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1
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Lei Y, Lai M. Epigenetic Regulation and Therapeutic Targeting of Alternative Splicing Dysregulation in Cancer. Pharmaceuticals (Basel) 2025; 18:713. [PMID: 40430531 PMCID: PMC12115227 DOI: 10.3390/ph18050713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 05/02/2025] [Accepted: 05/07/2025] [Indexed: 05/29/2025] Open
Abstract
Alternative splicing enables a single precursor mRNA to generate multiple mRNA isoforms, leading to protein variants with different structures and functions. Abnormal alternative splicing is frequently associated with cancer development and progression. Recent studies have revealed a complex and dynamic interplay between epigenetic modifications and alternative splicing. On the one hand, dysregulated epigenetic changes can alter splicing patterns; on the other hand, splicing events can influence epigenetic landscapes. The reversibility of epigenetic modifications makes epigenetic drugs, both approved and investigational, attractive therapeutic options. This review provides a comprehensive overview of the bidirectional relationship between epigenetic regulation and alternative splicing in cancer. It also highlights emerging therapeutic approaches aimed at correcting splicing abnormalities, with a special focus on drug-based strategies. These include epigenetic inhibitors, antisense oligonucleotides (ASOs), small-molecule compounds, CRISPR-Cas9 genome editing, and the SMaRT (splice-switching molecule) technology. By integrating recent advances in research and therapeutic strategies, this review provides novel insights into the molecular mechanisms of cancer and supports the development of more precise and effective therapies targeting aberrant splicing.
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Affiliation(s)
- Yan Lei
- Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China;
| | - Maode Lai
- Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China;
- Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Science (2019RU042), Key Laboratory of Disease Proteomics of Zhejiang Province, Department of Pathology, Zhejiang University School of Medicine, Hangzhou 310058, China
- Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
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Kridel R. Follicular lymphoma: contemporary clinical management with a focus on recent therapeutic advances. Korean J Intern Med 2025; 40:371-393. [PMID: 39987895 PMCID: PMC12081106 DOI: 10.3904/kjim.2024.279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 10/13/2024] [Accepted: 11/03/2024] [Indexed: 02/25/2025] Open
Abstract
Follicular lymphoma (FL) is the most common type of indolent lymphoma, and the prognosis is favorable for most patients. However, FL remains generally incurable, and relapse is common. Patients are at risk of developing treatment-resistant lymphoma, particularly when early disease progression occurs or transformation to aggressive lymphoma takes place. Furthermore, lymphoma is the leading cause of death among patients with FL, emphasizing the need for more effective treatment strategies. This review summarizes therapeutic approaches for FL, with a focus on therapies currently in development. Recent biological insights have driven the emergence of highly effective treatments, including novel immune and targeted therapies. Clinical trials are assessing the efficacy of these novel approaches, which are increasingly used in earlier line settings. In the future, FL therapy is expected to rely less on chemotherapeutic methods, extend remission, and potentially enable cures for a growing number of patients.
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Affiliation(s)
- Robert Kridel
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON,
Canada
- Faculty of Medicine, University of Toronto, Toronto, ON,
Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON,
Canada
- Institute of Medical Science, University of Toronto, Toronto, ON,
Canada
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3
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Zou Q, Zhang Y, Zhou H, Lai Y, Cao Y, Li Z, Su N, Li W, Huang H, Liu P, Ye X, Wu Y, Tan H, Zheng R, Wu B, Yang H, Zhong L, Lu Y, Liang Y, Sun P, Li L, Liu Y, Dai D, Xia Y, Cai Q. Chidamide, a Histone Deacetylase Inhibitor, Combined With R-GemOx in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (TRUST): A Multicenter, Single-Arm, Phase 2 Trial. Cancer Med 2025; 14:e70919. [PMID: 40318003 PMCID: PMC12046501 DOI: 10.1002/cam4.70919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 04/04/2025] [Accepted: 04/08/2025] [Indexed: 05/07/2025] Open
Abstract
BACKGROUND Histone deacetylase (HDAC) inhibitors demonstrated a synergistic anti-tumor effect with rituximab and chemotherapy in preclinical studies on diffuse large B-cell lymphoma (DLBCL). This phase 2 trial aimed to evaluate the efficacy and safety of chidamide, an orally active HDAC inhibitor, plus the R-GemOx regimen for relapsed/refractory (R/R) DLBCL. METHODS Patients with transplantation-ineligible R/R DLBCL received chidamide (20 mg, oral, days 1, 4, 8, 11, 15, and 18), rituximab (375 mg/m2, day 1), gemcitabine (1000 mg/m2, day 2), and oxaliplatin (100 mg/m2, day 2) in a 21-day cycle for 6 cycles (induction phase), followed by chidamide (20 mg, oral, twice weekly on Mondays and Thursdays) until disease progression or intolerable toxicity (maintenance phase). The primary endpoint was overall response rate (ORR). RESULTS Between June 19, 2019 and July 5, 2022, 54 patients were enrolled. The ORR was 59.3% (95% CI: 45.0-72.4). With a median follow-up of 38.1 months (interquartile range: 19.5-48.2), the median progression-free survival and overall survival were 7.4 (95% CI: 5.2-14.2) and 23.9 (95% CI: 15.2-not reached) months, respectively. The most common grade 3/4 treatment-emergent adverse events (TEAEs) were neutropenia (40.7%), thrombocytopenia (33.3%), and leukopenia (27.8%). Whole-exome sequencing showed that CREBBP mutations and BTG2 mutations were associated with poor response and survival. CONCLUSION Chidamide plus R-GemOx demonstrated promising anti-tumor activity with acceptable toxicities in transplantation-ineligible R/R DLBCL patients. Patients with CREBBP mutations and BTG2 mutations had inferior response and survival. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT04022005.
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MESH Headings
- Humans
- Male
- Female
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/pathology
- Lymphoma, Large B-Cell, Diffuse/mortality
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Aged
- Middle Aged
- Aminopyridines/administration & dosage
- Aminopyridines/adverse effects
- Aminopyridines/therapeutic use
- Histone Deacetylase Inhibitors/administration & dosage
- Histone Deacetylase Inhibitors/adverse effects
- Histone Deacetylase Inhibitors/therapeutic use
- Benzamides/administration & dosage
- Benzamides/adverse effects
- Benzamides/therapeutic use
- Adult
- Deoxycytidine/analogs & derivatives
- Deoxycytidine/administration & dosage
- Deoxycytidine/adverse effects
- Rituximab/administration & dosage
- Rituximab/adverse effects
- Oxaliplatin/administration & dosage
- Oxaliplatin/adverse effects
- Gemcitabine
- Neoplasm Recurrence, Local/drug therapy
- Aged, 80 and over
- Drug Resistance, Neoplasm
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Affiliation(s)
- Qihua Zou
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Experimental Research, Sun Yat‐Sen University Cancer CenterGuangzhouChina
| | - Yuchen Zhang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Medical OncologySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Hui Zhou
- Department of Lymphoma and HematologyHunan Cancer HospitalChangshaChina
| | - Yulin Lai
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Medical OncologySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Yi Cao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Medical OncologySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Zhiming Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Medical OncologySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Ning Su
- Department of OncologyGuangzhou Chest HospitalGuangzhouChina
| | - Wenyu Li
- Division of Lymphoma, Department of Clinical OncologyGuangdong Provincial People's HospitalGuangzhouChina
| | - Huiqiang Huang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Medical OncologySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Panpan Liu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Medical OncologySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Xu Ye
- Department of HematologyThe Second Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
| | - Yudan Wu
- Department of HematologySun Yat‐sen Memorial HospitalGuangzhouChina
| | - Huo Tan
- Department of HematologyThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
- Department of HematologyThe Fifth Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
| | - Runhui Zheng
- Department of HematologyThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
- Department of HematologyThe Fifth Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
| | - Bingyi Wu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Hematologic OncologySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Hui Yang
- Department of HematologyShunde Hospital of Southern Medical UniversityFoshanChina
| | - Liye Zhong
- Division of Lymphoma, Department of Clinical OncologyGuangdong Provincial People's HospitalGuangzhouChina
| | - Yuhong Lu
- International Cancer Medical CenterJinshazhou Hospital of Guangzhou University of Chinese MedicineGuangzhouChina
| | - Yang Liang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Hematologic OncologySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Peng Sun
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Medical OncologySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Lirong Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Medical OncologySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Yingxian Liu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Medical OncologySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Danling Dai
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Experimental Research, Sun Yat‐Sen University Cancer CenterGuangzhouChina
| | - Yi Xia
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Medical OncologySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Qingqing Cai
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Medical OncologySun Yat‐sen University Cancer CenterGuangzhouChina
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Zhang Y, Wang H, Zhan Z, Gan L, Bai O. Mechanisms of HDACs in cancer development. Front Immunol 2025; 16:1529239. [PMID: 40260239 PMCID: PMC12009879 DOI: 10.3389/fimmu.2025.1529239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Accepted: 03/17/2025] [Indexed: 04/23/2025] Open
Abstract
Histone deacetylases (HDACs) are a class of epigenetic regulators that play pivotal roles in key biological processes such as cell proliferation, differentiation, metabolism, and immune regulation. Based on this, HDAC inhibitors (HDACis), as novel epigenetic-targeted therapeutic agents, have demonstrated significant antitumor potential by inducing cell cycle arrest, activating apoptosis, and modulating the immune microenvironment. Current research is focused on developing highly selective HDAC isoform inhibitors and combination therapy strategies tailored to molecular subtypes, aiming to overcome off-target effects and resistance issues associated with traditional broad-spectrum inhibitors. This review systematically elaborates on the multidimensional regulatory networks of HDACs in tumor malignancy and assesses the clinical translation progress of next-generation HDACis and their prospects in precision medicine, providing a theoretical framework and strategic reference for the development of epigenetic-targeted antitumor drugs.
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Affiliation(s)
- Ying Zhang
- Department of Hematology, The First Hospital of Jilin University, Changchun, China
| | - Haotian Wang
- Department of Hematology, The First Hospital of Jilin University, Changchun, China
| | - Zhumei Zhan
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Lin Gan
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China
| | - Out Bai
- Department of Hematology, The First Hospital of Jilin University, Changchun, China
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5
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Kaya Çakir H, Eroğlu O. Investigation of the synergic effect of mocetinostat and capecitabine in a triple-negative breast neoplasms mouse model. J Investig Med 2025; 73:320-327. [PMID: 39690705 DOI: 10.1177/10815589241309603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2024]
Abstract
Combined administration of two or more drugs is emerging as a new strategy in triple-negative breast neoplasms. This is the first study to investigate the combination of the histone deacetylase inhibitor mocetinostat and the antimetabolite drug capecitabine in triple-negative mammary neoplasms in a preclinical mouse model. Thirty-five female mice were grouped into the control group, capecitabine group, mocetinostat group, and combined drugs group. At the end of the experimental period, body weight, and tumor weight were measured and tumor tissue and lung tissue were histologically examined. The results showed that the body weight of mice in the drug-treated groups was reduced by about 18%. Tumor weights were also reduced by 21% in the mocetinostat group, 27.5% in the capecitabine group, and 45% in the combined group. The combination of mocetinostat and capecitabine decreased the formation of tumors and metastases in lung tissue. In summary, the combination of mocetinostat and capecitabine was more effective than either drug alone in reducing the size of triple-negative breast neoplasms in a mouse model.
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Affiliation(s)
- Hacer Kaya Çakir
- Department of Molecular Biology and Genetics, Faculty of Science, Bilecik Seyh Edebali University, Bilecik, Turkey
| | - Onur Eroğlu
- Department of Molecular Biology and Genetics, Faculty of Science, Bilecik Seyh Edebali University, Bilecik, Turkey
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6
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Zhang W, Ge L, Zhang Y, Zhang Z, Zhang W, Song F, Huang P, Xu T. Targeted intervention of tumor microenvironment with HDAC inhibitors and their combination therapy strategies. Eur J Med Res 2025; 30:69. [PMID: 39905506 PMCID: PMC11792708 DOI: 10.1186/s40001-025-02326-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 01/23/2025] [Indexed: 02/06/2025] Open
Abstract
Histone deacetylation represents a significant epigenetic mechanism that involves the removal of acetyl groups from histones, subsequently influencing gene transcription. Overexpression of histone deacetylases (HDACs) is prevalent across various cancer types, positioning HDAC inhibitors as broadly applicable therapeutic agents. These inhibitors are known to enhance tumor immune antigenicity, potentially slowing tumor progression. Furthermore, the tumor microenvironment, which is intricately linked to cancer development, acts as a mediator in the proliferation of numerous cancers and presents a viable target for oncological therapies. This paper primarily explores how HDAC inhibitors can regulate cancer progression via the tumor microenvironment and suppress tumor growth through multiple pathways, in addition to examining the synergistic effects of combined drug therapies involving HDAC inhibitors.
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Affiliation(s)
- Wanli Zhang
- Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Luqi Ge
- Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Yiwen Zhang
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital(Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, 310014, China
- Clinical Research Center for Cancer of Zhejiang Province, Hangzhou, China
| | - Zhentao Zhang
- Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Wen Zhang
- Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - Feifeng Song
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital(Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, 310014, China.
| | - Ping Huang
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital(Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, 310014, China.
- Clinical Research Center for Cancer of Zhejiang Province, Hangzhou, China.
| | - Tong Xu
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital(Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, 310014, China.
