In recent years the use of patient-derived xenograft (PDX) models has become an important aspect of cancer research and the development of new therapeutics. Tumour tissue taken from patients is transplanted into immunocompromised mice and expanded and maintained by passaging cells directly from mouse to mouse. The mice can be used in efficacy studies and in some cases are being used as “avatars” to inform clinical decisions about the treatment of the patient from which PDX was established. However, the rate of implantation can be variable and subcutaneous implantations mean cancer cells are removed from an environment not necessarily faithfully recapitulated in the mouse.
Why we funded it
This fellowship aims to replace the need for PDX mice in the expansion of patient-derived leukaemia cells using a novel ex vivo human cell based platform.
192 PDX mice are required per year for expanding primary leukaemia samples and drug development in the Wolfson Childhood Cancer Research Centre at Newcastle University. These could all be replaced with the platform developed by Dr Pal. The platform also has the potential to be used in drug screening to optimise the selection of compounds before in vivo testing. The drug pipeline at Newcastle University typically requires 35-60 mice for preclinical testing, followed by a further 45-50 mice needed to assay a single drug. However, there is a high attrition rate in oncology research with seven percent of drugs tested through clinical trials approved for use in the clinic. Use of the ex vivo platform can reduce both the rate of attrition and the animals required for cancer drug development.
Dr Pal and colleagues from Newcastle University have previously shown that patient-derived leukaemia cells can be expanded ex vivo over long periods of time without losing their characteristics of self-renewal and while maintaining clonal heterogenity.1 The leukaemia cells are supported by human bone marrow mesenchymal stem cells (BM-MSCs) which act as feeder cells. Human BM-MSCs have limited capacity for in vitro proliferation and have to be regularly renewed from different individuals, which can compromise reproducibility between laboratories, as well as limiting the accessibility of in vitro studies. The aim of the fellowship is to address this by developing a uniform source of BM-MSC through induced pluripotent stem cell technology.
1 Pal, D. et al. (2016) Long-term in vitro maintenance of clonal abundance and leukaemia-initiating potential in acute lymphoblastic leukaemia. Leukemia 30, 1691-1700.
Fidyt K et al. (2019). Targeting the thioredoxin system as a novel strategy against B‐cell acute lymphoblastic leukemia. Molecula Oncology 13:1180-1195. doi: 10.1002/1878-0261.12476
Carr-Wilkinson J et al. (2018). Differentiation of Human Embryonic Stem Cells to Sympathetic Neurons: A Potential Model for Understanding Neuroblastoma Pathogenesis. Stem Cells International 2018:4391641. doi: 10.1155/2018/4391641
da Conceicao Ribeiro R et al. (2018). Reactive jet impingement bioprinting of high cell density gels for bone microtissue fabrication. Biofabrication 11(1):015014. doi: 10.1088/1758-5090/aaf625
Fordham SE et al. (2018). Inhibition of ATR acutely sensitizes acute myeloid leukemia cells to nucleoside analogs that target ribonucleotide reductase. Blood Advances 2(10):1157-1169. doi: 10.1182/bloodadvances.2017015214
Martinez-Soria N et al. (2018). The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation. Cancer cell 34(4):626–642.e8. doi: 10.1016/j.ccell.2018.08.015
da Conceicao Ribeiro R et al. (2017). Temporary Single-Cell Coating for Bioprocessing with a Cationic Polymer. ACS applied materials & interfaces 9(15):12967-12974. doi: 10.1021/acsami.6b16434