Towards genomic-based prognostication and precision therapy for diffuse large B-cell lymphoma.
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ABSTRACT:
SUBMITTER: Minderman M
PROVIDER: S-EPMC7556622 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
Publications
Towards genomic-based prognostication and precision therapy for diffuse large B-cell lymphoma.
Minderman Marthe M Pals Steven T ST
Haematologica 20200901 9
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Project description:Epigenetic mechanisms such as DNA hypermethylation or histone deacetylation normally silence gene expression that regulates numerous cellular activities. Germinal center-derived lymphomas such as follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) are characterized by frequent mutations of histone-modifying genes. EZH2 is essential to the formation of germinal center in the secondary lymphoid tissue (eg, lymph nodes and spleen) and is one of the most frequently mutated histone-modifying genes in human lymphomas. EZH2 encodes a histone methyltransferase, mediates transcriptional repression and acts as an oncogene that promotes the development and progression of a variety of human malignancies, including FL and DLBCL. Thus, recurrent mutations in the EZH2 and other non-histone epigenetic regulators represent important targets for therapeutic interventions. Recently, an orally active inhibitor of EZH2, tazemetostat, has received regulatory approval for patients with mutated EZH2 relapsed or refractory FL after ≥2 prior systemic therapies. It is also approved for those with relapsed or refractory FL who have no satisfactory alternative treatment options, regardless of their mutational status of EZH2. Currently, tazemetostat and its combination therapies for patients with relapsed or refractory germinal center-derived lymphomas, as well as frontline therapies for previously untreated patients, are in various phases of clinical investigations. Despite the promise of epigenetic therapies, potential pitfalls such as target selectivity, risk of oncogenic activation, risk of secondary malignancies associated with epigenetic therapies must be carefully monitored. Future applications of epigenetic approach that incorporate clinical and genomic features are needed to determine how individualized treatments can be used for these hematologic malignancies.
| S-EPMC9359712 | biostudies-literature
Project description: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.
| S-EPMC3770813 | biostudies-literature
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| S-EPMC10762105 | biostudies-literature
Project description:Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, is highly heterogeneous and invasive. Although the majority of DLBCL patients show a good response to rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone treatment, approximately one-third of patients still have a poor prognosis. Many immune-targeted drugs, such as bispecific T-cell engagers and CAR T-cell therapy, have been proven effective for refractory and relapsed patients. This article reviews the progress of immune targeted therapy for DLBCL.
| S-EPMC8975004 | biostudies-literature
Project description:Primary gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) is the most common gastrointestinal lymphoma, but its genetic features are poorly understood. We performed whole-exome sequencing of 25 primary tumor samples from patients with GI-DLBCL and 23 matched normal tissue samples. Oncogenic mutations were screened, and the correlations between genetic mutations and clinicopathological characteristics were analyzed. Twenty-five patients with GI-DLBCL were enrolled in the genetic mutation analysis with a median of 184 (range 79-382) protein-altering variants per patient. We identified recurrent oncogenic mutations in GI-DLBCL, including those in TP53, MUC16, B2M, CCND3, HIST1H1C, NEB, and ID3. Compared with nodal DLBCL, GI-DLBCL exhibited an increased mutation frequency of TP53 and reduced mutation frequencies of PIM1, CREBBP, BCL2, KMT2D, and EZH2. Moreover, GI-DLBCL exhibited fewer MYD88 and CD79B mutations than DLBCL in the testis and central nervous system. GI-DLBCLs with HLA-B, MEF2A, RHOA, and NAV3 mutations exhibited a tendency toward a high proliferation index. MUC16 and ETV6 mutations often occurred in tumors with early clinical staging. Our data provide a comprehensive understanding of the landscape of mutations in a small subset of GI-DLBCLs. The genetic mutation profiles of GI-DLBCL differ from those of nodal DLBCL and DLBCL in immune-privileged sites. The different mutated genes are related to the NF-κB and JAK-STAT pathways, and the different pathogenetic mechanisms leading to the development of DLBCL may be influenced by the tissue microenvironment. Differences in genetic alterations might influence the clinicopathological characteristics of GI-DLBCL.
| S-EPMC7973209 | biostudies-literature
Project description:BackgroundThe identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs that target essential survival pathways, but whether targeting multiple survival pathways may be curative in DLBCL is unknown.MethodsWe performed a single-center, phase 1b-2 study of a regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refractory DLBCL. In phase 1b, which included patients with DLBCL and indolent lymphomas, four dose levels of venetoclax were evaluated to identify the recommended phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles.ResultsIn phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively.ConclusionsTreatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events. (Funded by the Intramural Research Program of the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.).
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| S-EPMC8499090 | biostudies-literature
Project description:Rationally designed combinations of targeted therapies for refractory cancers, such as activated B cell-like diffuse large B cell lymphoma (ABC DLBCL), are likely required to achieve potent, durable responses. Here, we used a pharmacoproteomics approach to map the interactome of a tumor-enriched isoform of HSP90 (teHSP90). Specifically, we chemically precipitated teHSP90-client complexes from DLBCL cell lines with the small molecule PU-H71 and found that components of the proximal B cell receptor (BCR) signalosome were enriched within teHSP90 complexes. Functional assays revealed that teHSP90 facilitates BCR signaling dynamics by enabling phosphorylation of key BCR signalosome components, including the kinases SYK and BTK. Consequently, treatment of BCR-dependent ABC DLBCL cells with PU-H71 attenuated BCR signaling, calcium flux, and NF-?B signaling, ultimately leading to growth arrest. Combined exposure of ABC DLBCL cell lines to PU-H71 and ibrutinib, a BCR pathway inhibitor, more potently suppressed BCR signaling than either drug alone. Correspondingly, PU-H71 combined with ibrutinib induced synergistic killing of lymphoma cell lines, primary human lymphoma specimens ex vivo, and lymphoma xenografts in vivo, without notable toxicity. Together, our results demonstrate that a pharmacoproteome-driven rational combination therapy has potential to provide more potent BCR-directed therapy for ABC DLCBL patients.
| S-EPMC4665772 | biostudies-literature
Project description:At present, the use of the common chemotherapy regimen CHOP/R-CHOP for diffuse large B-cell lymphoma (DLBCL) has some shortcomings, especially for relapsed and refractory DLBCL. CD47 is now considered as a prominent target in cancer therapies, and CD47 blockade mainly inhibits the CD47-SIRPα axis to prevent tumor immune escape. Here, we evaluated the effects of the latest CD47 antibodies reported and the correlations of closely related genes with CD47 in this disease. In the future, therapeutic strategies for DLBCL will focus on multitarget antibody combined treatment and multigene joint attacks.
| S-EPMC8463246 | biostudies-literature