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7
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Gao Y, Siyu zhang, Zhang X, Du Y, Ni T, Hao S. Crosstalk between metabolic and epigenetic modifications during cell carcinogenesis. iScience 2024; 27:111359. [PMID: 39660050 PMCID: PMC11629229 DOI: 10.1016/j.isci.2024.111359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2024] Open
Abstract
Genetic mutations arising from various internal and external factors drive cells to become cancerous. Cancerous cells undergo numerous changes, including metabolic reprogramming and epigenetic modifications, to support their abnormal proliferation. This metabolic reprogramming leads to the altered expression of many metabolic enzymes and the accumulation of metabolites. Recent studies have shown that these enzymes and metabolites can serve as substrates or cofactors for chromatin-modifying enzymes, thereby participating in epigenetic modifications and promoting carcinogenesis. Additionally, epigenetic modifications play a role in the metabolic reprogramming and immune evasion of cancer cells, influencing cancer progression. This review focuses on the origins of cancer, particularly the metabolic reprogramming of cancer cells and changes in epigenetic modifications. We discuss how metabolites in cancer cells contribute to epigenetic remodeling, including lactylation, acetylation, succinylation, and crotonylation. Finally, we review the impact of epigenetic modifications on tumor immunity and the latest advancements in cancer therapies targeting these modifications.
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Affiliation(s)
- Yue Gao
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot 010070, China
| | - Siyu zhang
- Key Lab of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, School of Life Sciences, Ningxia University, Yinchuan 750021, China
| | - Xianhong Zhang
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot 010070, China
| | - Yitian Du
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot 010070, China
| | - Ting Ni
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot 010070, China
| | - Shuailin Hao
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot 010070, China
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8
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Dai W, Qiao X, Fang Y, Guo R, Bai P, Liu S, Li T, Jiang Y, Wei S, Na Z, Xiao X, Li D. Epigenetics-targeted drugs: current paradigms and future challenges. Signal Transduct Target Ther 2024; 9:332. [PMID: 39592582 PMCID: PMC11627502 DOI: 10.1038/s41392-024-02039-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 10/14/2024] [Accepted: 10/29/2024] [Indexed: 11/28/2024] Open
Abstract
Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone modification, RNA modification, chromatin remodeling, and non-coding RNA regulation. These mechanisms and their associated enzymes convey genetic information independently of DNA base sequences, playing essential roles in organismal development and homeostasis. Conversely, disruptions in epigenetic landscapes critically influence the pathogenesis of various human diseases. This understanding has laid a robust theoretical groundwork for developing drugs that target epigenetics-modifying enzymes in pathological conditions. Over the past two decades, a growing array of small molecule drugs targeting epigenetic enzymes such as DNA methyltransferase, histone deacetylase, isocitrate dehydrogenase, and enhancer of zeste homolog 2, have been thoroughly investigated and implemented as therapeutic options, particularly in oncology. Additionally, numerous epigenetics-targeted drugs are undergoing clinical trials, offering promising prospects for clinical benefits. This review delineates the roles of epigenetics in physiological and pathological contexts and underscores pioneering studies on the discovery and clinical implementation of epigenetics-targeted drugs. These include inhibitors, agonists, degraders, and multitarget agents, aiming to identify practical challenges and promising avenues for future research. Ultimately, this review aims to deepen the understanding of epigenetics-oriented therapeutic strategies and their further application in clinical settings.
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Affiliation(s)
- Wanlin Dai
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xinbo Qiao
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yuanyuan Fang
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Renhao Guo
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Peng Bai
- Department of Forensic Genetics, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China
| | - Shuang Liu
- Shenyang Maternity and Child Health Hospital, Shenyang, China
| | - Tingting Li
- Department of General Internal Medicine VIP Ward, Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Yutao Jiang
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shuang Wei
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhijing Na
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
- NHC Key Laboratory of Advanced Reproductive Medicine and Fertility (China Medical University), National Health Commission, Shenyang, China.
| | - Xue Xiao
- Department of Gynecology and Obstetrics, West China Second Hospital, Sichuan University, Chengdu, China.
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China.
| | - Da Li
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
- NHC Key Laboratory of Advanced Reproductive Medicine and Fertility (China Medical University), National Health Commission, Shenyang, China.
- Key Laboratory of Reproductive Dysfunction Diseases and Fertility Remodeling of Liaoning Province, Shenyang, China.
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He MY, Tong KI, Liu T, Whittaker Hawkins R, Shelton V, Zeng Y, Bakhtiari M, Xiao Y, Zheng G, Sakhdari A, Yang L, Xu W, Brooks DG, Laister RC, He HH, Kridel R. GNAS knockout potentiates HDAC3 inhibition through viral mimicry-related interferon responses in lymphoma. Leukemia 2024; 38:2210-2224. [PMID: 39117798 PMCID: PMC11436380 DOI: 10.1038/s41375-024-02325-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 06/18/2024] [Accepted: 06/20/2024] [Indexed: 08/10/2024]
Abstract
Despite selective HDAC3 inhibition showing promise in a subset of lymphomas with CREBBP mutations, wild-type tumors generally exhibit resistance. Here, using unbiased genome-wide CRISPR screening, we identify GNAS knockout (KO) as a sensitizer of resistant lymphoma cells to HDAC3 inhibition. Mechanistically, GNAS KO-induced sensitization is independent of the canonical G-protein activities but unexpectedly mediated by viral mimicry-related interferon (IFN) responses, characterized by TBK1 and IRF3 activation, double-stranded RNA formation, and transposable element (TE) expression. GNAS KO additionally synergizes with HDAC3 inhibition to enhance CD8+ T cell-induced cytotoxicity. Moreover, we observe in human lymphoma patients that low GNAS expression is associated with high baseline TE expression and upregulated IFN signaling and shares common disrupted biological activities with GNAS KO in histone modification, mRNA processing, and transcriptional regulation. Collectively, our findings establish an unprecedented link between HDAC3 inhibition and viral mimicry in lymphoma. We suggest low GNAS expression as a potential biomarker that reflects viral mimicry priming for enhanced response to HDAC3 inhibition in the clinical treatment of lymphoma, especially the CREBBP wild-type cases.
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Affiliation(s)
- Michael Y He
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Kit I Tong
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Ting Liu
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Ryder Whittaker Hawkins
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada
| | - Victoria Shelton
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Yong Zeng
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Mehran Bakhtiari
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Yufeng Xiao
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Guangrong Zheng
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Ali Sakhdari
- Laboratory Medicine and Pathobiology, University Health Network, Toronto, ON, Canada
| | - Lin Yang
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Wenxi Xu
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - David G Brooks
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Rob C Laister
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Housheng Hansen He
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Robert Kridel
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
- Department of Medicine, University of Toronto, Toronto, ON, Canada.
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10
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Chen G, Xue K, Zhang Q, Xia Z, Jin J, Li R, Liu Y, Lv F, Hong X, Li X, Cao J. Chidamide plus R-GDP for relapsed/refractory diffuse large B-cell lymphoma in patients ineligible for autologous transplantation: A prospective, single-arm, phase II study. Cancer Med 2024; 13:e70142. [PMID: 39206577 PMCID: PMC11358697 DOI: 10.1002/cam4.70142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 08/07/2024] [Accepted: 08/12/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND In relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), a negative prognosis is frequently linked to heightened epigenetic heterogeneity. Chidamide, a selective histone deacetylase inhibitor, shows promise as a targeted therapy for R/R DLBCL by targeting abnormal epigenetic changes associated with poor prognosis. METHODS A cohort of 27 ineligible patients with R/R DLBCL participated in an open - label, single - arm study. Chidamide was administered orally at a dose of 30 mg twice weekly for one week during the induction monotherapy phase. The subsequent combination therapy phase involved oral chidamide at a dose of 20 mg twice weekly for two weeks, followed by a one-week discontinuation period, in conjunction with intravenous R-GDP every 21 days. RESULTS Among the cohort of 31 patients who underwent screening (median age: 67 years), 27 were ultimately included in the study, with 14 individuals successfully completing six cycles of C-R-GDP treatment. The overall best objective response rate was determined to be 79.1% (95% CI: 75.1%-83.3%), comprising a complete response rate of 45.8% (95% CI: 41.6%-49.9%) and a partial response rate of 33.3% (95% CI: 29.3%-37.4%). Within the subgroup of 14 patients who completed the full treatment regimen, the best objective response rate reached 100%, with 71.4% achieving complete response (n = 10) and 28.6% achieving partial response (n = 4). The median follow-up period for these patients was 17.0 months, ranging from 3.5 to 55 months. Progression-free survival was 5.9 months and overall survival was 48.3 months. Anemia was the most common adverse event, affecting all patients. Thrombocytopenia led to treatment interruption or dose reduction in 13 patients. Other common adverse events included hypocalcemia, hyponatremia, and hypokalemia. Three patients experienced grade 3 pneumonitis and one had grade 3 skin rash. CONCLUSIONS Chidamide combined with R-GDP is a safe and effective treatment option for patients with R/R DLBCL who are not eligible for autologous stem cell transplantation.
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Affiliation(s)
- Guang‐Liang Chen
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College Fudan UniversityShanghaiChina
| | - Kai Xue
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College Fudan UniversityShanghaiChina
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Qunling Zhang
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College Fudan UniversityShanghaiChina
| | - Zu‐guang Xia
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College Fudan UniversityShanghaiChina
| | - Jia Jin
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College Fudan UniversityShanghaiChina
| | - Ran Li
- Department of Hematology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer MedicineNanjing Medical UniversityNanjingChina
| | - Yizhen Liu
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College Fudan UniversityShanghaiChina
| | - Fangfang Lv
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College Fudan UniversityShanghaiChina
| | - Xiaonan Hong
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College Fudan UniversityShanghaiChina
| | - Xiaoqiu Li
- Department of OncologyShanghai Medical College Fudan UniversityShanghaiChina
- Department of PathologyFudan University Shanghai Cancer CenterShanghaiChina
| | - Junning Cao
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical College Fudan UniversityShanghaiChina
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11
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Zhuang S, Yang Z, Cui Z, Zhang Y, Che F. Epigenetic alterations and advancement of lymphoma treatment. Ann Hematol 2024; 103:1435-1454. [PMID: 37581713 DOI: 10.1007/s00277-023-05395-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 07/29/2023] [Indexed: 08/16/2023]
Abstract
Lymphomas, complex and heterogeneous malignant tumors, originate from the lymphopoietic system. These tumors are notorious for their high recurrence rates and resistance to treatment, which leads to poor prognoses. As ongoing research has shown, epigenetic modifications like DNA methylation, histone modifications, non-coding RNA regulation, and RNA modifications play crucial roles in lymphoma pathogenesis. Epigenetic modification-targeting drugs have exhibited therapeutic efficacy and tolerability in both monotherapy and combination lymphoma therapy. This review discusses pathogenic mechanisms and potential epigenetic therapeutic targets in common lymphomas, offering new avenues for lymphoma diagnosis and treatment. We also discuss the shortcomings of current lymphoma treatments, while suggesting potential areas for future research, in order to improve the prediction and prognosis of lymphoma.
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Affiliation(s)
- Shuhui Zhuang
- Affiliated Hospital of Weifang Medical University, School of Clinical Medicine, Weifang Medical University, Weifang, China
- Department of Hematology, Linyi People's Hospital, Shandong University, Linyi, 276000, Shandong, China
| | - Zhaobo Yang
- Spine Surgery, Linyi People's Hospital, Shandong University, Linyi, 276000, Shandong, China
| | - Zhuangzhuang Cui
- Department of Hematology, Linyi People's Hospital, Shandong University, Linyi, 276000, Shandong, China
| | - Yuanyuan Zhang
- Department of Hematology, Linyi People's Hospital, Shandong University, Linyi, 276000, Shandong, China.
- Department of Hematology, Shandong Key Laboratory of Immunohematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People's Republic of China.
| | - Fengyuan Che
- Department of Neurology, Central Laboratory and Key Laboratory of Neurophysiology, Linyi People's Hospital, Shandong University, Linyi, 276000, China.
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12
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Watanabe T. Gene targeted and immune therapies for nodal and gastrointestinal follicular lymphomas. World J Gastroenterol 2023; 29:6179-6197. [PMID: 38186866 PMCID: PMC10768399 DOI: 10.3748/wjg.v29.i48.6179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 11/02/2023] [Accepted: 12/18/2023] [Indexed: 12/27/2023] Open
Abstract
Follicular lymphoma (FL) is the most common indolent B-cell lymphoma (BCL) globally. Recently, its incidence has increased in Europe, the United States, and Asia, with the number of gastrointestinal FL cases expected to increase. Genetic abnormalities related to t(14;18) translocation, BCL2 overexpression, NF-κB pathway-related factors, histone acetylases, and histone methyltransferases cause FL and enhance its proliferation. Meanwhile, microRNAs are commonly used in diagnosing FL and predicting patient prognosis. Many clinical trials on novel therapeutics targeting these genetic abnormalities and immunomodulatory mechanisms have been conducted, resulting in a marked improvement in therapeutic outcomes for FL. Although developing these innovative therapeutic agents targeting specific genetic mutations and immune pathways has provided hope for curative options, FL treatment has become more complex, requiring combinatorial therapeutic regimens. However, optimal treatment combinations have not yet been achieved, highlighting the importance of a complete under-standing regarding the pathogenesis of gastrointestinal FL. Accordingly, this article reviews key research on the molecular pathogenesis of nodal FL and novel therapies targeting the causative genetic mutations. Moreover, the results of clinical trials are summarized, with a particular focus on treating nodal and gastrointestinal FLs.
