فایل ورد کامل بیان ژن مرتبط با سلول بنیادی سرطان به عنوان یک بیومارکر بالقوه برای پاسخ به ایمی پریدن ONC201 رده اولی در تومورهای جامد

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بخشی از مقاله انگلیسیعنوان انگلیسی:Cancer stem cell-related gene expression as a potential biomarker of response for first-inclass imipridone ONC201 in solid tumors~~en~~

Abstract

Cancer 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 selfrenewing, 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.

Introduction

Several clinical studies have demonstrated the relevance of cancer stem cells (CSCs) that clearly correlate with recurrence, metastasis and poor survival in solid tumors [1–]. Recent objective responses observed in Phase I/II clinical trials of various CSC-targeted agents in a number of advanced refractory solid tumors have further established the importance of CSCs as a therapeutic target [4–].

The first-in-class small molecule imipridone ONC201 is currently in Phase I/II clinical trials for advanced cancer [7]. The first-in-human Phase I study in advanced solid tumors demonstrated ONC201 to be safe, and exhibit predicted pharmacokinetics, sustained pharmacodynamics and tumor shrinkage [8]. The anti-CSC efficacy of ONC201 has been previously demonstrated in vitro and in vivo in colorectal cancer and acute myeloid leukemia (AML) [9, 10]. ONC201-mediated depletion of chemotherapy-resistant colorectal CSCs involves dual inactivation of Akt and ERK signaling that results in transcription factor Foxo3 activation that leads to DR5/TRAIL-dependent inhibition of self-renewal [9, 11]. In the current study, we evaluated whether the anti-CSC effects of ONC201 involve early changes in stem-cell related gene expression prior to tumor cell death. We examined if ONC201-mediated inhibition of CSCs extends to other solid tumors. Additionally, we tested whether CSC expression can serve as a potential biomarker of ONC201 response.

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