Open Access
Prediction of response to therapy with ezatiostat in lower risk myelodysplastic syndrome
Naomi Galili,Pablo Tamayo,Olga B Botvinnik,Jill P. Mesirov,Margarita R Brooks,Gail L. Brown,Azra Raza +6 more
TLDR
In this paper, the authors used gene expression profiling and grouping by response to construct a predictive score that indicates the likelihood that patients without deletion 5q will respond to lenalidomide.Abstract:
Approximately 70% of all patients with myelodysplastic syndrome (MDS) present with lower-risk disease. Some of these patients will initially respond to treatment with growth factors to improve anemia but will eventually cease to respond, while others will be resistant to growth factor therapy. Eventually, all lower-risk MDS patients require multiple transfusions and long-term therapy. While some patients may respond briefly to hypomethylating agents or lenalidomide, the majority will not, and new therapeutic options are needed for these lower-risk patients. Our previous clinical trials with ezatiostat (ezatiostat hydrochloride, Telentra®, TLK199), a glutathione S-transferase P1-1 inhibitor in clinical development for the treatment of low- to intermediate-risk MDS, have shown significant clinical activity, including multilineage responses as well as durable red-blood-cell transfusion independence. It would be of significant clinical benefit to be able to identify patients most likely to respond to ezatiostat before therapy is initiated. We have previously shown that by using gene expression profiling and grouping by response, it is possible to construct a predictive score that indicates the likelihood that patients without deletion 5q will respond to lenalidomide. The success of that study was based in part on the fact that the profile for response was linked to the biology of the disease. RNA was available on 30 patients enrolled in the trial and analyzed for gene expression on the Illumina HT12v4 whole genome array according to the manufacturer’s protocol. Gene marker analysis was performed. The selection of genes associated with the responders (R) vs. non-responders (NR) phenotype was obtained using a normalized and rescaled mutual information score (NMI). We have shown that an ezatiostat response profile contains two miRNAs that regulate expression of genes known to be implicated in MDS disease pathology. Remarkably, pathway analysis of the response profile revealed that the genes comprising the jun-N-terminal kinase/c-Jun molecular pathway, which is known to be activated by ezatiostat, are under-expressed in patients who respond and over-expressed in patients who were non-responders to the drug, suggesting that both the biology of the disease and the molecular mechanism of action of the drug are positively correlated.read more
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Journal ArticleDOI
Synthesis of β-Thiolated-α-arylated Ketones Enabled by Photoredox and N-Heterocyclic Carbene-Catalyzed Radical Relay of Alkenes with Disulfides and Aldehydes.
Haifeng Du,Mingshun Liu,Wei Shu +2 more
TL;DR: A straightforward protocol to access β-thiolated ketones from aldehydes, alkenes, and disulfides enabled by the combination of photocatalysis and N-heterocyclic carbene catalysis is reported.
References
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Book
Elements of information theory
Thomas M. Cover,Joy A. Thomas +1 more
TL;DR: The author examines the role of entropy, inequality, and randomness in the design of codes and the construction of codes in the rapidly changing environment.
Journal ArticleDOI
International Scoring System for Evaluating Prognosis in Myelodysplastic Syndromes
Peter L. Greenberg,Christopher Cox,Michelle M. LeBeau,Pierre Fenaux,Pierre Morel,Guillermo Sanz,Miguel A. Sanz,Teresa Vallespi,Terry J. Hamblin,David Oscier,Kazuma Ohyashiki,Keisuke Toyama,Carlo Aul,Ghulam J. Mufti,John M. Bennett +14 more
TL;DR: The International MDS Risk Analysis Workshop combined cytogenetic, morphological, and clinical data from seven large previously reported risk-based studies that had generated prognostic systems as discussed by the authors.
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