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Affiliation(s)
- Takuya Watanabe
- Department of Internal Medicine and Gastroenterology, Watanabe Internal Medicine Aoyama Clinic, Niigata 9502002, Japan
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13
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Kawata M, McClatchy DB, Diedrich JK, Olmer M, Johnson KA, Yates JR, Lotz MK. Mocetinostat activates Krüppel-like factor 4 and protects against tissue destruction and inflammation in osteoarthritis. JCI Insight 2023; 8:e170513. [PMID: 37681413 PMCID: PMC10544226 DOI: 10.1172/jci.insight.170513] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 07/19/2023] [Indexed: 09/09/2023] Open
Abstract
Osteoarthritis (OA) is the most common joint disorder, and disease-modifying OA drugs (DMOADs) represent a major need in OA management. Krüppel-like factor 4 (KLF4) is a central transcription factor upregulating regenerative and protective functions in joint tissues. This study was aimed to identify small molecules activating KLF4 expression and to determine functions and mechanisms of the hit compounds. High-throughput screening (HTS) with 11,948 clinical-stage compounds was performed using a reporter cell line detecting endogenous KLF4 activation. Eighteen compounds were identified through the HTS and confirmed in a secondary screen. After testing in SW1353 chondrosarcoma cells and human chondrocytes, mocetinostat - a class I selective histone deacetylase (HDAC) inhibitor - had the best profile of biological activities. Mocetinostat upregulated cartilage signature genes in human chondrocytes, meniscal cells, and BM-derived mesenchymal stem cells, and it downregulated hypertrophic, inflammatory, and catabolic genes in those cells and synoviocytes. I.p. administration of mocetinostat into mice reduced severity of OA-associated changes and improved pain behaviors. Global gene expression and proteomics analyses revealed that regenerative and protective effects of mocetinostat were dependent on peroxisome proliferator-activated receptor γ coactivator 1-α. These findings show therapeutic and protective activities of mocetinostat against OA, qualifying it as a candidate to be used as a DMOAD.
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Affiliation(s)
- Manabu Kawata
- Department of Molecular Medicine, Scripps Research, La Jolla, California, USA
| | - Daniel B. McClatchy
- Department of Molecular Medicine, Scripps Research, La Jolla, California, USA
| | - Jolene K. Diedrich
- Department of Molecular Medicine, Scripps Research, La Jolla, California, USA
| | - Merissa Olmer
- Department of Molecular Medicine, Scripps Research, La Jolla, California, USA
| | | | - John R. Yates
- Department of Molecular Medicine, Scripps Research, La Jolla, California, USA
| | - Martin K. Lotz
- Department of Molecular Medicine, Scripps Research, La Jolla, California, USA
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14
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Helmi YY, Papenkordt N, Rennar G, Gbahou F, El-Hady AK, Labani N, Schmidtkunz K, Boettcher S, Jockers R, Abdel-Halim M, Jung M, Zlotos DP. Melatonin-vorinostat hybrid ligands show higher histone deacetylase and cancer cell growth inhibition than vorinostat. Arch Pharm (Weinheim) 2023; 356:e2300149. [PMID: 37339785 DOI: 10.1002/ardp.202300149] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 05/31/2023] [Accepted: 06/01/2023] [Indexed: 06/22/2023]
Abstract
Anticancer drug conjugates are an emerging approach for future cancer treatment. Here, we report a series of hybrid ligands merging the neurohormone melatonin with the approved histone deacetylase (HDAC) inhibitor vorinostat, using melatonin's amide side chain (3a-e), its indolic nitrogen (5a-d), and its ether oxygen (7a-d) as attachment points. Several hybrid ligands showed higher potency thanvorinostat in both HDAC inhibition and cellular assays on different cultured cancer cell lines. In the most potent HDAC1 and HDAC6 inhibitors, 3e, 5c, and 7c, the hydroxamic acid moiety of vorinostat is linked to melatonin through a hexamethylene spacer. Hybrid ligands 5c and 7c were also found to be potent growth inhibitors of MCF-7, PC-3M-Luc, and HL-60 cancer cell lines. As these compounds showed only weak agonist activity at melatonin MT1 receptors, the findings indicate that their anticancer actions are driven by HDAC inhibition.
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Affiliation(s)
- Youssef Y Helmi
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, The German University in Cairo, New Cairo City, Cairo, Egypt
| | - Niklas Papenkordt
- Institute of Pharmaceutical Sciences, University of Freiburg, Freiburg, Germany
| | - Georg Rennar
- Institute of Pharmaceutical Sciences, University of Freiburg, Freiburg, Germany
| | - Florence Gbahou
- Université Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France
| | - Ahmed K El-Hady
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, The German University in Cairo, New Cairo City, Cairo, Egypt
- Department of Organic and Pharmaceutical Chemistry, School of Life and Medical Sciences, University of Hertfordshire hosted by Global Academic Foundation, New Administrative Capitol, Cairo, Egypt
| | - Nedjma Labani
- Université Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France
| | - Karin Schmidtkunz
- Institute of Pharmaceutical Sciences, University of Freiburg, Freiburg, Germany
| | - Stefan Boettcher
- Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbruecken, Germany
| | - Ralf Jockers
- Université Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France
| | - Mohammad Abdel-Halim
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, The German University in Cairo, New Cairo City, Cairo, Egypt
| | - Manfred Jung
- Institute of Pharmaceutical Sciences, University of Freiburg, Freiburg, Germany
| | - Darius P Zlotos
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, The German University in Cairo, New Cairo City, Cairo, Egypt
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15
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Lu T, Zhang J, Xu-Monette ZY, Young KH. The progress of novel strategies on immune-based therapy in relapsed or refractory diffuse large B-cell lymphoma. Exp Hematol Oncol 2023; 12:72. [PMID: 37580826 PMCID: PMC10424456 DOI: 10.1186/s40164-023-00432-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 07/30/2023] [Indexed: 08/16/2023] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) can be cured with standard front-line immunochemotherapy, whereas nearly 30-40% of patients experience refractory or relapse. For several decades, the standard treatment strategy for fit relapsed/refractory (R/R) DLBCL patients has been high-dose chemotherapy followed by autologous hematopoietic stem cell transplant (auto-SCT). However, the patients who failed in salvage treatment or those ineligible for subsequent auto-SCT have dismal outcomes. Several immune-based therapies have been developed, including monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engaging antibodies, chimeric antigen receptor T-cells, immune checkpoint inhibitors, and novel small molecules. Meanwhile, allogeneic SCT and radiotherapy are still necessary for disease control for fit patients with certain conditions. In this review, to expand clinical treatment options, we summarize the recent progress of immune-related therapies and prospect the future indirections in patients with R/R DLBCL.
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Affiliation(s)
- Tingxun Lu
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu Province, 214122, China
- Division of Hematopathology, Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA
| | - Jie Zhang
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu Province, 214122, China
| | - Zijun Y Xu-Monette
- Division of Hematopathology, Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA
- Duke Cancer Institute, Durham, NC, 27710, USA
| | - Ken H Young
- Division of Hematopathology, Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA.
- Duke Cancer Institute, Durham, NC, 27710, USA.
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16
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Watanabe T. Recent advances in treatment of nodal and gastrointestinal follicular lymphoma. World J Gastroenterol 2023; 29:3574-3594. [PMID: 37398889 PMCID: PMC10311612 DOI: 10.3748/wjg.v29.i23.3574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/14/2023] [Accepted: 05/22/2023] [Indexed: 06/16/2023] Open
Abstract
Follicular lymphoma (FL) is the most common low-grade lymphoma, and although nodal FL is highly responsive to treatment, the majority of patients relapse repeatedly, and the disease has been incurable with a poor prognosis. However, primary FL of the gastrointestinal tract has been increasingly detected in Japan, especially due to recent advances in small bowel endoscopy and increased opportunities for endoscopic examinations and endoscopic diagnosis. However, many cases are detected at an early stage, and the prognosis is good in many cases. In contrast, in Europe and the United States, gastrointestinal FL has long been considered to be present in 12%-24% of Stage-IV patients, and the number of advanced gastrointestinal cases is expected to increase. This editorial provides an overview of the recent therapeutic advances in nodal FL, including antibody-targeted therapy, bispecific antibody therapy, epigenetic modulation, and chimeric antigen receptor T-cell therapy, and reviews the latest therapeutic manuscripts published in the past year. Based on an understanding of the therapeutic advances in nodal FL, we also discuss future possibilities for gastroenterologists to treat gastrointestinal FL, especially in advanced cases.
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Affiliation(s)
- Takuya Watanabe
- Department of Internal Medicine and Gastroenterology, Watanabe Internal Medicine Aoyama Clinic, Niigata-city 9502002, Japan
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17
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Li SY, Guo YL, Tian JW, Zhang HJ, Li RF, Gong P, Yu ZL. Anti-Tumor Strategies by Harnessing the Phagocytosis of Macrophages. Cancers (Basel) 2023; 15:2717. [PMID: 37345054 DOI: 10.3390/cancers15102717] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 05/07/2023] [Accepted: 05/09/2023] [Indexed: 06/23/2023] Open
Abstract
Macrophages are essential for the human body in both physiological and pathological conditions, engulfing undesirable substances and participating in several processes, such as organism growth, immune regulation, and maintenance of homeostasis. Macrophages play an important role in anti-bacterial and anti-tumoral responses. Aberrance in the phagocytosis of macrophages may lead to the development of several diseases, including tumors. Tumor cells can evade the phagocytosis of macrophages, and "educate" macrophages to become pro-tumoral, resulting in the reduced phagocytosis of macrophages. Hence, harnessing the phagocytosis of macrophages is an important approach to bolster the efficacy of anti-tumor treatment. In this review, we elucidated the underlying phagocytosis mechanisms, such as the equilibrium among phagocytic signals, receptors and their respective signaling pathways, macrophage activation, as well as mitochondrial fission. We also reviewed the recent progress in the area of application strategies on the basis of the phagocytosis mechanism, including strategies targeting the phagocytic signals, antibody-dependent cellular phagocytosis (ADCP), and macrophage activators. We also covered recent studies of Chimeric Antigen Receptor Macrophage (CAR-M)-based anti-tumor therapy. Furthermore, we summarized the shortcomings and future applications of each strategy and look into their prospects with the hope of providing future research directions for developing the application of macrophage phagocytosis-promoting therapy.
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Affiliation(s)
- Si-Yuan Li
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Yong-Lin Guo
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Jia-Wen Tian
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - He-Jing Zhang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Rui-Fang Li
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Ping Gong
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
- Department of Anesthesiology, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Zi-Li Yu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
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18
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Rosenthal AC, Munoz JL, Villasboas JC. Clinical advances in epigenetic therapies for lymphoma. Clin Epigenetics 2023; 15:39. [PMID: 36871057 PMCID: PMC9985856 DOI: 10.1186/s13148-023-01452-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 02/19/2023] [Indexed: 03/06/2023] Open
Abstract
BACKGROUND Advances in understanding of cancer biology, genomics, epigenomics, and immunology have resulted in development of several therapeutic options that expand cancer care beyond traditional chemotherapy or radiotherapy, including individualized treatment strategies, novel treatments based on monotherapies or combination therapy to reduce toxicities, and implementation of strategies for overcoming resistance to anticancer therapy. RESULTS This review covers the latest applications of epigenetic therapies for treatment of B cell, T cell, and Hodgkin lymphomas, highlighting key clinical trial results with monotherapies and combination therapies from the main classes of epigenetic therapies, including inhibitors of DNA methyltransferases, protein arginine methyltransferases, enhancer of zeste homolog 2, histone deacetylases, and the bromodomain and extraterminal domain. CONCLUSION Epigenetic therapies are emerging as an attractive add-on to traditional chemotherapy and immunotherapy regimens. New classes of epigenetic therapies promise low toxicity and may work synergistically with other cancer treatments to overcome drug resistance mechanisms.
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Affiliation(s)
- Allison C Rosenthal
- Division of Hematology, Medical Oncology, Mayo Clinic, 5777 E. Mayo Blvd, Phoenix, AZ, 85054, USA.
| | - Javier L Munoz
- Division of Hematology, Medical Oncology, Mayo Clinic, 5777 E. Mayo Blvd, Phoenix, AZ, 85054, USA
| | - J C Villasboas
- Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA
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19
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Qualls D, Noy A, Straus D, Matasar M, Moskowitz C, Seshan V, Dogan A, Salles G, Younes A, Zelenetz AD, Batlevi CL. Molecularly targeted epigenetic therapy with mocetinostat in relapsed and refractory non-Hodgkin lymphoma with CREBBP or EP300 mutations: an open label phase II study. Leuk Lymphoma 2023; 64:738-741. [PMID: 36642966 PMCID: PMC10841916 DOI: 10.1080/10428194.2022.2164194] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/22/2022] [Accepted: 12/24/2022] [Indexed: 01/17/2023]
Affiliation(s)
- David Qualls
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ariela Noy
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - David Straus
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Matthew Matasar
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Craig Moskowitz
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Venkatraman Seshan
- Department of Epidemiology and Biostatistics, Biostatistics Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ahmet Dogan
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Gilles Salles
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Anas Younes
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Andrew D Zelenetz
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Connie Lee Batlevi
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Department of Medicine, Weill Cornell Medical College, New York, NY, USA
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20
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Shimkus G, Nonaka T. Molecular classification and therapeutics in diffuse large B-cell lymphoma. Front Mol Biosci 2023; 10:1124360. [PMID: 36818048 PMCID: PMC9936827 DOI: 10.3389/fmolb.2023.1124360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 01/09/2023] [Indexed: 02/05/2023] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) encompasses a wide variety of disease states that have to date been subgrouped and characterized based on immunohistochemical methods, which provide limited prognostic value to clinicians and no alteration in treatment regimen. The addition of rituximab to CHOP therapy was the last leap forward in terms of treatment, but regimens currently follow a standardized course when disease becomes refractory with no individualization based on genotype. Research groups are tentatively proposing new strategies for categorizing DLBCL based on genetic abnormalities that are frequently found together to better predict disease course following dysregulation of specific pathways and to deliver targeted treatment. Novel algorithms in combination with next-generation sequencing techniques have identified between 4 and 7 subgroups of DLBCL, depending on the research team, with potentially significant and actionable genetic alterations. Various drugs aimed at pathways including BCR signaling, NF-κB dysfunction, and epigenetic regulation have shown promise in their respective groups and may show initial utility as second or third line therapies to patients with recurrent DLBCL. Implementation of subgroups will allow collection of necessary data to determine which groups are significant, which treatments may be indicated, and will provide better insight to clinicians and patients on specific disease course.
