Epigenetic Targeting of Ovarian Cancer Stem Cells. Nephew, K. P, Wang, Y., Cardenas, H., Fang, F., Condello, S., Taverna, P., Segar, M., Liu, Y., & Matei, D. Cancer Research, 74(14):4922--4936, 2014. ![Epigenetic Targeting of Ovarian Cancer Stem Cells. [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex Emerging results indicate that cancer stem-like cells contribute to chemoresistance and poor clinical outcomes in many cancers, including ovarian cancer (OC). As epigenetic regulators play a major role in the control of normal stem cell differentiation, epigenetics may offer a useful arena to develop strategies to target cancer stem-like cells. Epigenetic aberrations, especially DNA methylation, silence tumor suppressor and differentiation-associated genes that regulate the survival of ovarian cancer stem-like cell (OCSC). In this study, we tested the hypothesis that DNA hypomethylating agents may be able to reset OCSC towards a differentiated phenotype, by evaluating the effects of the new DNA methytransferase inhibitor SGI-110 on OCSC phenotype, as defined by expression of the cancer stem-like marker aldehyde dehydrogenase (ALDH). We demonstrated that ALDH+ OC cells possess multiple stem cell characteristics, were highly chemoresistant, and were enriched in xenografts residual after platinum therapy. Low dose SGI-110 reduced the stem-like properties of ALDH+ cells, including their tumor initiating capacity, resensitized these OCSCs to platinum, and induced re-expression of differentiation-associated genes. Maintenance treatment with SGI-110 after carboplatin inhibited OCSC growth, causing global tumor hypomethylation and decreased tumor progression. Our work offers preclinical evidence that epigenome-targeting strategies have the potential to delay tumor progression by re-programming residual cancer stem-like cells. Further, the results suggest that SGI-110 might be administered in combination with platinum to prevent the development of recurrent and chemoresistant ovarian cancer.
@article{Nephew2014,
abstract = {Emerging results indicate that cancer stem-like cells contribute to chemoresistance and poor clinical outcomes in many cancers, including ovarian cancer (OC). As epigenetic regulators play a major role in the control of normal stem cell differentiation, epigenetics may offer a useful arena to develop strategies to target cancer stem-like cells. Epigenetic aberrations, especially DNA methylation, silence tumor suppressor and differentiation-associated genes that regulate the survival of ovarian cancer stem-like cell (OCSC). In this study, we tested the hypothesis that DNA hypomethylating agents may be able to reset OCSC towards a differentiated phenotype, by evaluating the effects of the new DNA methytransferase inhibitor SGI-110 on OCSC phenotype, as defined by expression of the cancer stem-like marker aldehyde dehydrogenase (ALDH). We demonstrated that ALDH+ OC cells possess multiple stem cell characteristics, were highly chemoresistant, and were enriched in xenografts residual after platinum therapy. Low dose SGI-110 reduced the stem-like properties of ALDH+ cells, including their tumor initiating capacity, resensitized these OCSCs to platinum, and induced re-expression of differentiation-associated genes. Maintenance treatment with SGI-110 after carboplatin inhibited OCSC growth, causing global tumor hypomethylation and decreased tumor progression. Our work offers preclinical evidence that epigenome-targeting strategies have the potential to delay tumor progression by re-programming residual cancer stem-like cells. Further, the results suggest that SGI-110 might be administered in combination with platinum to prevent the development of recurrent and chemoresistant ovarian cancer.},
author = {Nephew, Kenneth P and Wang, Yinu and Cardenas, Horacio and Fang, Fang and Condello, Salvatore and Taverna, Pietro and Segar, Matthew and Liu, Yunlong and Matei, Daniela},
doi = {10.1158/0008-5472.CAN-14-1022},
file = {:Users/Matt/Documents/Publications/Cancer Research.pdf:pdf},
issn = {1538-7445},
journal = {Cancer Research},
number = {14},
pages = {4922--4936},
pmid = {25035395},
title = {{Epigenetic Targeting of Ovarian Cancer Stem Cells.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/25035395},
volume = {74},
year = {2014}
}
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