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000170569 1001_ $$0P:(DE-He78)f0ba5845b4da12c9b76df3ec64013b23$$aMüller, Michael$$b0$$eFirst author$$udkfz
000170569 245__ $$aCombining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma.
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000170569 520__ $$aAPR-246 (Eprenetapopt/PRIMA-1Met) is a very potent anti-cancer drug in clinical trials and was initially developed as a p53 refolding agent. As an alternative mode of action, the elevation of reactive oxygen species (ROS) has been proposed. Through an in silico analysis, we investigated the responses of approximately 800 cancer cell lines (50 entities; Cancer Therapeutics Response Portal, CTRP) to APR-246 treatment. In particular, neuroblastoma, lymphoma and acute lymphocytic leukemia cells were highly responsive. With gene expression data from the Cancer Cell Line Encyclopedia (CCLE; n = 883) and patient samples (n = 1643) from the INFORM registry study, we confirmed that these entities express low levels of SLC7A11, a previously described predictive biomarker for APR-246 responsiveness. Combining the CTRP drug response data with the respective CCLE gene expression profiles, we defined a novel gene signature, predicting the effectiveness of APR-246 treatment with a sensitivity of 90% and a specificity of 94%. We confirmed the predicted APR-246 sensitivity in 8/10 cell lines and in ex vivo cultures of patient samples. Moreover, the combination of ROS detoxification-impeding APR-246 with approved HDAC-inhibitors, known to elevate ROS, substantially increased APR-246 sensitivity in cell cultures and in vivo in two zebrafish neuroblastoma xenograft models. These data provide evidence that APR-246, in combination with HDAC-inhibitors, displays a novel potent targeted treatment option for neuroblastoma patients.
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000170569 650_7 $$2Other$$aROS
000170569 650_7 $$2Other$$aTP53
000170569 650_7 $$2Other$$ahistone deacetylases
000170569 650_7 $$2Other$$apediatric tumors of the nervous system
000170569 650_7 $$2Other$$aprecision medicine
000170569 650_7 $$2Other$$aresponse prediction biomarker
000170569 650_7 $$2Other$$asmall molecule inhibitors
000170569 7001_ $$0P:(DE-He78)11a5984ad9d927df64e2bd688545375f$$aRösch, Lisa$$b1$$udkfz
000170569 7001_ $$0P:(DE-He78)f08873535c440e3ce033c84d5786f70f$$aNajafi, Sara$$b2$$udkfz
000170569 7001_ $$0P:(DE-He78)35c44ba0995477242f21a01ca69d6945$$aGatzweiler, Charlotte$$b3$$udkfz
000170569 7001_ $$0P:(DE-He78)53112ef656923758316e7079710bc988$$aRidinger, Johannes$$b4$$udkfz
000170569 7001_ $$0P:(DE-He78)4302629f88822e785a2ba95b985cc952$$aGerloff, Xenia F$$b5$$udkfz
000170569 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David T W$$b6$$udkfz
000170569 7001_ $$00000-0002-7441-7867$$aBaßler, Jochen$$b7
000170569 7001_ $$0P:(DE-He78)21d657d65d4ad0fd8b0bbfe10fa65172$$aKreth, Sina$$b8$$udkfz
000170569 7001_ $$0P:(DE-He78)311fe8118b7563b455ba84e94fccb3a8$$aStainczyk, Sabine$$b9$$udkfz
000170569 7001_ $$aFrese, Karen$$b10
000170569 7001_ $$aMeder, Benjamin$$b11
000170569 7001_ $$0P:(DE-He78)91f32735ee876c579d63c05a7f4778dd$$aWestermann, Frank$$b12$$udkfz
000170569 7001_ $$0P:(DE-He78)0be2f86573954f87e97f8a4dbb05cb0f$$aMilde, Till$$b13$$udkfz
000170569 7001_ $$0P:(DE-He78)2727b5cb63b52d0137d4f4e8f110ee7e$$aPeterziel, Heike$$b14$$udkfz
000170569 7001_ $$0P:(DE-He78)143af26de9d57bf624771616318aaf7c$$aWitt, Olaf$$b15$$udkfz
000170569 7001_ $$0P:(DE-He78)908367a659dea9e28dac34592b3c46e5$$aOehme, Ina$$b16$$eLast author$$udkfz
000170569 773__ $$0PERI:(DE-600)2527080-1$$a10.3390/cancers13174476$$gVol. 13, no. 17, p. 4476 -$$n17$$p4476$$tCancers$$v13$$x2072-6694$$y2021
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