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Affiliation(s)
- Gaelen Shimkus
- School of Medicine, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Taichiro Nonaka
- Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA, United States,Feist-Weiller Cancer Center, Louisiana State University Health Shreveport, Shreveport, LA, United States,*Correspondence: Taichiro Nonaka,
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21
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Montaner-Angoiti E, Marín-García PJ, Llobat L. Epigenetic Alterations in Canine Malignant Lymphoma: Future and Clinical Outcomes. Animals (Basel) 2023; 13:468. [PMID: 36766357 PMCID: PMC9913421 DOI: 10.3390/ani13030468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/25/2023] [Accepted: 01/28/2023] [Indexed: 02/02/2023] Open
Abstract
Canine malignant lymphoma is a common neoplasia in dogs, and some studies have used dogs as a research model for molecular mechanisms of lymphomas in humans. In two species, chemotherapy is the treatment of choice, but the resistance to conventional anticancer drugs is frequent. The knowledge of molecular mechanisms of development and progression of neoplasia has expanded in recent years, and the underlying epigenetic mechanisms are increasingly well known. These studies open up new ways of discovering therapeutic biomarkers. Histone deacetylases and demethylase inhibitors could be a future treatment for canine lymphoma, and the use of microRNAs as diagnosis and prognosis biomarkers is getting closer. This review summarises the epigenetic mechanisms underlying canine lymphoma and their possible application as treatment and biomarkers, both prognostic and diagnostic.
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Affiliation(s)
| | - Pablo Jesús Marín-García
- Departamento Producción y Sanidad Animal, Salud Pública y Ciencia y Tecnología de los Alimentos, Facultad de Veterinaria, Universidad Cardenal Herrera-CEU, CEU Universities, 46115 Valencia, Spain
| | - Lola Llobat
- Departamento Producción y Sanidad Animal, Salud Pública y Ciencia y Tecnología de los Alimentos, Facultad de Veterinaria, Universidad Cardenal Herrera-CEU, CEU Universities, 46115 Valencia, Spain
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22
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Hui L, Ziyue Z, Chao L, Bin Y, Aoyu L, Haijing W. Epigenetic Regulations in Autoimmunity and Cancer: from Basic Science to Translational Medicine. Eur J Immunol 2023; 53:e2048980. [PMID: 36647268 DOI: 10.1002/eji.202048980] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 08/25/2022] [Accepted: 01/10/2023] [Indexed: 01/18/2023]
Abstract
Epigenetics, as a discipline that aims to explain the differential expression of phenotypes arising from the same gene sequence and the heritability of epigenetic expression, has received much attention in medicine. Epigenetic mechanisms are constantly being discovered, including DNA methylation, histone modifications, noncoding RNAs and m6A. The immune system mainly achieves an immune response through the differentiation and functional expression of immune cells, in which epigenetic modification will have an important impact. Because of immune infiltration in the tumor microenvironment, immunotherapy has become a research hotspot in tumor therapy. Epigenetics plays an important role in autoimmune diseases and cancers through immunology. An increasing number of drugs targeting epigenetic mechanisms, such as DNA methyltransferase inhibitors, histone deacetylase inhibitors, and drug combinations, are being evaluated in clinical trials for the treatment of various cancers (including leukemia and osteosarcoma) and autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis). This review summarizes the progress of epigenetic regulation for cancers and autoimmune diseases to date, shedding light on potential therapeutic strategies.
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Affiliation(s)
- Li Hui
- Department of Orthopedics, Second Xiangya Hospital of Central South University, Changsha, Hunan, P. R. China
| | - Zhao Ziyue
- Department of Orthopedics, Second Xiangya Hospital of Central South University, Changsha, Hunan, P. R. China
| | - Liu Chao
- Department of Orthopedics, Second Xiangya Hospital of Central South University, Changsha, Hunan, P. R. China
| | - Yu Bin
- Department of Orthopedics, Second Xiangya Hospital of Central South University, Changsha, Hunan, P. R. China
| | - Li Aoyu
- Department of Orthopedics, Second Xiangya Hospital of Central South University, Changsha, Hunan, P. R. China
| | - Wu Haijing
- Hunan Key Laboratory of Medical Epigenetics, Department of Dermatology, Second Xiangya Hospital of Central South University, Changsha, Hunan, P. R. China
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23
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Gordon MJ, Smith MR, Nastoupil LJ. Follicular lymphoma: The long and winding road leading to your cure? Blood Rev 2023; 57:100992. [PMID: 35908982 DOI: 10.1016/j.blre.2022.100992] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 07/18/2022] [Accepted: 07/20/2022] [Indexed: 01/28/2023]
Abstract
Follicular lymphoma, the most common indolent lymphoma, though highly responsive to therapy is coupled with multiple relapses for the majority of patients. Advances in biologic understanding of molecular events in lymphoma cells and the tumor microenvironment, along with novel cellular and targeted therapies, suggest this may soon change. Here we first review the development of the molecular concepts and classification of follicular lymphoma, along with therapeutic development of treatments based on chemotherapy plus monoclonal antibodies targeting CD20. We then focus on developments over the last decade in further defining follicular lymphoma pathophysiology, leading to targeted therapeutics, as well as novel immunotherapeutic strategies effective against B cell lymphomas including follicular, particularly patients with advanced stage disease. Additional alterations beyond the hallmark t(14;18) translocation are necessary for development of follicular lymphoma. Epigenetic mutations are almost universally identified in follicular lymphoma, most commonly involving histone-lysine N-methyltransferase 2D (KMT2D, the histone acetyltransferases, cAMP response element-binding protein binding protein (CREBBP) and E1A binding protein P300 (EP300) and the histone methyltransferase enhancer of zeste homologue 2 (EZH2). Mutations are also commonly identified in other proliferation/survival pathways such as B-cell receptor, RAS, mTOR and JAK-STAT pathways, as well as immune escape mutations. The host immune response plays a key role as well, based on studies correlating various immune cell subsets and gene expression signatures with outcomes. Over the last decade, many therapeutic options beyond the commonly used bendamustine-rituximab induction regimen have become available or are being investigated. We focus on these newer agents in the relapsed setting. New antibody-based agents include the naked CD19 directed antibody tafasitamab, the CD79b directed antibody drug conjugate (ADC) polatuzumab vedotin and the CD47 directed antibody magrolimab that targets macrophages rather than FL cells directly. Immune modulation by lenalidomide has moved to earlier lines of therapy and in combinations. Several small molecule inhibitors of proliferation signal pathways involving PI3kinase and BTK have activity against FL. Apoptotic pathway modulators also have activity. With increasing recognition of the high rate of epigenetic mutations in FL, HDAC inhibition has a role. More importantly, the EZH2 inhibitor tazemetostat is FDA approved for FL after 2 prior lines of therapy. The most exciting data currently involve immune attack against follicular lymphoma by chimeric antigen receptor T-cells (CART) or bispecific antibody constructs. Given these multiple potentially non-crossreactive mechanisms, studies of rationally designed combination strategies hold the promise of improving outcomes and possibly cure of follicular lymphoma.
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Affiliation(s)
- Max J Gordon
- Dept. of Lymphoma & Myeloma, MD Anderson Cancer Center, Houston, TX, USA.
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24
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Abdelsalam M, Ibrahim HS, Krauss L, Zessin M, Vecchio A, Hastreiter S, Schutkowski M, Schneider G, Sippl W. Development of Pyrazine-Anilinobenzamides as Histone Deacetylase HDAC1-3 Selective Inhibitors and Biological Testing Against Pancreas Cancer Cell Lines. Methods Mol Biol 2023; 2589:145-155. [PMID: 36255623 DOI: 10.1007/978-1-0716-2788-4_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Class I histone deacetylase (HDAC) enzymes are key regulators of cell proliferation and are frequently dysregulated in cancer cells. Here we describe the synthesis of a novel series of class-I selective HDAC inhibitors containing anilinobenzamide moieties as ZBG connected with a central (piperazin-1-yl)pyrazine moiety. Compounds were tested in vitro against class-I HDAC1, 2, and 3 isoforms. Some highly potent HDAC inhibitors were obtained and were tested in pancreatic cancer cells and showed promising activity. Moreover, we summarize how the growth-inhibitory effects of these compounds can be determined in murine pancreatic cancer cell lines.
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Affiliation(s)
- Mohamed Abdelsalam
- Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, Halle/Saale, Germany
- Institute of Pharmacy, University of Alexandria, Alexandria, Egypt
| | - Hany S Ibrahim
- Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, Halle/Saale, Germany
| | - Lukas Krauss
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
| | - Matthes Zessin
- Institute of Biochemistry, Martin-Luther University of Halle-Wittenberg, Halle/Saale, Germany
| | - Anita Vecchio
- Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, Halle/Saale, Germany
| | - Sieglinde Hastreiter
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
- Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, Neuherberg, Germany
| | - Mike Schutkowski
- Institute of Biochemistry, Martin-Luther University of Halle-Wittenberg, Halle/Saale, Germany
| | - Günter Schneider
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
- Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
| | - Wolfgang Sippl
- Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, Halle/Saale, Germany.
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25
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Yang Q, Falahati A, Khosh A, Mohammed H, Kang W, Corachán A, Bariani MV, Boyer TG, Al-Hendy A. Targeting Class I Histone Deacetylases in Human Uterine Leiomyosarcoma. Cells 2022; 11:cells11233801. [PMID: 36497061 PMCID: PMC9735512 DOI: 10.3390/cells11233801] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/19/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
Uterine leiomyosarcoma (uLMS) is the most frequent subtype of uterine sarcoma that presents a poor prognosis, high rates of recurrence, and metastasis. Currently, the molecular mechanism of the origin and development of uLMS is unknown. Class I histone deacetylases (including HDAC1, 2, 3, and 8) are one of the major classes of the HDAC family and catalyze the removal of acetyl groups from lysine residues in histones and cellular proteins. Class I HDACs exhibit distinct cellular and subcellular expression patterns and are involved in many biological processes and diseases through diverse signaling pathways. However, the link between class I HDACs and uLMS is still being determined. In this study, we assessed the expression panel of Class I HDACs in uLMS and characterized the role and mechanism of class I HDACs in the pathogenesis of uLMS. Immunohistochemistry analysis revealed that HDAC1, 2, and 3 are aberrantly upregulated in uLMS tissues compared to adjacent myometrium. Immunoblot analysis demonstrated that the expression levels of HDAC 1, 2, and 3 exhibited a graded increase from normal and benign to malignant uterine tumor cells. Furthermore, inhibition of HDACs with Class I HDACs inhibitor (Tucidinostat) decreased the uLMS proliferation in a dose-dependent manner. Notably, gene set enrichment analysis of differentially expressed genes (DEGs) revealed that inhibition of HDACs with Tucidinostat altered several critical pathways. Moreover, multiple epigenetic analyses suggested that Tucidinostat may alter the transcriptome via reprogramming the oncogenic epigenome and inducing the changes in microRNA-target interaction in uLMS cells. In the parallel study, we also determined the effect of DL-sulforaphane on the uLMS. Our study demonstrated the relevance of class I HDACs proteins in the pathogenesis of malignant uLMS. Further understanding the role and mechanism of HDACs in uLMS may provide a promising and novel strategy for treating patients with this aggressive uterine cancer.
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Affiliation(s)
- Qiwei Yang
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
- Correspondence:
| | - Ali Falahati
- Department of Biology, Yazd University, Yazd 891581841, Iran
| | - Azad Khosh
- Department of Biology, Yazd University, Yazd 891581841, Iran
| | - Hanaa Mohammed
- Anatomy Department, Faculty of Medicine, Sohag University, Sohag 82524, Egypt
| | - Wenjun Kang
- Center for Research Informatics, University of Chicago, Chicago, IL 60637, USA
| | - Ana Corachán
- Department of Paediatrics, University of Valencia, Obstetrics and Gynecology, 46026 Valencia, Spain
| | | | - Thomas G. Boyer
- Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Ayman Al-Hendy
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
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26
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Markouli M, Strepkos D, Piperi C. Impact of Histone Modifications and Their Therapeutic Targeting in Hematological Malignancies. Int J Mol Sci 2022; 23:13657. [PMID: 36362442 PMCID: PMC9654260 DOI: 10.3390/ijms232113657] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/31/2022] [Accepted: 11/02/2022] [Indexed: 11/09/2022] Open
Abstract
Hematologic malignancies are a large and heterogeneous group of neoplasms characterized by complex pathogenetic mechanisms. The abnormal regulation of epigenetic mechanisms and specifically, histone modifications, has been demonstrated to play a central role in hematological cancer pathogenesis and progression. A variety of epigenetic enzymes that affect the state of histones have been detected as deregulated, being either over- or underexpressed, which induces changes in chromatin compaction and, subsequently, affects gene expression. Recent advances in the field of epigenetics have revealed novel therapeutic targets, with many epigenetic drugs being investigated in clinical trials. The present review focuses on the biological impact of histone modifications in the pathogenesis of hematologic malignancies, describing a wide range of therapeutic agents that have been discovered to target these alterations and are currently under investigation in clinical trials.
