SHR2554, an EZH2 inhibitor, in relapsed or refractory mature lymphoid neoplasms: a first-in-human, dose-escalation, dose-expansion, and clinical expansion phase 1 trial

Song, Yuqin; Liu, Yanyan; Li, Zhiming; Li, Lanfang; Jin, Zhengming; Zuo, Xuelan; Wu, Jianyuan; Zhou, Hui; Li, Kunyan; He, Chuan; Zhou, Jianfeng; Qi, Junyuan; Hao, Siguo; Zhang, Cai; Li, Yijing; Wang, Weiwei; Zhang, Xiaojing; Zou, Jianjun; Zhu, Jun

doi:10.1016/s2352-3026(22)00134-x

Cited by 22 publications

(7 citation statements)

References 23 publications

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“…Different types of EZH2 inhibitors have been developed ( 128 ) with Tazemetostat being approved by FDA for routine use in epithelioid sarcoma treatment ( 129 ). Recently phase I clinical study of EZH2 inhibitor SHR2554 ( Table 1 ) was conducted on patients with relapsed or refractory mature lymphoid neoplasms including HL and it has shown that the molecule was safe and exhibited promising antitumor activity ( 130 ).…”

Section: Aberrant Epigenetic Mechanisms In Hlmentioning

confidence: 99%

New molecular targets in Hodgkin and Reed-Sternberg cells

et al. 2023

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Recent discoveries shed light on molecular mechanisms responsible for classical Hodgkin lymphoma (HL) development and progression, along with features of Hodgkin – Reed and Sternberg cells (HRS). Here, we summarize current knowledge on characteristic molecular alterations in HL, as well as existing targeted therapies and potential novel treatments for this disease. We discuss the importance of cluster of differentiation molecule 30 (CD30) and the programmed cell death-1 protein (PD-1) and ligands (PD-L1/2), and other molecules involved in immune modulation in HL. We highlight emerging evidence indicating that the altered function of SWI/SNF-type chromatin remodeling complexes, PRC2, and other epigenetic modifiers, contribute to variations in chromatin status, which are typical for HL. We postulate that despite of the existence of plentiful molecular data, the understanding of HL development remains incomplete. We therefore propose research directions involving analysis of reverse signaling in the PD-1/PD-L1 mechanism, chromatin remodeling, and epigenetics-related alterations, in order to identify HL features at the molecular level. Such attempts may lead to the identification of new molecular targets, and thus will likely substantially contribute to the future development of more effective targeted therapies.

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Section: Aberrant Epigenetic Mechanisms In Hlmentioning

confidence: 99%

New molecular targets in Hodgkin and Reed-Sternberg cells

et al. 2023

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“…Fortunately, the development of new drugs in recent years has broadened the treatment options for R/R FL. Several studies have suggested that novel agents exhibited promising antilymphoma activities ( 5 , 10 , 16 , 26 , 27 ). The ELARA and ZUMA-5 studies demonstrated high ORR and durable remission with tisagenlecleucel and axicabtagene ciloleucel (CD19 CAR T-cell therapies), with ORRs of 86.2% and 94%, respectively ( 10 , 11 ).…”

Section: Discussionmentioning

confidence: 99%

“…However, all have been withdrawn afterward, with the exception of copanlisib, due to unbearable adverse events ( 5 , 14 ). In addition, enhancer of zeste homolog 2 specific (EZH2) inhibitor, another kind of small-molecule agent, has shown effectiveness in R/R FL patients with both mutant-type and wild-type EZH2 mutations, although the clinical efficacy appears to be better in the former group ( 15 , 16 ). While B-cell leukemia/lymphoma-2 (BCL-2) overexpression is required for the pathogenesis of FL, the efficacy of BCL-2 inhibitor venetoclax as monotherapy was suboptimal ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

Management and clinical outcomes of follicular lymphoma across continuous lines of treatments: a retrospective analysis in China

Liu,

Hu,

Zhao

et al. 2023

Front. Oncol.

