Title | Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Clozel T, Yang SN, Elstrom RL, Tam W, Martin P, Kormaksson M, Banerjee S, Vasanthakumar A, Culjkovic B, Scott DW, Wyman S, Leser M, Shaknovich R, Chadburn A, Tabbo F, Godley LA, Gascoyne RD, Borden KL, Inghirami G, Leonard JP, Melnick A, Cerchietti L |
Journal | Cancer Discov |
Volume | 3 |
Issue | 9 |
Pagination | 1002-19 |
Date Published | 2013 Sep |
ISSN | 2159-8290 |
Keywords | Adult, 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 |
Abstract | UNLABELLED: 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. SIGNIFICANCE: 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. |
DOI | 10.1158/2159-8290.CD-13-0117 |
Alternate Journal | Cancer Discov |
PubMed ID | 23955273 |
PubMed Central ID | PMC3770813 |
Grant List | CA129831-03S1 / CA / NCI NIH HHS / United States UL1-RR024996 / RR / NCRR NIH HHS / United States CA129831 / CA / NCI NIH HHS / United States |
Related Faculty:
Giorgio Inghirami, M.D.