This technology is a method of treating germinal center (GC) diffuse large B-cell lymphoma (DLBCL) by targeting multiple associated mutations in epigenetic modulators, specifically in EZH2-dysregulated lymphoma.
Unmet Need: Combination treatment for relapsed/refractory germinal center diffuse large B-cell lymphoma (GC-DLBCL)
Germinal center (GC) diffuse large B-cell lymphoma (DLBCL) is strongly linked to mutations in epigenetic modulators, such as histone methyltransferases (e.g. EZH2, MLL), histone deacetylases (e.g. HDAC), and DNA methyltransferases (e.g. DNMT). Approximately 30% of DLBCL patients relapse following first-line treatment and are then treated with second-line chemotherapy, followed by autologous stem cell transplantation (AutoSCT). However, there is currently no FDA-approved treatment for patients who are not eligible for AutoSCT or who relapse following AutoSCT, highlighting a need for alternative therapies. Furthermore, there are currently no treatments for GC-DLBCL utilizing a drug combination targeting EZH2, MLL, HDACs, and DNMTs.
The Technology: Personalized epigenetic combination therapy for GC-DLBCL
This technology describes the use of a combination of drugs to target various epigenetic modulators as a therapy for GC-DLBCL. This combination therapy elicits a synergistic effect by dual inhibition of EZH2 and HDAC and can be tailored to individual patient needs by identifying optimal drug combinations based on the discrete repertoire of mutations found in an individual’s disease. The combination of drugs targeting the various epigenetic modulators is synergistic, as these targets work together to regulate gene expression and transcription factor activation. As a result, this personalized treatment has the potential to offer improved outcomes for GC-DLBCL patients as compared to other chemotherapeutic approaches, increasing overall response rate, duration of response, and progression-free survival.
This technology has been validated in a panel of lymphoma cell lines.
Applications:
- Therapy for germinal center diffuse large B-cell lymphoma (GC-DLBCL) patients who have relapsed and are not eligible for AutoSCT
- Therapy for GC-DLBCL patients who have relapsed after AutoSCT
- Treatment for other lymphomas associated with defects in epigenetic modulators EZH2 and HDAC
- Treatment for non-lymphoma diseases associated with defects in epigenetic modulators
- Assay for rapid screening of related epigenetic modulators in affected patients
- More specific and targeted therapy for EZH2-dysregulated lymphoma (e.g. GC-DLBCL or adult T-cell leukemia lymphoma (ATLL)) due to EZH2 gene mutation or overexpression
Advantages:
- Provides a treatment method for currently untreatable relapses of GC-DLBCL
- Treatments may be personalized to individual patients
- Combination therapy uses drugs that are already available
- Synergistic effect of dual EZH2 and HDAC inhibition
- Administration of EZH2 and HDAC inhibitors simultaneously, sequentially, or separately
- Synergistic increase in cancer cell apoptosis or reduction in viability and tumor volume using dual inhibitor therapy
- Administration as a small molecule, polynucleotide, or antibody or antigen-binding portion
Lead Inventor:
Jennifer Amengual, M.D.
Patent Information:
Patent Pending (US20230167451)
Related Publications:
Ricker ED, Estrella B, Pazos II MA, Amengual JE. “Dual targeting of EZH2 and HDAC with tazemetostat and belinostat promotes immunogenicity in GC-DLBCL” Blood. 2021;138:pp.2410,
Lue JK, Prabhu SA, Liu Y, Gonzalez Y, Verma A, Mundi PS, Abshiru N, Camarillo JM, Mehta S, Chen EI, Qiao C, Nandakumar R, Cremers S, Kelleher NL, Elemento O, Amengual JE. “Precision targeting with EZH2 and HDAC inhibitors in epigenetically dysregulated lymphomas” Hematological Oncology. 2019; 25(17): pp. 5271-5283,
Lue JK, Prabhu SA, Liu Y, O’Connor OA, Amengual JE. “Epigenetic targeting with EZH2 and HDAC inhibitors is synergistic in EZH2 deregulated lymphomas” Blood. 2016; 128: 839.
Amengual JE, O’Connor OA. “Manipulating the epigenome in germinal center lymphomas: is it getting easier and ezier?” Clin Cancer Res. 2014 Jun 15; 20(12): 3047-3049.
Lue JK, Amengual JE, O’Connor OA. “Epigenetics and Lymphoma: Can We Use Epigenetics to Prime or Reset Chemoresistant Lymphoma Programs?” Curr Oncol Rep. 2015 Sep; 17(9): 40.
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