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BackgroundFollicular lymphoma (FL) is characterized by an incurable course that frequently necessitates multiple lines of treatment. While a range of new approaches have broadened therapeutic options for patients in later lines, data regarding treatment patterns and outcomes of Chinese patients with relapsed/refractory(R/R) FL was scarcely reported.MethodsThis retrospective single-center study included patients diagnosed with FL grades 1–3a at our institution between January 2002 and December 2019. Endpoints of interest were analyzed according to lines and types of interventions. The endpoints mainly included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).ResultsThe study enrolled 566 biopsy-proven patients. Among them, 544 patients initiated the first line of treatment, followed by 240 initiating the second line, 146 initiating the third line, 88 initiating the fourth line, 47 initiating the fifth line, and 28 initiating the sixth line. In terms of treatment patterns, anti-CD20 chemotherapy was a major modality in the first and second lines. However, for patients in the third line and subsequent lines, treatment approaches were diverse, and participation in clinical trials for new medications was common, which correlated with a survival benefit. The study also revealed that clinical indicators (such as ORR, PFS, and OS) gradually decreased with each subsequent line of treatment. The ORR at the first line was 86.6%, but decreased to 48.6% at the third line and 40.4% at the sixth line, respectively. Similarly, median OS and PFS decreased to 88.8 and 7.1 months at the third line and further reduced to 21.7 and 2.8 months at the sixth line, respectively. A total of 133 patients developed progression within 24 months from the initiation of first line anti-CD20 chemotherapy (POD24), and these patients exhibited poorer response rates and outcomes in subsequent lines of therapycompared to the non-POD24 group.ConclusionThis study revealed the clinical routine practices and prognosis of R/R FL patients within the Chinese population. It underscored the unmet need for optimal strategies to improve survival and also served as a benchmark for future trials.

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“…No patient presented a complete response, but two developed a partial response to treatment, which lasted for different time intervals (18 and 42 weeks). Another clinical trial (NCT03603951) targeting EZH2 was the first human study investigating the safety, pharmacokinetics, pharmacodynamics and preliminary clinical outcomes of SHR2554, an oral selective inhibitor of EZH2 [ 82 ]. The inhibitor was prescribed to patients suffering from mature lymphoid neoplasms, such as B and T cell lymphomas and classical Hodgkin lymphoma, conducted in China.…”

Section: Clinical Trials Based On Histone Methyltransferase Activitymentioning

confidence: 99%

Impact of Histone Lysine Methyltransferase SUV4-20H2 on Cancer Onset and Progression with Therapeutic Potential

Papadaki,

Piperi

2024

IJMS

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Histone lysine methyltransferase SUV4-20H2, a member of the suppressor of variegation 4–20 homolog (SUV4-20) family, has a critical impact on the regulation of chromatin structure and gene expression. This methyltransferase establishes the trimethylation of histone H4 lysine 20 (H4K20me3), a repressive histone mark that affects several cellular processes. Deregulated SUV4-20H2 activity has been associated with altered chromatin dynamics, leading to the misregulation of key genes involved in cell cycle control, apoptosis and DNA repair. Emerging research evidence indicates that SUV4-20H2 acts as a potential epigenetic modifier, contributing to the development and progression of several malignancies, including breast, colon and lung cancer, as well as renal, hepatocellular and pancreatic cancer. Understanding the molecular mechanisms that underlie SUV4-20H2-mediated effects on chromatin structure and gene expression may provide valuable insights into novel therapeutic strategies for targeting epigenetic alterations in cancer. Herein, we discuss structural and functional aspects of SUV4-20H2 in cancer onset, progression and prognosis, along with current targeting options.

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SHR2554, an EZH2 inhibitor, in relapsed or refractory mature lymphoid neoplasms: a first-in-human, dose-escalation, dose-expansion, and clinical expansion phase 1 trial

Cited by 22 publications

References 23 publications

New molecular targets in Hodgkin and Reed-Sternberg cells

New molecular targets in Hodgkin and Reed-Sternberg cells

Management and clinical outcomes of follicular lymphoma across continuous lines of treatments: a retrospective analysis in China

Impact of Histone Lysine Methyltransferase SUV4-20H2 on Cancer Onset and Progression with Therapeutic Potential

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