Objective Gastro-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.
Methods Extensive 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.
Results Overexpression 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.
Conclusions Our 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.
- gastrointestinal cancer
- gene expression
- molecular oncology
- oesophageal cancer
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Contributors Conception and design: SS and JAA. Development of methodology: QC, SS, AS, LH, GL, YL, CYL, JJ, LM, BL, YW and MPP. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc): QC, SS, JHE, AS, LH, GL, YL, CYL, JJ, LM, BL, YW, MPP, WLH, JHL, BW, MB, NS, RLJ, SW and JAA. Analysis and interpretation of data (eg, statistical analysis, biostatistics, computational analysis): SS, AC, LX and JAA. Writing, review, and/or revision of the manuscript: SS, QC and JAA. Administrative, technical, or material support (ie, reporting or organizing data, constructing databases): SS, QC, BG and JAA. Study supervision: SS. Other (financial support): JAA and SS.
Funding Funding supports for this study was in part by the donations received from the Caporella, Dallas, Sultan, Park, Smith, Frazier, Oaks, Sultan, Vansteklenberg, Planjery, and Cantu Families, the Stupid Strong Foundation, the V foundation, the Schecter Private Foundation, Rivercreek Foundation, Kevin Fund, Myer Fund, Dio Fund, Milrod Fund, and the Multidisciplinary Research Grants provided by the University of Texas M. D. Anderson Cancer Centre, Houston, USA; Public Health Service Grant DF56338 which supports the Texas Medical Centre Digestive DiseasesCentre (Song S); UTMDACC IRG(3-0026317,Song S). CA160433 and CA170906 from the Department of Defence (Song S). CA129906, CA127672, CA138671, and CA172741 from the National Cancer Institute and CA150334 and CA160445 from the Department of Defence (JAA).
Competing interests The authors declare that there are no conflicts of interest.
Patient consent for publication Not required.
Ethics approval Ethical approval for this study was obtained from the Institutional Review Board of The University of Texas MD Anderson Cancer Center. All patients who volunteered to provide research specimens signed an approved written consent document.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. NA.
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