Mechanism-Based Epigenetic Chemosensitization Therapy of Diffuse Large B-Cell Lymphoma

Abstract

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 chemo-resistance is associated with aberrant DNA methylation programming. Prolonged exposure to low-dose DNMT inhibitors (DNMTIs) reprogrammed chemo-resistant cells to become doxorubicin sensitive without major toxicity in vivo. Nine genes were recurrently hypermethylated in chemo-resistant DLBCL. Of these, SMAD1 was a critical contributor, and reactivation was required for chemosensitization. A phase I clinical study was performed evaluating azacitidine priming followed by standard chemoimmunotherapy in high-risk newly diagnosed DLBCL patients. 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.

Emergence of cytotoxic resistance in cancer cell populations*

“…In particular, we suggested that the absence of non-genetic instability can result in the stabilization of the DTP phenotype in the surviving population, so that DTEPs do not emerge, or even in extinction. This is a key result since it supports the idea that epigenetic therapy may be a promising therapeutic strategy in the war against cancer [16][17][18]. Another important prediction of our models is that the transient dominance of DTPs is strictly related to the use of high doses of cytotoxic drugs.…”

DNA Methylation in Mammalian Cells

“…The DMRs can also be used to predict response of patients with chronic myelomonocytic leukaemia to DNMTi [109]. Hypermethylation and silencing of SMAD1 was useful as a predictive biomarker for chemotherapy resistance in patients with high-risk diffuse large B-cell lymphoma (DLBCL) [110]. SMAD1 silencing also showed contribution to chemotherapy resistance that can be reversed by DNMTis in patients [110].…”

“…Hypermethylation and silencing of SMAD1 was useful as a predictive biomarker for chemotherapy resistance in patients with high-risk diffuse large B-cell lymphoma (DLBCL) [110]. SMAD1 silencing also showed contribution to chemotherapy resistance that can be reversed by DNMTis in patients [110]. Results were favourable for the use of DNMTi in patients diagnosed with high-risk DLBCL, in combination with decitabine before rituximab in combination of cyclophosphamide, doxorubine, vincristine and prednisone chemo-immunotherapy.…”

DNA methylation in cancer

“…Indeed DNA methylation has a critical role in genome integrity by repressing transcription at repeated sequences, including highly mutagenic retrotransposon elements. When located in promoters, CpG island DNA hypermethylation is also associated with a repressed chromatin and thus transcription inhibition (Iguchi-Ariga and Schaffner, 1989;Watt and Molloy, 1988;Prendergast and Ziff, 1991;Clozel et al, 2013). Genes located downstream are silenced although their genomic sequence is intact.…”

“…By targeting DNA methylation, cells are reprogrammed; reexpression of TSG can induce cell arrest, differentiation and death, but also sensitivity to apoptosis, immuno-response and drug treatment. An example is the reversal of the resistance to doxorubicine in diffuse large B-cell lymphoma (DLBL) by low-doses of DNMT inhibitors (Clozel et al, 2013). It exists two classes of DNMT inhibitors (DNMTi): the nucleoside analogues that are incorporated into nucleic acids and form a covalent complex with the enzyme, and the non-nucleoside inhibitors that present different mechanisms of inhibition.…”