Journal
CANCER DISCOVERY
Volume 3, Issue 9, Pages 1002-1019Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-13-0117
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Funding
- NIH [CA129831, CA129831-03S1]
- Clinical Translational Science Center (CTSC)
- National Center for Advancing Translational Sciences (NCATS) [UL1-RR024996]
- Burroughs-Wellcome Foundation
- Chemotherapy Foundation
- V Foundation
- Charles, Lillian and Betty Neuwirth Clinical Scholar Award
- Irma T. Hirschl Trust
- Doris Duke Charitable Foundation
- [LLS SCOR 7017-9]
- [K08 CA127353]
- [LLS 6304-11]
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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. (C) 2013 AACR.
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