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Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma
- Source :
- Gut
- Publication Year :
- 2021
- Publisher :
- BMJ, 2021.
-
Abstract
- ObjectiveGastro-oesophageal cancers (GEC) are resistant to therapy and lead to poor prognosis. The cancer stem cells (CSCs) and antiapoptotic pathways often confer therapy resistance. We sought to elucidate the antitumour action of a BCL-2 inhibitor, AT101 in GEC in vitro, in vivo and in a clinical trial.MethodsExtensive preclinical studies in vitro and in vivo were carried out to establish the mechanism action of AT101 on targeting CSCs and antiapoptotic proteins. A pilot clinical trial in patients with GEC was completed with AT-101 added to standard chemoradiation.ResultsOverexpression of BCL-2 and MCL-1 was noted in gastric cancer tissues (GC). AT-101 induced apoptosis, reduced proliferation and tumour sphere formation in MCL-1/BCL-2 high GC cells. Interestingly, AT101 dramatically downregulated genes (YAP-1/Sox9) that control CSCs in GEC cell lines regardless of BCL-2/MCL-1 expression. Addition of docetaxel to AT-101 amplified its antiproliferation and induced apoptosis effects. In vivo studies confirmed the combination of AT101 and docetaxel demonstrated stronger antitumour activity accompanied with significant decrease of CSCs biomarkers (YAP1/SOX9). In a pilot clinical trial, 13 patients with oesophageal cancer (EC) received AT101 orally concurrently with chemoradiation. We observed dramatic clinical complete responses and encouraging overall survival in these patients. Clinical specimen analyses revealed that AT-101 dramatically reduced the expression of CSCs genes in treated EC specimens indicating antitumour activity of AT101 relies more on its anti-CSCs activity.ConclusionsOur preclinical and clinical data suggest that AT-101 overcomes resistance by targeting CSCs pathways suggesting a novel mechanism of action of AT101 in patients with GEC.
- Subjects :
- Male
0301 basic medicine
Esophageal Neoplasms
Apoptosis
Pilot Projects
Docetaxel
Molecular oncology
Article
Mice
03 medical and health sciences
0302 clinical medicine
Stomach Neoplasms
In vivo
Cancer stem cell
Cell Line, Tumor
medicine
Animals
Humans
Gastrointestinal cancer
YAP1
business.industry
Gossypol
Gastroenterology
Cancer
Middle Aged
medicine.disease
Antineoplastic Agents, Phytogenic
Disease Models, Animal
030104 developmental biology
Proto-Oncogene Proteins c-bcl-2
030220 oncology & carcinogenesis
Neoplastic Stem Cells
Cancer research
Female
business
medicine.drug
Subjects
Details
- ISSN :
- 14683288 and 00175749
- Volume :
- 70
- Database :
- OpenAIRE
- Journal :
- Gut
- Accession number :
- edsair.doi.dedup.....1f9075c7eb8e0bd0d26a8e7c400cb58b