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Pleural mesothelioma: new therapeutic approach to enhance sensitivity to chemo- and radiotherapy

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(Vienna, 11 October 2023) Pleural mesothelioma (PM) is mainly caused by asbestos exposure and characterized by poor prognosis and limited therapeutic options. A recent research study led by Karin Schelch and Michael Grusch from MedUni Vienna identified the oncoprotein YB-1 as an attractive therapeutic target in PM and demonstrates that indirect targeting of YB-1 is a promising approach to enhance sensitivity to chemo- and radiotherapy. The study results were published in the medical journal "Cancer Letters”.

The study follows on from findings published earlier this year by the research group led by Michael Grusch (Center for Cancer Research at MedUni Vienna and Comprehensive Cancer Center at MedUni Vienna and University Hospital Vienna), according to which the oncoprotein YB-1 is involved in regulating multiple traits of pleural mesothelioma (PM) such as cell growth, cell death and migration. The current study proves its relevance also in drug response. Accordingly, YB-1 knockdown via siRNA resulted in significantly reduced tumor growth and furthermore enhanced the sensitivity to cisplatin and radiation.

Reaching the target
Histone deaceylase inhibitors (HDACi) have already been shown in trials to be effective in fighting tumor cells of different types. Since there are no pharmaceutical YB-1 inhibitors available, indirect targeting of YB-1 was achieved by the HDACi entinostat which also inhibits YB-1 deacetylation, thereby modifying its function. "Our findings provide the basis for the development of novel, clinically feasible therapy approaches" says principal investigator Michael Grusch from the Center of Cancer Research and Comprehensive Cancer Center, highlighting the study's high clinical relevance.

Combination instead of single therapy
Entinostat proved to be very effective against PM cells and furthermore showed strong synergistic interactions with cisplatin chemotherapy, which was linked to significantly increased cellular platinum uptake. In a mouse model, the combination of cisplatin and entinostat also resulted in stronger growth inhibition than each treatment alone.
"These data go hand in hand with another study performed in parallel in Small Cell Lung Cancer where we showed similar synergistic effects between these two drugs” says Karin Schelch also from MedUni Vienna's Center for Cancer Research, Comprehensive Cancer Center and Department of Thoracic Surgery at MedUni Vienna and University Hospital Vienna, first author of the present and last author of the parallel study recently published in Clinical Cancer Research.
Taken together, this study highlights YB-1 as an attractive target in PM and demonstrates that targeting YB-1 via entinostat is an urgently needed novel treatment approach for PM.

Publication: Cancer Letters
Targeting YB-1 via entinostat enhances cisplatin sensitivity of pleural mesothelioma in vitro and in vivo.
Schelch K, Emminger D, Zitta B, Johnson TG, Kopatz V, Eder S, Ries A, Stefanelli A, Heffeter P, Hoda MA, Hoetzenecker K, Dome B, Berger W, Reid G, Grusch M.
Cancer Lett. 2023 Sep 18:216395. doi: 10.1016/j.canlet.2023.216395. Online ahead of print.