Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma
Thomas Clozel1, ShaoNing Yang, Rebecca L Elstrom
11Division of Hematology and Oncology, Department of Medicine, 2Division of Biostatistics and Epidemiology, Department of Public Health, 3Weill Cornell Cancer Center, and Departments of 4Pathology and 5Pharmacology, Weill Cornell Medical College, Cornell University, New York, New York; 6Section of Hematology/Oncology, Department of Medicine, The University of Chicago; Department of Pathology, Northwestern University, Chicago, Illinois; 8Institute for Research in Immunology and Cancer and Department of Pathology and Cell Biology, University of Montreal, Montreal, Quebec; 9Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada; 10IBM Research, Rio de Janeiro, Brazil; and 11Department of Oncological Sciences, University of Turin, Turin, Italy.
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.
Insights
DNA methyltransferase inhibitors (DNMTI) can re-sensitize chemoresistant diffuse large B-cell lymphoma (DLBCL) to chemotherapy. A phase I trial combining azacitidine with standard treatment showed high remission rates and confirmed SMAD1 demethylation.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Aberrant DNA methylation is a cancer hallmark, but its role in diffuse large B-cell lymphoma (DLBCL) chemoresistance is not fully understood.
- Chemoresistance in DLBCL is linked to aberrant DNA methylation programming.
- Targeting DNA methyltransferases (DNMT) offers a potential therapeutic strategy.
Purpose of the Study:
- To investigate the role of DNA methylation in DLBCL chemoresistance.
- To evaluate the efficacy and safety of DNMT inhibitors (DNMTI) in chemoresistant DLBCL.
- To explore a personalized strategy for DNMTI use in DLBCL treatment.
Main Methods:
- In vitro studies with prolonged exposure to low-dose DNMT inhibitors on chemoresistant DLBCL cells.
- In vivo studies to assess toxicity and efficacy of DNMTI treatment.
- A phase I clinical trial combining azacitidine with standard chemoimmunotherapy in newly diagnosed high-risk DLBCL patients.
- Analysis of pre- and post-treatment biopsies to confirm target engagement (SMAD1 demethylation) and clinical response.
Main Results:
- Low-dose DNMTI reprogrammed chemoresistant DLBCL cells to become doxorubicin sensitive without significant in vivo toxicity.
- Nine genes were recurrently hypermethylated in chemoresistant DLBCL, with SMAD1 identified as a critical contributor to chemosensitization.
- The combination of azacitidine priming followed by standard chemoimmunotherapy was well-tolerated in high-risk DLBCL patients.
- High rates of complete remission were observed in the clinical trial.
- Biopsies confirmed SMAD1 demethylation and chemosensitization post-azacitidine treatment.
Conclusions:
- Aberrant DNA methylation programming is associated with chemoresistance in DLBCL.
- DNMT inhibitors, exemplified by azacitidine, represent a promising therapeutic approach for chemoresistant DLBCL.
- A mechanism-based, personalized strategy involving DNMTI can be rationally translated for clinical use in high-risk DLBCL.
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