TitleMechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma.
Publication TypeJournal Article
Year of Publication2013
AuthorsClozel, Thomas, Yang ShaoNing, Elstrom Rebecca L., Tam Wayne, Martin Peter, Kormaksson Matthias, Banerjee Samprit, Vasanthakumar Aparna, Culjkovic Biljana, Scott David W., Wyman Sarah, Leser Micheal, Shaknovich Rita, Chadburn Amy, Tabbò Fabrizio, Godley Lucy A., Gascoyne Randy D., Borden Katherine L., Inghirami Giorgio, Leonard John P., Melnick Ari, and Cerchietti Leandro
JournalCancer Discov
Date Published2013 Sep
KeywordsAdult, Aged, Aged, 80 and over, Antimetabolites, Antineoplastic, Azacitidine, Cell Line, Tumor, DNA Damage, DNA Methylation, DNA Modification Methylases, Doxorubicin, Drug Resistance, Neoplasm, Epigenesis, Genetic, Humans, Lymphoma, Large B-Cell, Diffuse, Middle Aged, RNA Interference, RNA, Small Interfering, Smad1 Protein, Young Adult

<p><b>UNLABELLED: </b>Although aberrant DNA methylation patterning is a hallmark of cancer, the relevance of targeting DNA methyltransferases (DNMT) remains unclear for most tumors. In diffuse large B-cell lymphoma (DLBCL) we observed that chemoresistance is associated with aberrant DNA methylation programming. Prolonged exposure to low-dose DNMT inhibitors (DNMTI) reprogrammed chemoresistant cells to become doxorubicin sensitive without major toxicity in vivo. Nine genes were recurrently hypermethylated in chemoresistant DLBCL. Of these, SMAD1 was a critical contributor, and reactivation was required for chemosensitization. A phase I clinical study was conducted evaluating azacitidine priming followed by standard chemoimmunotherapy in high-risk patients newly diagnosed with DLBCL. The combination was well tolerated and yielded a high rate of complete remission. Pre- and post-azacitidine treatment biopsies confirmed SMAD1 demethylation and chemosensitization, delineating a personalized strategy for the clinical use of DNMTIs.</p><p><b>SIGNIFICANCE: </b>The problem of chemoresistant DLBCL remains the most urgent challenge in the clinical management of patients with this disease. We describe a mechanism-based approach toward the rational translation of DNMTIs for the treatment of high-risk DLBCL.</p>

Alternate JournalCancer Discov
PubMed ID23955273
PubMed Central IDPMC3770813
Grant ListCA129831-03S1 / CA / NCI NIH HHS / United States
K08 CA127353 / CA / NCI NIH HHS / United States
R01 CA080728 / CA / NCI NIH HHS / United States
UL1-RR024996 / RR / NCRR NIH HHS / United States
CA129831 / CA / NCI NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States
R01 CA129831 / CA / NCI NIH HHS / United States
UL1 RR024996 / RR / NCRR NIH HHS / United States