| Autor: |
Roundhill EA; Children's Cancer Research Group, Leeds Institute of Medical Research, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK., Pantziarka P; Anticancer Fund, Brusselsesteenweg 11, 1860 Meise, Belgium., Liddle DE; Children's Cancer Research Group, Leeds Institute of Medical Research, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK., Shaw LA; Children's Cancer Research Group, Leeds Institute of Medical Research, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK., Albadrani G; Children's Cancer Research Group, Leeds Institute of Medical Research, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK., Burchill SA; Children's Cancer Research Group, Leeds Institute of Medical Research, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK. |
| Abstrakt: |
Outcomes for most patients with Ewing sarcoma (ES) have remained unchanged for the last 30 years, emphasising the need for more effective and tolerable treatments. We have hypothesised that using small-molecule inhibitors to kill the self-renewing chemotherapy-resistant cells (Ewing sarcoma cancer stem-like cells; ES-CSCs) responsible for progression and relapse could improve outcomes and minimise treatment-induced morbidities. For the first time, we demonstrate that ABCG1, a potential oncogene in some cancers, is highly expressed in ES-CSCs independently of CD133. Using functional models, transcriptomics and a bespoke in silico drug-repurposing pipeline, we have prioritised a group of tractable small-molecule inhibitors for further preclinical studies. Consistent with the cellular origin of ES, 21 candidate molecular targets of pluripotency, stemness and chemoresistance were identified. Small-molecule inhibitors to 13 of the 21 molecular targets (62%) were identified. POU5F1/OCT4 was the most promising new therapeutic target in Ewing sarcoma, interacting with 10 of the 21 prioritised molecular targets and meriting further study. The majority of small-molecule inhibitors (72%) target one of two drug efflux proteins, p-glycoprotein ( n = 168) or MRP1 ( n = 13). In summary, we have identified a novel cell surface marker of ES-CSCs and cancer/non-cancer drugs to targets expressed by these cells that are worthy of further preclinical evaluation. If effective in preclinical models, these drugs and drug combinations might be repurposed for clinical evaluation in patients with ES. |
