Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma

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.

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.