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Exploiting the Stemness and Chemoresistance Transcriptome of Ewing Sarcoma to Identify Candidate Therapeutic Targets
Elizabeth Ann Roundhill1, Pan Pantziarka2, Danielle E Liddle1
1Children's Cancer Research Group, Leeds Institute of Medical Research, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
Abstract:
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.
Insights
New research identifies ABCG1 as a marker for Ewing sarcoma cancer stem-like cells (ES-CSCs). Small-molecule inhibitors targeting these cells and POU5F1/OCT4 show promise for improved Ewing sarcoma treatment.
Area of Science:
- Oncology
- Cancer Stem Cell Biology
- Pharmacology
Background:
- Outcomes for Ewing sarcoma (ES) patients have stagnated for 30 years, necessitating novel therapeutic strategies.
- Ewing sarcoma cancer stem-like cells (ES-CSCs) drive disease progression and relapse, exhibiting chemotherapy resistance.
- Targeting ES-CSCs offers a potential avenue to improve treatment efficacy and reduce toxicity.
Purpose of the Study:
- To identify novel therapeutic targets and small-molecule inhibitors for Ewing sarcoma.
- To investigate the role of ABCG1 in ES-CSCs and its potential as a therapeutic target.
- To discover drugs that can overcome chemotherapy resistance in Ewing sarcoma.
Main Methods:
- Utilized functional models, transcriptomics, and an in silico drug-repurposing pipeline.
- Identified and prioritized molecular targets associated with pluripotency, stemness, and chemoresistance in ES-CSCs.
- Screened for existing small-molecule inhibitors against prioritized targets, including drug efflux proteins.
Main Results:
- ABCG1 was identified as highly expressed in ES-CSCs, independent of CD133.
- 21 candidate molecular targets related to stemness and chemoresistance were identified.
- Small-molecule inhibitors were found for 62% of these targets, with POU5F1/OCT4 emerging as a key target.
- A majority of identified inhibitors targeted p-glycoprotein or MRP1 drug efflux proteins.
Conclusions:
- ABCG1 is a novel marker for ES-CSCs, offering a new therapeutic avenue.
- A panel of small-molecule inhibitors targeting key pathways in ES-CSCs has been identified.
- POU5F1/OCT4 and drug efflux proteins are promising targets for Ewing sarcoma therapy.
- Repurposed drugs targeting ES-CSCs warrant further preclinical and clinical evaluation.
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