payload optimisation. They will develop and characterise a novel ADC targeting a solid tumour antigen using analytical techniques such as LC-MS and HIC. In vitro assays will be established to assess ADC stability, cell permeability, and cytotoxicity. Co-culture experiments will explore early interactions between ADCs and TAMs, supported by pharmacological profiling.
Year 2:
In vivo cancer models will be used to assess ADC efficacy and TAM-mediated resistance. Medicinal chemistry will be applied to optimise linker and payload design. TAM-modulating compounds will be tested in combination with ADCs, and bioanalytical methods will characterise tissue distribution.
Year 3:
Detailed tumour profiling using flow cytometry, immunofluorescence, and sequencing will identify resistance mechanisms. The student will undertake a three-month industrial placement with Aethox Therapeutics.
Year 4:
Findings will be validated, therapeutic strategies refined, and the thesis and publications prepared for dissemination.

This project offers a unique opportunity to combine chemical biology and tumour immunology providing valuable skills and knowledge for a future career in biomedical science.

Representative Publications

Co-1A
1. Anstee, J.E., Feehan, K.T., Opzoomer, J.W., Dean, I., Muller, H.P., Bahri, M., Cheung, T.S., Liakath-Ali, K., Liu, Z., Choy, D., Caron, J., Sosnowska, D., Beatson, R., Muliaditan, T., An, Z., Gillett, C.E., Lan, G., Zou, X., Watt, F.M., Ng, T., Burchell, J.M., Kordasti, D., Withers, D.R., Lawrence, T., Arnold, J.N. (2023) LYVE-1+ macrophages form a collaborative CCR5-dependent perivascular niche that influences chemotherapy responses in murine breast cancer. Developmental Cell. 58:17. 10.1016/j.devcel.2023.06.006

2. Opzoomer, J.W., Anstee, J.E., Dean, I., Hill, E.J., Bouybayoune, I., Caron, J., Muliaditan, T., Gordon, P., Sosnowska, D., Nuamah, R., Pinder, S.E., Ng, T., Dazzi, F., Kordasti, S., Withers, D.R., Lawrence, T., Arnold J.N. (2021) Macrophages orchestrate the expansion of a proangiogenic perivascular niche during cancer progression. Science Advances. 7:45. 10.1126/sciadv.abg9518

3. Kosti, P., Opzoomer, J.W., Larios-Martinez, K., Henley-Smith, R., Scudamore, C.L., Okesola, M, Taher, M.Y.M., Davies, D.M., Muliaditan, T., Larcombe-Young, D., Woodman, N., Gillett, C.E., M., Thavaraj, S., Maher, J.* and Arnold, J.N.* (2021) Hypoxia-sensing CAR T-cells provide safety and efficacy in treating solid tumors. Cell Reports Medicine, 12:658315. * co-senior authors 10.1016/j.xcrm.2021.100227

Co-1B
1. Andriollo, Paolo, Daniella di Mascio, Paul JM Jackson, Md Mahbub Hasan, Ilona Pysz-Hosey, George Procopiou, Keith R. Fox, Khondaker Miraz Rahman, and David E. Thurston. “A novel DNA sequence-selective, guanine mono-alkylating ADC payload suitable for solid tumour treatment.” RSC Medicinal Chemistry (2025). DOI: https://doi.org/10.1039/D4MD01040J

2. Jin, Peiqin, Md Mahbub Hasan, Andrea GS Pepper, Simon Mitchell, Khondaker Miraz Rahman, and Chris Pepper. “Design, synthesis and evaluation of pyrrolobenzodiazepine (PBD)-based PROTAC conjugates for the selective degradation of the NF-κB RelA/p65 subunit.” RSC Medicinal Chemistry (2025). DOI: https://doi.org/10.1039/D5MD00316D

3. Corcoran, David B., Thomas Lewis, Kazi S. Nahar, Shirin Jamshidi, Christopher Fegan, Chris Pepper, David E. Thurston, and Khondaker Miraz Rahman. “Effects of systematic shortening of noncovalent C8 side chain on the cytotoxicity and NF-κB inhibitory capacity of pyrrolobenzodiazepines (PBDs).” Journal of Medicinal Chemistry 62, no. 4 (2019): 2127-2139. DOI: https://doi.org/10.1021/acs.jmedchem.8b01849