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Affiliation(s)
| | | | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.M.); (D.S.)
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27
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Wang Y, Xue H, Song W, Xiao S, Jing F, Dong T, Wang L. Chidamide with PEL regimen (prednisone, etoposide, lenalidomide) for elderly or frail patients with relapsed/refractory diffuse large B-Cell lymphoma -results of a single center, retrospective cohort in China. Hematol Oncol 2022; 40:617-625. [PMID: 35165928 PMCID: PMC9790240 DOI: 10.1002/hon.2979] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 02/10/2022] [Indexed: 12/30/2022]
Abstract
Treatment for relapsed/refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL) is evolving rapidly due to the emergence of novel drugs, of which histone deacetylase inhibitors (HDACis) are an important example. This study showed efficacy in patients with R/R DLBCL after failure of conventional therapies. We conducted a single-center, retrospective study of 34 frail or elderly R/R DLBCL patients who had been treated off-label with chidamide-containing regimens from 2018 to 2020. X2 or Fisher test were used to compare response rate and Kaplan-Meier method was used to perform the survival analyses which compared with log-rank test between different groups. The test standard was p < 0.05. In total, 34 patients with R/R DLBCL received CPEL+/-R for at least 1 cycle were included. Most of them were refractory patients (n = 28,82.4%). The interim objective response rate (ORR) was 73.5% (32.4% complete remission [CR]), and the ultimate ORR was 50.0% (35.3% CR). After a median follow-up of 13.1 months, the median progression-free survival (PFS) was 10.5 months (95%CI 6.4-14.6) and the median overall survival (OS) was 19.3 months (95%CI 11.8-26.9). The 1 year expected PFS and OS rate was 43.0% and 73.7%, respectively. The most common grade 3/4 hematologic adverse events (AEs) were neutropenia (n = 11,32.3%) and anemia (n = 4, 11.8%) 0.23.5% (8/34) of all patients experienced grade 3/4 nonhematologic AEs. No treatment-related deaths were observed. The study showed chidamide-included regimen could be an option for R/R DLBCL patients ineligible for intensive chemotherapies. Current data showed favorable efficiency and moderate safety profile. Further study is warranted for better illustration of efficacy and usage in combination therapies.
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Affiliation(s)
- Yawen Wang
- Department of HematologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Hongwei Xue
- Department of HematologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Wei Song
- Department of HematologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Shuxin Xiao
- Department of HematologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Fanjing Jing
- Department of HematologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Tieying Dong
- Department of HematologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Lili Wang
- Department of PathologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
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28
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Large-Scale Identification of Multiple Classes of Host Defense Peptide-Inducing Compounds for Antimicrobial Therapy. Int J Mol Sci 2022; 23:ijms23158400. [PMID: 35955551 PMCID: PMC9368921 DOI: 10.3390/ijms23158400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/23/2022] [Accepted: 07/27/2022] [Indexed: 12/10/2022] Open
Abstract
The rapid emergence of antibiotic resistance demands new antimicrobial strategies that are less likely to develop resistance. Augmenting the synthesis of endogenous host defense peptides (HDPs) has been proven to be an effective host-directed therapeutic approach. This study aimed to identify small-molecule compounds with a strong ability to induce endogenous HDP synthesis for further development as novel antimicrobial agents. By employing a stable HDP promoter-driven luciferase reporter cell line known as HTC/AvBD9-luc, we performed high-throughput screening of 5002 natural and synthetic compounds and identified 110 hits with a minimum Z-score of 2.0. Although they were structurally and functionally diverse, half of these hits were inhibitors of class I histone deacetylases, the phosphoinositide 3-kinase pathway, ion channels, and dopamine and serotonin receptors. Further validations revealed mocetinostat, a benzamide histone deacetylase inhibitor, to be highly potent in enhancing the expression of multiple HDP genes in chicken macrophage cell lines and jejunal explants. Importantly, mocetinostat was more efficient than entinostat and tucidinostat, two structural analogs, in promoting HDP gene expression and the antibacterial activity of chicken macrophages. Taken together, mocetinostat, with its ability to enhance HDP synthesis and the antibacterial activity of host cells, could be potentially developed as a novel antimicrobial for disease control and prevention.
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29
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Herp D, Ridinger J, Robaa D, Shinsky SA, Schmidtkunz K, Yesiloglu TZ, Bayer T, Steimbach RR, Herbst‐Gervasoni CJ, Merz A, Romier C, Sehr P, Gunkel N, Miller AK, Christianson DW, Oehme I, Sippl W, Jung M. First Fluorescent Acetylspermidine Deacetylation Assay for HDAC10 Identifies Selective Inhibitors with Cellular Target Engagement. Chembiochem 2022; 23:e202200180. [PMID: 35608330 PMCID: PMC9308754 DOI: 10.1002/cbic.202200180] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/18/2022] [Indexed: 11/06/2022]
Abstract
Histone deacetylases (HDACs) are important epigenetic regulators involved in many diseases, especially cancer. Five HDAC inhibitors have been approved for anticancer therapy and many are in clinical trials. Among the 11 zinc-dependent HDACs, HDAC10 has received relatively little attention by drug discovery campaigns, despite its involvement, e. g., in the pathogenesis of neuroblastoma. This is due in part to a lack of robust enzymatic conversion assays. In contrast to the protein lysine deacetylase and deacylase activity of most other HDAC subtypes, it has recently been shown that HDAC10 has strong preferences for deacetylation of oligoamine substrates like acetyl-putrescine or -spermidine. Hence, it is also termed a polyamine deacetylase (PDAC). Here, we present the first fluorescent enzymatic conversion assay for HDAC10 using an aminocoumarin-labelled acetyl-spermidine derivative to measure its PDAC activity, which is suitable for high-throughput screening. Using this assay, we identified potent inhibitors of HDAC10-mediated spermidine deacetylation in vitro. Based on the oligoamine preference of HDAC10, we also designed inhibitors with a basic moiety in appropriate distance to the zinc binding hydroxamate that showed potent inhibition of HDAC10 with high selectivity, and we solved a HDAC10-inhibitor structure using X-ray crystallography. We could demonstrate selective cellular target engagement for HDAC10 but a lysosomal phenotype in neuroblastoma cells that was previously associated with HDAC10 inhibition was not observed. Thus, we have developed new chemical probes for HDAC10 that allow further clarification of the biological role of this enzyme.
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Affiliation(s)
- Daniel Herp
- Institute of Pharmaceutical SciencesUniversity of FreiburgAlbertstraße 2579104FreiburgGermany
| | - Johannes Ridinger
- Hopp Children's Cancer Center Heidelberg (KiTZ)Im Neuenheimer Feld 28069120HeidelbergGermany
- Clinical Cooperation Unit Pediatric OncologyGerman Cancer Research Center (DKFZ)Im Neuenheimer Feld 28069120HeidelbergGermany
- German Cancer Consortium (DKTK)Im Neuenheimer Feld 28069120HeidelbergGermany
| | - Dina Robaa
- Institute of PharmacyMartin-Luther University of Halle-Wittenberg06120Halle (Saale)Halle/SaaleGermany
| | - Stephen A. Shinsky
- Roy and Diana Vagelos LaboratoriesDepartment of ChemistryUniversity of Pennsylvania231 South 34th StreetPhiladelphiaPennsylvania19104-6323USA
| | - Karin Schmidtkunz
- Institute of Pharmaceutical SciencesUniversity of FreiburgAlbertstraße 2579104FreiburgGermany
| | - Talha Z. Yesiloglu
- Institute of PharmacyMartin-Luther University of Halle-Wittenberg06120Halle (Saale)Halle/SaaleGermany
| | - Theresa Bayer
- Institute of PharmacyMartin-Luther University of Halle-Wittenberg06120Halle (Saale)Halle/SaaleGermany
| | | | - Corey J. Herbst‐Gervasoni
- Roy and Diana Vagelos LaboratoriesDepartment of ChemistryUniversity of Pennsylvania231 South 34th StreetPhiladelphiaPennsylvania19104-6323USA
| | - Annika Merz
- Institute of Pharmaceutical SciencesUniversity of FreiburgAlbertstraße 2579104FreiburgGermany
| | - Christophe Romier
- Université de StrasbourgCNRSINSERMInstitut de Génétique et de Biologie Moléculaire et CellulaireUMR 7104, U 125867404IllkirchFrance
- IGBMCDepartment of Integrated Structural Biology1 rue Laurent Fries, B.P. 1014267404Illkirch CedexFrance
| | - Peter Sehr
- Chemical Biology Core FacilityEuropean Molecular Biology Laboratory69117HeidelbergGermany
| | - Nikolas Gunkel
- German Cancer Consortium (DKTK)Im Neuenheimer Feld 28069120HeidelbergGermany
- Cancer Drug Development GroupIm Neuenheimer Feld 28069120HeidelbergGermany
| | - Aubry K. Miller
- German Cancer Consortium (DKTK)Im Neuenheimer Feld 28069120HeidelbergGermany
- Cancer Drug Development GroupIm Neuenheimer Feld 28069120HeidelbergGermany
| | - David W. Christianson
- Roy and Diana Vagelos LaboratoriesDepartment of ChemistryUniversity of Pennsylvania231 South 34th StreetPhiladelphiaPennsylvania19104-6323USA
| | - Ina Oehme
- Hopp Children's Cancer Center Heidelberg (KiTZ)Im Neuenheimer Feld 28069120HeidelbergGermany
- Clinical Cooperation Unit Pediatric OncologyGerman Cancer Research Center (DKFZ)Im Neuenheimer Feld 28069120HeidelbergGermany
- German Cancer Consortium (DKTK)Im Neuenheimer Feld 28069120HeidelbergGermany
| | - Wolfgang Sippl
- Institute of PharmacyMartin-Luther University of Halle-Wittenberg06120Halle (Saale)Halle/SaaleGermany
| | - Manfred Jung
- Institute of Pharmaceutical SciencesUniversity of FreiburgAlbertstraße 2579104FreiburgGermany
- German Cancer Consortium (DKTK), Partner site FreiburgHugstetter Str. 5579106FreiburgGermany
- CIBSS - Centre for Integrative Biological Signalling StudiesUniversity of Freiburg (Germany)
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30
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Zhu W, Tao S, Miao W, Liu H, Yuan X. Case Report: Dual Inhibition of HDAC and BTK for Diffuse Large B-Cell Lymphoma After Failure to CD19-Targeted CAR-T Therapy. Front Immunol 2022; 13:894787. [PMID: 35757723 PMCID: PMC9226330 DOI: 10.3389/fimmu.2022.894787] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 05/16/2022] [Indexed: 01/31/2023] Open
Abstract
Background Failure to CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), is an emerging clinical problem. There is no consensus on the treatment for these patients and treatment remains empirical. Case Report We reported a case of an elderly R/R DLBCL patient who had TP53 mutation and relapsed 12 months after initial response to CAR T-cell therapy. The patient did not respond to salvage chemotherapy with the GDP regimen and could not tolerate any aggressive chemotherapy. Thereafter, the patient was given chidamide and zanubrutinib. After two months of treatment, the patient achieved sustained complete remission. At the last follow-up, the patient remains in radiographic CR 22 months after CAR-T infusion and 10 months after the initiation of the combination treatment. Conclusion We report the first successful case of dual inhibition of HDAC and BTK for the treatment of R/R DLBCL after failure to CAR-T cell therapy, which opens a new therapeutic possibility for the future.
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Affiliation(s)
- Weiguo Zhu
- Department of Hematology, Shaoxing Second Hospital, Shaoxing, China
| | - Shi Tao
- Department of Hematology, Shaoxing Second Hospital, Shaoxing, China
| | - Wenchun Miao
- Department of Hematology, Shaoxing Second Hospital, Shaoxing, China
| | - Hui Liu
- Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xianggui Yuan
- Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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31
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Jin Y, Liu T, Luo H, Liu Y, Liu D. Targeting Epigenetic Regulatory Enzymes for Cancer Therapeutics: Novel Small-Molecule Epidrug Development. Front Oncol 2022; 12:848221. [PMID: 35419278 PMCID: PMC8995554 DOI: 10.3389/fonc.2022.848221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 03/04/2022] [Indexed: 11/13/2022] Open
Abstract
Dysregulation of the epigenetic enzyme-mediated transcription of oncogenes or tumor suppressor genes is closely associated with the occurrence, progression, and prognosis of tumors. Based on the reversibility of epigenetic mechanisms, small-molecule compounds that target epigenetic regulation have become promising therapeutics. These compounds target epigenetic regulatory enzymes, including DNA methylases, histone modifiers (methylation and acetylation), enzymes that specifically recognize post-translational modifications, chromatin-remodeling enzymes, and post-transcriptional regulators. Few compounds have been used in clinical trials and exhibit certain therapeutic effects. Herein, we summarize the classification and therapeutic roles of compounds that target epigenetic regulatory enzymes in cancer treatment. Finally, we highlight how the natural compounds berberine and ginsenosides can target epigenetic regulatory enzymes to treat cancer.
