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Prabhu VV , Lulla AR , Madhukar NS , Ralff MD , Zhao D , Kline CLB , Van den Heuvel APJ , Lev A , Garnett MJ , McDermott U , Benes CH , Batchelor TT , Chi AS , Elemento O , Allen JE , El-Deiry WS
Cancer stem cell-related gene expression as a potential biomarker of response for first-in-class imipridone ONC201 in solid tumors
PLoS One. 2017 Aug;12(8) :e0180541
PMID: 28767654 PMCID: PMC5540272
AbstractCancer stem cells (CSCs) correlate with recurrence, metastasis and poor survival in clinical studies. Encouraging results from clinical trials of CSC inhibitors have further validated CSCs as therapeutic targets. ONC201 is a first-in-class small molecule imipridone in Phase I/II clinical trials for advanced cancer. We have previously shown that ONC201 targets self-renewing, chemotherapy-resistant colorectal CSCs via Akt/ERK inhibition and DR5/TRAIL induction. In this study, we demonstrate that the anti-CSC effects of ONC201 involve early changes in stem cell-related gene expression prior to tumor cell death induction. A targeted network analysis of gene expression profiles in colorectal cancer cells revealed that ONC201 downregulates stem cell pathways such as Wnt signaling and modulates genes (ID1, ID2, ID3 and ALDH7A1) known to regulate self-renewal in colorectal, prostate cancer and glioblastoma. ONC201-mediated changes in CSC-related gene expression were validated at the RNA and protein level for each tumor type. Accordingly, we observed inhibition of self-renewal and CSC markers in prostate cancer cell lines and patient-derived glioblastoma cells upon ONC201 treatment. Interestingly, ONC201-mediated CSC depletion does not occur in colorectal cancer cells with acquired resistance to ONC201. Finally, we observed that basal expression of CSC-related genes (ID1, CD44, HES7 and TCF3) significantly correlate with ONC201 efficacy in >1000 cancer cell lines and combining the expression of multiple genes leads to a stronger overall prediction. These proof-of-concept studies provide a rationale for testing CSC expression at the RNA and protein level as a predictive and pharmacodynamic biomarker of ONC201 response in ongoing clinical studies.
Notes1932-6203 Prabhu, Varun V Lulla, Amriti R Madhukar, Neel S Ralff, Marie D Zhao, Dan Kline, Christina Leah B Van den Heuvel, A Pieter J Lev, Avital Garnett, Mathew J McDermott, Ultan Benes, Cyril H Batchelor, Tracy T Chi, Andrew S Elemento, Olivier Allen, Joshua E El-Deiry, Wafik S ORCID: http://orcid.org/0000-0002-9577-8266 Journal Article United States PLoS One. 2017 Aug 2;12(8):e0180541. doi: 10.1371/journal.pone.0180541. eCollection 2017.