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Affiliation(s)
- Ye Jin
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Tianjia Liu
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Haoming Luo
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Yangyang Liu
- Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Da Liu
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
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Zhuang Y, Che J, Wu M, Guo Y, Xu Y, Dong X, Yang H. Altered pathways and targeted therapy in double hit lymphoma. J Hematol Oncol 2022; 15:26. [PMID: 35303910 PMCID: PMC8932183 DOI: 10.1186/s13045-022-01249-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 03/07/2022] [Indexed: 12/20/2022] Open
Abstract
High-grade B-cell lymphoma with translocations involving MYC and BCL2 or BCL6, usually referred to as double hit lymphoma (DHL), is an aggressive hematological malignance with distinct genetic features and poor clinical prognosis. Current standard chemoimmunotherapy fails to confer satisfying outcomes and few targeted therapeutics are available for the treatment against DHL. Recently, the delineating of the genetic landscape in tumors has provided insight into both biology and targeted therapies. Therefore, it is essential to understand the altered signaling pathways of DHL to develop treatment strategies with better clinical benefits. Herein, we summarized the genetic alterations in the two DHL subtypes (DHL-BCL2 and DHL-BCL6). We further elucidate their implications on cellular processes, including anti-apoptosis, epigenetic regulations, B-cell receptor signaling, and immune escape. Ongoing and potential therapeutic strategies and targeted drugs steered by these alterations were reviewed accordingly. Based on these findings, we also discuss the therapeutic vulnerabilities that coincide with these genetic changes. We believe that the understanding of the DHL studies will provide insight into this disease and capacitate the finding of more effective treatment strategies.
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Affiliation(s)
- Yuxin Zhuang
- Department of Lymphoma, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, People’s Republic of China
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People’s Republic of China
| | - Jinxin Che
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People’s Republic of China
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, People’s Republic of China
| | - Meijuan Wu
- Department of Pathology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, People’s Republic of China
| | - Yu Guo
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, People’s Republic of China
| | - Yongjin Xu
- Department of Lymphoma, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, People’s Republic of China
| | - Xiaowu Dong
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People’s Republic of China
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, People’s Republic of China
- Cancer Center, Zhejiang University, Hangzhou, People’s Republic of China
| | - Haiyan Yang
- Department of Lymphoma, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, People’s Republic of China
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Ruzic D, Djoković N, Srdić-Rajić T, Echeverria C, Nikolic K, Santibanez JF. Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention. Pharmaceutics 2022; 14:pharmaceutics14010209. [PMID: 35057104 PMCID: PMC8778744 DOI: 10.3390/pharmaceutics14010209] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/06/2022] [Accepted: 01/12/2022] [Indexed: 02/06/2023] Open
Abstract
The dysregulation of gene expression is a critical event involved in all steps of tumorigenesis. Aberrant histone and non-histone acetylation modifications of gene expression due to the abnormal activation of histone deacetylases (HDAC) have been reported in hematologic and solid types of cancer. In this sense, the cancer-associated epigenetic alterations are promising targets for anticancer therapy and chemoprevention. HDAC inhibitors (HDACi) induce histone hyperacetylation within target proteins, altering cell cycle and proliferation, cell differentiation, and the regulation of cell death programs. Over the last three decades, an increasing number of synthetic and naturally derived compounds, such as dietary-derived products, have been demonstrated to act as HDACi and have provided biological and molecular insights with regard to the role of HDAC in cancer. The first part of this review is focused on the biological roles of the Zinc-dependent HDAC family in malignant diseases. Accordingly, the small-molecules and natural products such as HDACi are described in terms of cancer therapy and chemoprevention. Furthermore, structural considerations are included to improve the HDACi selectivity and combinatory potential with other specific targeting agents in bifunctional inhibitors and proteolysis targeting chimeras. Additionally, clinical trials that combine HDACi with current therapies are discussed, which may open new avenues in terms of the feasibility of HDACi’s future clinical applications in precision cancer therapies.
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Affiliation(s)
- Dusan Ruzic
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia; (D.R.); (N.D.); (K.N.)
| | - Nemanja Djoković
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia; (D.R.); (N.D.); (K.N.)
| | - Tatjana Srdić-Rajić
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia;
| | - Cesar Echeverria
- Facultad de Medicina, Universidad de Atacama, Copayapu 485, Copiapo 1531772, Chile;
| | - Katarina Nikolic
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia; (D.R.); (N.D.); (K.N.)
| | - Juan F. Santibanez
- Group for Molecular Oncology, Institute for Medical Research, National Institute of the Republic of Serbia, University of Belgrade, Dr. Subotica 4, POB 102, 11129 Belgrade, Serbia
- Centro Integrativo de Biología y Química Aplicada (CIBQA), Universidad Bernardo O’Higgins, Santiago 8370854, Chile
- Correspondence: ; Tel.: +381-11-2685-788; Fax: +381-11-2643-691
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Ibrahim HS, Abdelsalam M, Zeyn Y, Zessin M, Mustafa AHM, Fischer MA, Zeyen P, Sun P, Bülbül EF, Vecchio A, Erdmann F, Schmidt M, Robaa D, Barinka C, Romier C, Schutkowski M, Krämer OH, Sippl W. Synthesis, Molecular Docking and Biological Characterization of Pyrazine Linked 2-Aminobenzamides as New Class I Selective Histone Deacetylase (HDAC) Inhibitors with Anti-Leukemic Activity. Int J Mol Sci 2021; 23:ijms23010369. [PMID: 35008795 PMCID: PMC8745332 DOI: 10.3390/ijms23010369] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 12/23/2021] [Accepted: 12/27/2021] [Indexed: 12/19/2022] Open
Abstract
Class I histone deacetylases (HDACs) are key regulators of cell proliferation and they are frequently dysregulated in cancer cells. We report here the synthesis of a novel series of class-I selective HDAC inhibitors (HDACi) containing a 2-aminobenzamide moiety as a zinc-binding group connected with a central (piperazin-1-yl)pyrazine or (piperazin-1-yl)pyrimidine moiety. Some of the compounds were additionally substituted with an aromatic capping group. Compounds were tested in vitro against human HDAC1, 2, 3, and 8 enzymes and compared to reference class I HDACi (Entinostat (MS-275), Mocetinostat, CI994 and RGFP-966). The most promising compounds were found to be highly selective against HDAC1, 2 and 3 over the remaining HDAC subtypes from other classes. Molecular docking studies and MD simulations were performed to rationalize the in vitro data and to deduce a complete structure activity relationship (SAR) analysis of this novel series of class-I HDACi. The most potent compounds, including 19f, which blocks HDAC1, HDAC2, and HDAC3, as well as the selective HDAC1/HDAC2 inhibitors 21a and 29b, were selected for further cellular testing against human acute myeloid leukemia (AML) and erythroleukemic cancer (HEL) cells, taking into consideration their low toxicity against human embryonic HEK293 cells. We found that 19f is superior to the clinically tested class-I HDACi Entinostat (MS-275). Thus, 19f is a new and specific HDACi with the potential to eliminate blood cancer cells of various origins.
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Affiliation(s)
- Hany S. Ibrahim
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; (H.S.I.); (M.A.); (M.Z.); (P.Z.); (P.S.); (E.F.B.); (A.V.); (F.E.); (M.S.); (D.R.)
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt
| | - Mohamed Abdelsalam
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; (H.S.I.); (M.A.); (M.Z.); (P.Z.); (P.S.); (E.F.B.); (A.V.); (F.E.); (M.S.); (D.R.)
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
| | - Yanira Zeyn
- Department of Toxicology, University Medical Center, 55131 Mainz, Germany; (Y.Z.); (A.-H.M.M.); (M.A.F.)
| | - Matthes Zessin
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; (H.S.I.); (M.A.); (M.Z.); (P.Z.); (P.S.); (E.F.B.); (A.V.); (F.E.); (M.S.); (D.R.)
- Department of Enzymology, Institute of Biochemistry, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany;
| | - Al-Hassan M. Mustafa
- Department of Toxicology, University Medical Center, 55131 Mainz, Germany; (Y.Z.); (A.-H.M.M.); (M.A.F.)
- Department of Zoology, Faculty of Science, Aswan University, Aswan 81528, Egypt
| | - Marten A. Fischer
- Department of Toxicology, University Medical Center, 55131 Mainz, Germany; (Y.Z.); (A.-H.M.M.); (M.A.F.)
| | - Patrik Zeyen
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; (H.S.I.); (M.A.); (M.Z.); (P.Z.); (P.S.); (E.F.B.); (A.V.); (F.E.); (M.S.); (D.R.)
| | - Ping Sun
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; (H.S.I.); (M.A.); (M.Z.); (P.Z.); (P.S.); (E.F.B.); (A.V.); (F.E.); (M.S.); (D.R.)
| | - Emre F. Bülbül
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; (H.S.I.); (M.A.); (M.Z.); (P.Z.); (P.S.); (E.F.B.); (A.V.); (F.E.); (M.S.); (D.R.)
| | - Anita Vecchio
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; (H.S.I.); (M.A.); (M.Z.); (P.Z.); (P.S.); (E.F.B.); (A.V.); (F.E.); (M.S.); (D.R.)
| | - Frank Erdmann
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; (H.S.I.); (M.A.); (M.Z.); (P.Z.); (P.S.); (E.F.B.); (A.V.); (F.E.); (M.S.); (D.R.)
| | - Matthias Schmidt
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; (H.S.I.); (M.A.); (M.Z.); (P.Z.); (P.S.); (E.F.B.); (A.V.); (F.E.); (M.S.); (D.R.)
| | - Dina Robaa
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; (H.S.I.); (M.A.); (M.Z.); (P.Z.); (P.S.); (E.F.B.); (A.V.); (F.E.); (M.S.); (D.R.)
| | - Cyril Barinka
- Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Prumyslova 595, 25250 Vestec, Czech Republic;
| | - Christophe Romier
- Département de Biologie Structurale Intégrative, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS, INSERM, Université de Strasbourg, CEDEX, 67404 Illkirch, France;
| | - Mike Schutkowski
- Department of Enzymology, Institute of Biochemistry, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany;
| | - Oliver H. Krämer
- Department of Toxicology, University Medical Center, 55131 Mainz, Germany; (Y.Z.); (A.-H.M.M.); (M.A.F.)
- Correspondence: (O.H.K.); (W.S.)
| | - Wolfgang Sippl
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; (H.S.I.); (M.A.); (M.Z.); (P.Z.); (P.S.); (E.F.B.); (A.V.); (F.E.); (M.S.); (D.R.)
- Correspondence: (O.H.K.); (W.S.)
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Fernández-Serrano M, Winkler R, Santos JC, Le Pannérer MM, Buschbeck M, Roué G. Histone Modifications and Their Targeting in Lymphoid Malignancies. Int J Mol Sci 2021; 23:253. [PMID: 35008680 PMCID: PMC8745418 DOI: 10.3390/ijms23010253] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/22/2021] [Accepted: 12/24/2021] [Indexed: 12/12/2022] Open
Abstract
In a wide range of lymphoid neoplasms, the process of malignant transformation is associated with somatic mutations in B cells that affect the epigenetic machinery. Consequential alterations in histone modifications contribute to disease-specific changes in the transcriptional program. Affected genes commonly play important roles in cell cycle regulation, apoptosis-inducing signal transduction, and DNA damage response, thus facilitating the emergence of malignant traits that impair immune surveillance and favor the emergence of different B-cell lymphoma subtypes. In the last two decades, the field has made a major effort to develop therapies that target these epigenetic alterations. In this review, we discuss which epigenetic alterations occur in B-cell non-Hodgkin lymphoma. Furthermore, we aim to present in a close to comprehensive manner the current state-of-the-art in the preclinical and clinical development of epigenetic drugs. We focus on therapeutic strategies interfering with histone methylation and acetylation as these are most advanced in being deployed from the bench-to-bedside and have the greatest potential to improve the prognosis of lymphoma patients.
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Affiliation(s)
- Miranda Fernández-Serrano
- Lymphoma Translational Group, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain; (M.F.-S.); (J.C.S.)
- Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, 08014 Barcelona, Spain
| | - René Winkler
- Chromatin, Metabolism and Cell Fate Group, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain; (R.W.); (M.-M.L.P.)
| | - Juliana C. Santos
- Lymphoma Translational Group, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain; (M.F.-S.); (J.C.S.)
| | - Marguerite-Marie Le Pannérer
- Chromatin, Metabolism and Cell Fate Group, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain; (R.W.); (M.-M.L.P.)
| | - Marcus Buschbeck
- Chromatin, Metabolism and Cell Fate Group, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain; (R.W.); (M.-M.L.P.)
- Program of Personalized and Predictive Medicine of Cancer, Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain
| | - Gaël Roué
- Lymphoma Translational Group, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain; (M.F.-S.); (J.C.S.)
- Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, 08014 Barcelona, Spain
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Sawalha Y. Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Look at the Approved and Emerging Therapies. J Pers Med 2021; 11:1345. [PMID: 34945817 PMCID: PMC8708171 DOI: 10.3390/jpm11121345] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/12/2021] [Accepted: 11/28/2021] [Indexed: 12/11/2022] Open
Abstract
Approximately 40% of patients with diffuse large B cell lymphoma (DLBCL) do not respond or develop relapsed disease after first-line chemoimmunotherapy. A minority of these patients can be cured with autologous hematopoietic stem cell transplantation (AHCT). Although chimeric antigen receptor (CAR) T cells have transformed the treatment paradigm of relapsed/refractory DLBCL, only 30-40% of patients achieve durable remissions. In addition, many patients with relapsed/refractory DLBCL are ineligible to receive treatment with CAR T cells due to comorbidities or logistical limitations. Since 2019, the following four non-CAR T-cell treatments have been approved in relapsed/refractory DLBCL: polatuzumab in combination with bendamustine and rituximab, selinexor, tafasitamab plus lenalidomide, and loncastuximab. In this article, I review the data behind these four approvals and discuss important considerations on their use in clinical practice. I also review emerging therapies that have shown promising early results in relapsed/refractory DLBCL including the bispecific antibodies, antibody-drug conjugates, Bruton tyrosine kinase inhibitors, BCL2 inhibitors, immune checkpoint inhibitors, and epigenetic modifiers.
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Affiliation(s)
- Yazeed Sawalha
- Department of Internal Medicine, Division of Hematology, Arthur G. James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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Chen C, Zhang W, Zhou D, Zhang Y. Sintilimab and Chidamide for Refractory Transformed Diffuse Large B Cell Lymphoma: A Case Report and A Literature Review. Front Oncol 2021; 11:757403. [PMID: 34820328 PMCID: PMC8606549 DOI: 10.3389/fonc.2021.757403] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 10/18/2021] [Indexed: 01/22/2023] Open
Abstract
Patients with relapsed/refractory (R/R) transformed diffused large B cell lymphoma (tDLBCL) have a poor prognosis and a low survival rate. In addition, no standard therapy has yet been established for R/R tDLBCL. Herein we presented a single case of a patient with R/R tDLBCL who was successfully treated with sintilimab and chidamide. The patient was a 71-year-old man with pulmonary mucosa-associated lymphoid tissue lymphoma. He did not receive any treatment until tDLBCL was confirmed 2 years later. The tDLBCL was primary refractory to R2-CHOP, R2-MTX, and Gemox regimens. However, the patient achieved sustained complete remission after the combination therapy of sintilimab and chidamide. To the best of our knowledge, this is the first report of sintilimab combined with chidamide for the treatment of R/R tDLBCL, which opens up new therapeutic possibilities for this new combination therapy in future prospective clinical trials.
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Affiliation(s)
- Chao Chen
- Department of Hematology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences (CAMS), Beijing, China
| | - Wei Zhang
- Department of Hematology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences (CAMS), Beijing, China
| | - Daobin Zhou
- Department of Hematology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences (CAMS), Beijing, China
| | - Yan Zhang
- Department of Hematology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences (CAMS), Beijing, China
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38
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Islam P, Rizzieri D, Lin C, de Castro C, Diehl L, Li Z, Moore J, Morris T, Beaven A. Phase II Study of Single-Agent and Combination Everolimus and Panobinostat in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Cancer Invest 2021; 39:871-879. [PMID: 34643126 DOI: 10.1080/07357907.2021.1983584] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Novel therapeutics are needed for patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL). Everolimus is an mTOR pathway inhibitor with synergistic anti-tumor activity when combined with histone deacetylase inhibitors, such as panobinostat, in preclinical lymphoma models. In this Phase II study, we evaluated overall response rate to single and combination everolimus and panobinostat in R/R DLBCL. Fifteen patients were enrolled to single-agent and 18 to combination. One patient responded to everolimus, while none responded to panobinostat. Though 25% of patients responded to combination therapy, responses were not durable with significant toxicity. We demonstrated minimal single-agent activity and prohibitive toxicity with combination therapy.
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Affiliation(s)
- Prioty Islam
- Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina, USA
| | - David Rizzieri
- Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina, USA
| | - Chenyu Lin
- Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina, USA
| | - Carlos de Castro
- Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina, USA
| | - Louis Diehl
- Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina, USA
| | - Zhiguo Li
- Duke Cancer Institute, Biostatistics Shared Resources, Duke University, Durham, North Carolina, USA
| | - Joseph Moore
- Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina, USA
| | - Tod Morris
- Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina, USA
| | - Anne Beaven
- Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina, USA
- Division of Hematology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Mehta‐Shah N, Lunning MA, Moskowitz AJ, Boruchov AM, Ruan J, Lynch P, Hamlin PA, Leonard J, Matasar MJ, Myskowski PL, Marzouk E, Nair S, Sholklapper T, Minnal V, Palomba ML, Vredenburgh J, Kumar A, Noy A, Straus DJ, Zelenetz AD, Schoder H, Rademaker J, Schaffer W, Galasso N, Ganesan N, Horwitz SM. Romidepsin and lenalidomide-based regimens have efficacy in relapsed/refractory lymphoma: Combined analysis of two phase I studies with expansion cohorts. Am J Hematol 2021; 96:1211-1222. [PMID: 34251048 DOI: 10.1002/ajh.26288] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 06/06/2021] [Accepted: 07/02/2021] [Indexed: 12/17/2022]
Abstract
Romidepsin (histone deacetylase inhibitor), lenalidomide (immunomodulatory agent), and carfilzomib (proteasome inhibitor), have efficacy and lack cumulative toxicity in relapsed/refractory lymphoma. We performed two investigator initiated sequential phase I studies to evaluate the maximum tolerated dose (MTD) of romidepsin and lenalidomide (regimen A) and romidepsin, lenalidomide, and carfilzomib (regimen B) in relapsed/refractory lymphoma. Cohorts in T-cell lymphoma (TCL), B-cell lymphoma (BCL) were enrolled at the MTD. Forty-nine patients were treated in study A (27 TCL, 17 BCL, 5 Hodgkin lymphoma (HL)) and 27 (16 TCL, 11 BCL) in study B. The MTD of regimen A was romidepsin 14 mg/m2 IV on days 1, 8, and 15 and lenalidomide 25 mg oral on days 1-21 of a 28-day cycle. The MTD of regimen B was romidepsin 8 mg/m2 on days 1 and 8, lenalidomide 10 mg oral on days 1-14 and carfilzomib 36 mg/m2 IV on days 1 and 8 of a 21-day cycle. In study A, 94% had AEs ≥Grade 3, most commonly neutropenia (49%), thrombocytopenia (53%), and electrolyte abnormalities (49%). In study B 59% had AEs ≥Grade 3, including thrombocytopenia (30%) and neutropenia (26%). In study A the ORR was 49% (50% TCL, 47% BCL, 50% HL). In study B the ORR was 48% (50% TCL, 50% BCL). For study A and B the median progression free survival (PFS) was 5.7 months and 3.4 months respectively with 11 patients proceeding to allogeneic transplant. The combinations of romidepsin and lenalidomide and of romidepsin, lenalidomide and carfilzomib showed activity in relapsed/refractory lymphoma with an acceptable safety profile.
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Affiliation(s)
- Neha Mehta‐Shah
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
- Washington University School of Medicine in St. Louis St. Louis Missouri USA
| | - Matthew A. Lunning
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
- Department of Medicine University of Nebraska Medical Center Omaha Nebraska USA
| | - Alison J. Moskowitz
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Adam M. Boruchov
- Department of Medicine St. Francis Medical Center Hartford Connecticut USA
| | - Jia Ruan
- Department of Medicine Weill Cornell Medical Center New York New York USA
| | - Peggy Lynch
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Paul A. Hamlin
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - John Leonard
- Department of Medicine Weill Cornell Medical Center New York New York USA
| | - Matthew J. Matasar
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Patricia L. Myskowski
- Dermatology Service, Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Evan Marzouk
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Sumithra Nair
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Tamir Sholklapper
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Veena Minnal
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Maria L. Palomba
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - James Vredenburgh
- Department of Medicine St. Francis Medical Center Hartford Connecticut USA
| | - Anita Kumar
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Ariela Noy
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - David J. Straus
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Andrew D. Zelenetz
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Heiko Schoder
- Department of Radiology Memorial Sloan Kettering Cancer Center New York New York USA
| | - Jurgen Rademaker
- Department of Radiology Memorial Sloan Kettering Cancer Center New York New York USA
| | - Wendy Schaffer
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Natasha Galasso
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Nivetha Ganesan
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
| | - Steven M. Horwitz
- Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
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40
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Sun Y, Gao Y, Chen J, Huang L, Deng P, Chen J, Chai KXY, Hong JH, Chan JY, He H, Wang Y, Cheah D, Lim JQ, Chia BKH, Huang D, Liu L, Liu S, Wang X, Teng Y, Pang D, Grigoropoulos NF, Teh BT, Yu Q, Lim ST, Li W, Ong CK, Huang H, Tan J. CREBBP cooperates with the cell cycle machinery to attenuate chidamide sensitivity in relapsed/refractory diffuse large B-cell lymphoma. Cancer Lett 2021; 521:268-280. [PMID: 34481935 DOI: 10.1016/j.canlet.2021.09.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 08/16/2021] [Accepted: 09/01/2021] [Indexed: 10/20/2022]
Abstract
Diffuse large B-cell lymphoma (DLBCL) exhibits frequent inactivating mutations of the histone acetyltransferase CREBBP, highlighting the attractiveness of targeting CREBBP deficiency as a therapeutic strategy. In this study, we demonstrate that chidamide, a novel histone deacetylase (HDAC) inhibitor, is effective in treating a subgroup of relapsed/refractory DLBCL patients, achieving an overall response rate (ORR) of 25.0% and a complete response (CR) rate of 15.0%. However, the clinical response to chidamide remains poor, as most patients exhibit resistance, hampering the clinical utility of the drug. Functional in vitro and in vivo studies have shown that CREBBP loss of function is correlated with chidamide sensitivity, which is associated with modulation of the cell cycle machinery. A combinatorial drug screening of 130 kinase inhibitors targeting cell cycle regulators identified AURKA inhibitors, which inhibit the G2/M transition during the cell cycle, as top candidates that synergistically enhanced the antitumor effects of chidamide in CREBBP-proficient DLBCL cells. Our study demonstrates that CREBBP inactivation can serve as a potential biomarker to predict chidamide sensitivity, while combination of an AURKA inhibitor and chidamide is a novel therapeutic strategy for the treatment of relapsed/refractory DLBCL.
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Affiliation(s)
- Yichen Sun
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yan Gao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jianfeng Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ling Huang
- Lymphoma Division, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology Guangzhou, China
| | - Peng Deng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jinghong Chen
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Kelila Xin Ye Chai
- Lymphoma Genomic Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore
| | - Jing Han Hong
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore
| | - Jason Yongsheng Chan
- Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore
| | - Haixia He
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yali Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Daryl Cheah
- Lymphoma Genomic Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore
| | - Jing Quan Lim
- Lymphoma Genomic Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore
| | - Burton Kuan Hui Chia
- Lymphoma Genomic Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore
| | - Dachuan Huang
- Lymphoma Genomic Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore
| | - Lizhen Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shini Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiaoxiao Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yan Teng
- Lymphoma Division, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology Guangzhou, China
| | - Diwen Pang
- Lymphoma Division, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology Guangzhou, China
| | | | - Bin Tean Teh
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore; Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore; Institute of Molecular and Cell Biology, Singapore; SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore; Genome Institute of Singapore, A*STAR, Singapore
| | - Qiang Yu
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore; Genome Institute of Singapore, A*STAR, Singapore
| | - Soon Thye Lim
- Director's Office, National Cancer Centre Singapore, Singapore; Office of Education, Duke-NUS Medical School, Singapore
| | - Wenyu Li
- Lymphoma Division, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology Guangzhou, China
| | - Choon Kiat Ong
- Lymphoma Genomic Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore; Genome Institute of Singapore, A*STAR, Singapore.
| | - Huiqiang Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
| | - Jing Tan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China.
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41
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Landsburg DJ, Barta SK, Ramchandren R, Batlevi C, Iyer S, Kelly K, Micallef IN, Smith SM, Stevens DA, Alvarez M, Califano A, Shen Y, Bosker G, Parker J, Soikes R, Martinez E, von Roemeling R, Martell RE, Oki Y. Fimepinostat (CUDC-907) in patients with relapsed/refractory diffuse large B cell and high-grade B-cell lymphoma: report of a phase 2 trial and exploratory biomarker analyses. Br J Haematol 2021; 195:201-209. [PMID: 34341990 DOI: 10.1111/bjh.17730] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 07/13/2021] [Indexed: 12/28/2022]
Abstract
Fimepinostat (CUDC-907), a first-in-class oral small-molecule inhibitor of histone deacetylase and phosphatidylinositol 3-kinase, demonstrated efficacy in a phase 1 study of patients with relapsed/refractory (R/R) diffuse large and high-grade B-cell lymphomas (DLBCL/HGBL), particularly those with increased MYC protein expression and/or MYC gene rearrangement/copy number gain (MYC-altered disease). Therefore, a phase 2 study of fimepinostat was conducted in this patient population with 66 eligible patients treated. The primary end-point of overall response (OR) rate for patients with MYC-IHC ≥40% (n = 46) was 15%. Subsequently, exploratory pooled analyses were performed including patients treated on both the phase 1 and 2 studies based upon the presence of MYC-altered disease as well as a biomarker identified by Virtual Inference of Protein activity by Enriched Regulon analysis (VIPER). For these patients with MYC-altered disease (n = 63), the overall response (OR) rate was 22% with seven responding patients remaining on treatment for approximately two years or longer, and VIPER yielded a three-protein biomarker classification with positive and negative predictive values of ≥85%. Prolonged durations of response were achieved by patients with MYC-altered R/R DLBCL/HGBL treated with single-agent fimepinostat. Combination therapies and/or biomarker-based patient selection strategies may lead to higher response rates in future clinical trials.
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Affiliation(s)
| | - Stefan K Barta
- University of Pennsylvania, Philadelphia, PA, USA.,Fox Chase Cancer Center, Philadelphia, PA, USA
| | | | - Connie Batlevi
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Swaminathan Iyer
- MD Anderson Cancer Center, Houston, TX, USA.,Houston Methodist Hospital, Houston, TX, USA
| | - Kevin Kelly
- University of Southern California, Los Angeles, CA, USA
| | | | | | | | | | | | - Yao Shen
- DarwinHealth, Inc, New York, NY, USA
| | | | | | | | | | | | | | - Yasuhiro Oki
- MD Anderson Cancer Center, Houston, TX, USA.,Genentech, San Francisco, CA, USA
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Hanel W, Epperla N. Evolving therapeutic landscape in follicular lymphoma: a look at emerging and investigational therapies. J Hematol Oncol 2021; 14:104. [PMID: 34193230 PMCID: PMC8247091 DOI: 10.1186/s13045-021-01113-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 06/04/2021] [Indexed: 02/08/2023] Open
Abstract
Follicular Lymphoma (FL) is the most common subtype of indolent B cell non-Hodgkin lymphoma. The clinical course can be very heterogeneous with some patients being safely observed over many years without ever requiring treatment to other patients having more rapidly progressive disease requiring multiple lines of treatment for disease control. Front-line treatment of advanced FL has historically consisted of chemoimmunotherapy but has extended to immunomodulatory agents such as lenalidomide. In the relapsed setting, several exciting therapies that target the underlying biology and immune microenvironment have emerged, most notable among them include targeted therapies such as phosphoinositide-3 kinase and Enhancer of Zeste 2 Polycomb Repressive Complex 2 inhibitors and cellular therapies including chimeric antigen receptor T cells and bispecific T cell engagers. There are several combination therapies currently in clinical trials that appear promising. These therapies will likely reshape the treatment approach for patients with relapsed and refractory FL in the coming years. In this article, we provide a comprehensive review of the emerging and investigational therapies in FL and discuss how these agents will impact the therapeutic landscape in FL.
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Affiliation(s)
- Walter Hanel
- Division of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State University, 460 W 10th Ave, Columbus, OH 43210 USA
| | - Narendranath Epperla
- Division of Hematology, Department of Medicine, The James Cancer Hospital and Solove Research Institute, The Ohio State University, 460 W 10th Ave, Columbus, OH 43210 USA
- The Ohio State University Comprehensive Cancer Center, 1110E Lincoln Tower, 1800 Cannon Drive, Columbus, OH 43210 USA
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43
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Adhikari N, Jha T, Ghosh B. Dissecting Histone Deacetylase 3 in Multiple Disease Conditions: Selective Inhibition as a Promising Therapeutic Strategy. J Med Chem 2021; 64:8827-8869. [PMID: 34161101 DOI: 10.1021/acs.jmedchem.0c01676] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The acetylation of histone and non-histone proteins has been implicated in several disease states. Modulation of such epigenetic modifications has therefore made histone deacetylases (HDACs) important drug targets. HDAC3, among various class I HDACs, has been signified as a potentially validated target in multiple diseases, namely, cancer, neurodegenerative diseases, diabetes, obesity, cardiovascular disorders, autoimmune diseases, inflammatory diseases, parasitic infections, and HIV. However, only a handful of HDAC3-selective inhibitors have been reported in spite of continuous efforts in design and development of HDAC3-selective inhibitors. In this Perspective, the roles of HDAC3 in various diseases as well as numerous potent and HDAC3-selective inhibitors have been discussed in detail. It will surely open up a new vista in the discovery of newer, more effective, and more selective HDAC3 inhibitors.
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Affiliation(s)
- Nilanjan Adhikari
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, P.O. Box 17020, Kolkata, 700032 West Bengal, India
| | - Tarun Jha
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, P.O. Box 17020, Kolkata, 700032 West Bengal, India
| | - Balaram Ghosh
- Epigenetic Research Laboratory, Department of Pharmacy, BITS-Pilani, Hyderabad Campus, Shamirpet, Hyderabad 500078, India
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Abstract
Tazemetostat represents the first epigenetic therapy approved for the treatment of follicular lymphoma (FL). It inhibits the activity of the enhancer of zeste homolog 2 (EZH2) histone methyltransferase, the first of a multitude of epigenetic regulators that have been identified as recurrently mutated in FL and germinal center diffuse large B-cell lymphoma. In this review, we discuss the initial discovery and ongoing exploration of the functional role of EZH2 mutations in lymphomagenesis. We also explore the path from the preclinical development of tazemetostat to its approval for the treatment of relapsed FL, and potential future therapeutic applications. We discuss the clinical data that led to the approval of tazemetostat and ongoing research into the function of EZH2 and of tazemetostat in lymphomas that derive from the germinal center, which could increase the applicability of this drug in the future.
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45
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Study of the antilymphoma activity of pracinostat reveals different sensitivities of DLBCL cells to HDAC inhibitors. Blood Adv 2021; 5:2467-2480. [PMID: 33999145 DOI: 10.1182/bloodadvances.2020003566] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 03/15/2021] [Indexed: 12/27/2022] Open
Abstract
Histone deacetylase inhibitors (HDACis) are antitumor agents with distinct efficacy in hematologic tumors. Pracinostat is a pan-HDACi with promising early clinical activity. However, similar to other HDACis, its activity as a single agent is limited. Diffuse large B-cell lymphoma (DLBCL) includes distinct molecular subsets or metabolically defined subtypes that rely in different ways on the B-cell receptor signaling pathway, oxidative phosphorylation, and glycolysis for their survival. The antitumor activity of pracinostat has not been determined in lymphomas. We performed preclinical in vitro activity screening of 60 lymphoma cell lines that included 25 DLBCLs. DLBCL cells belonging to distinct metabolic subtypes were treated with HDACis for 6 hours or 14 days followed by transcriptional profiling. DLBCL xenograft models enabled assessment of the in vivo antilymphoma activity of pracinostat. Combination treatments with pracinostat plus 10 other antilymphoma agents were performed. Western blot was used to assess acetylation levels of histone and nonhistone proteins after HDACi treatment. Robust antiproliferative activity was observed across all lymphoma histotypes represented. Focusing on DLBCL, we identified a low-sensitivity subset that almost exclusively consists of the oxidative phosphorylation (OxPhos)-DLBCL metabolic subtype. OxPhos-DLBCL cells also showed poorer sensitivity to other HDACis, including vorinostat. Transcriptomic analysis revealed fewer modulated transcripts but an enrichment of antioxidant pathway genes after HDACi treatment of OxPhos-DLBCLs compared with high-sensitivity B-cell receptor (BCR)-DLBCLs. Pharmacologic inhibition of antioxidant production rescued sensitivity of OxPhos-DLBCLs to pracinostat whereas BCR-DLBCLs were unaffected. Our study provides novel insights into the antilymphoma activity of pracinostat and identifies a differential response of DLBCL metabolic subtypes to HDACis.
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46
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Abstract
Follicular lymphoma (FL) is a heterogeneous disease with varying prognosis owing to differences in clinical, laboratory, and disease parameters. Although generally considered incurable, prognosis for early and advanced stage disease has improved because of therapeutic advances, several of which have resulted from elucidation of the biologic and molecular basis of the disease. The choice of treatment for FL is highly dependent on patient and disease characteristics. Several tools are available for risk stratification, although limitations in their routine clinical use exist. For limited disease, treatment options include radiotherapy, rituximab monotherapy or combination regimens, and surveillance. Treatment of advanced disease is often determined by tumor burden, with surveillance or rituximab considered for low tumor burden and chemoimmunotherapy for high tumor burden disease. Treatment for relapsed or refractory disease is influenced by initial first-line therapy and the duration and quality of the response. At present, there is no consensus for treatment of patients with early or multiply-relapsed disease; however, numerous agents, combination regimens, and transplant options have demonstrated efficacy. While the number of therapies available to treat FL has increased together with an improved understanding of the underlying biologic basis of disease, the best approach to select the most appropriate treatment strategy for an individual patient at a particular time continues to be elucidated. This chapter considers prognostic factors and the evolving treatment landscape of FL, including recent and emerging therapies, as well as remaining unmet needs.
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Longley J, Johnson PWM. Epigenetics of Indolent Lymphoma and How It Drives Novel Therapeutic Approaches-Focus on EZH2-Targeted Drugs. Curr Oncol Rep 2021; 23:76. [PMID: 33937922 PMCID: PMC8088902 DOI: 10.1007/s11912-021-01076-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/31/2021] [Indexed: 11/26/2022]
Abstract
Purpose of Review Epigenetic modifier gene mutations are common in patients with follicular lymphoma. Here we review the pathogenesis of these mutations and how they are targeted by epigenetic drugs including EZH2 inhibitors in both mutated and wild-type disease. Recent Findings The use of EZH2 inhibitor tazematostat in early phase clinical trials has proved encouraging in the treatment of follicular lymphoma harbouring an EZH2 mutation; however, responses are also seen in patients with wild-type disease which is partially explained by the off target effects of EZH2 inhibition on immune cells within the tumour microenvironment. Summary Further studies incorporating prospective molecular profiling are needed to allow stratification of patients at both diagnosis and relapse to further our understanding of how epigenetic modifier mutations evolve over time. The use of tazematostat in combination or upfront in patients with an EZH2 mutation remains unanswered; however, given durable responses, ease of oral administration, and tolerability, it is certainly an attractive option.
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Nepali K, Liou JP. Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends. J Biomed Sci 2021; 28:27. [PMID: 33840388 PMCID: PMC8040241 DOI: 10.1186/s12929-021-00721-x] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 03/29/2021] [Indexed: 12/13/2022] Open
Abstract
Epigenetic drug discovery field has evidenced significant advancement in the recent times. A plethora of small molecule inhibitors have progressed to clinical stage investigations and are being explored exhaustively to ascertain conclusive benefits in diverse malignancies. Literature precedents indicates that substantial amount of efforts were directed towards the use of epigenetic tools in monotherapy as well as in combination regimens at the clinical level, however, the preclinical/preliminary explorations were inclined towards the identification of prudent approaches that can leverage the anticancer potential of small molecule epigenetic inhibitors as single agents only. This review article presents an update of FDA approved epigenetic drugs along with the epigenetic inhibitors undergoing clinical stage investigations in different cancer types. A detailed discussion of the pragmatic strategies that are expected to steer the progress of the epigenetic therapy through the implementation of emerging approaches such as PROTACS and CRISPR/Cas9 along with logical ways for scaffold fabrication to selectively approach the enzyme isoforms in pursuit of garnering amplified antitumor effects has been covered. In addition, the compilation also presents the rational strategies for the construction of multi-targeting scaffold assemblages employing previously identified pharmacophores as potential alternatives to the combination therapy.
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Affiliation(s)
- Kunal Nepali
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan
| | - Jing-Ping Liou
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.
- Biomedical Commercialization Center, Taipei Medical University, Taipei, 11031, Taiwan.
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49
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Manji F, Puckrin R, Stewart DA. Novel synthetic drugs for the treatment of non-Hodgkin lymphoma. Expert Opin Pharmacother 2021; 22:1417-1427. [PMID: 33711241 DOI: 10.1080/14656566.2021.1902988] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Introduction: Over the past two decades, deeper understanding of B-cell signaling pathways and other mechanisms of lymphomagenesis have yielded promising targets for novel drugs in the treatment of non-Hodgkin lymphoma.Areas covered: This article provides a comprehensive review of approved synthetic drugs targeting the BTK, PI3K, immunomodulation, proteasome, HDAC, EZH2, and nuclear export pathways in non-Hodgkin lymphoma. The review includes coverage of the pharmacology, efficacy, toxicity, and active areas of research for each drug. The authors also provide their expert perspectives on the field and their opinions for the future.Expert opinion: Although novel synthetic drugs have generally not impacted clinical practice to the same extent as immune and cellular therapies, there remains an important role for targeted drugs in the treatment of non-Hodgkin lymphoma, particularly in the relapsed setting and for patients ineligible for more intensive therapies. Clinical outcomes and tolerability may improve further with the development of newer generations of synthetic drugs and emerging combination regimens with other targeted and immune therapies.
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Affiliation(s)
- Farheen Manji
- Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontaria, Canada
| | - Robert Puckrin
- Postgraduate Medical Education, University of Calgary, Calgary, Alberta, Canada
| | - Douglas A Stewart
- Department of Oncology, University of Calgary, Calgary, Alberta, Canada
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50
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Alonso-Alonso R, Rodriguez M, Morillo D, Cordoba R, Piris MA. An analysis of genetic targets for guiding clinical management of follicular lymphoma. Expert Rev Hematol 2020; 13:1361-1372. [PMID: 33176509 DOI: 10.1080/17474086.2020.1850252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Introduction: Follicular lymphoma (FL) is one of the most common non-Hodgkin lymphoma (NHL) types, where genomic studies have accumulated potentially useful information about frequently mutated genes and deregulated pathways, which has allowed to a better understanding of the molecular pathogenesis of this tumor and the complex interrelationship between the tumoral cells and the stroma. Areas covered: The results of the molecular studies performed on Follicular Lymphoma have been here reviewed, summarizing the results of the clinical trials so far developed on this basis and discussing the reasons for the successes and failures. Searches were performed on June 1st, 2020, in PubMed and ClinicalTrials.gov. Expert opinion: Targeted therapy for follicular lymphoma has multiple opportunities including the use of epigenetic drugs, PI3K inhibitors, modifiers of the immune stroma and others. Data currently known on FL pathogenesis suggest that combining these treatments with immunotherapy should be explored in clinical trials, mainly for patients with clinical progression or adverse prognostic markers. Association of targeted trials with dynamic molecular studies of the tumor and serum samples is advised. Chemotherapy-free approaches should also be explored as first-line therapy for FL patients.
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Affiliation(s)
- Ruth Alonso-Alonso
- Services of Pathology and Haematology, Fundación Jimenez Diaz , Madrid, Spain
| | - Marta Rodriguez
- Services of Pathology and Haematology, Fundación Jimenez Diaz , Madrid, Spain
| | - Daniel Morillo
- Services of Pathology and Haematology, Fundación Jimenez Diaz , Madrid, Spain
| | - Raul Cordoba
- Services of Pathology and Haematology, Fundación Jimenez Diaz , Madrid, Spain
| | - Miguel A Piris
- Services of Pathology and Haematology, Fundación Jimenez Diaz , Madrid, Spain
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