Chromatin remodellers as therapeutic targets

Nature Reviews Drug Discovery, Journal Year: 2024, Volume and Issue: 23(9), P. 661 - 681

Published: July 16, 2024

Language: Английский

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Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(8), P. 1352 - 1369.e13

Published: July 18, 2024

Small cell lung cancers (SCLCs) are composed of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLCs, ∼12% all cases, uniquely dependent on POU2F3 itself; as such, approaches to attenuate expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators SCLC proliferation, we define mSWI/SNF complexes top dependencies specific SCLC. Notably, chemical disruption ATPase activity attenuates proliferation while non-canonical BAF (ncBAF) via BRD9 degradation is effective in pure non-neuroendocrine POU2F3-SCLCs. targets maintains accessibility over gene loci central POU2F3-mediated regulatory networks. Finally, clinical-grade pharmacologic SMARCA4/2 ATPases decreases POU2F3-SCLC tumor growth increases survival vivo. These results demonstrate mSWI/SNF-mediated governance the oncogenic program suggest inhibition a strategy SCLCs.

Language: Английский

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Tumor energy metabolism: implications for therapeutic targets

Molecular Biomedicine, Journal Year: 2024, Volume and Issue: 5(1)

Published: Nov. 29, 2024

Abstract Tumor energy metabolism plays a crucial role in the occurrence, progression, and drug resistance of tumors. The study tumor has gradually become an emerging field treatment. Recent studies have shown that epigenetic regulation is closely linked to metabolism, influencing metabolic remodeling biological traits cells. This review focuses on primary pathways explores therapeutic strategies target these pathways. It covers key areas such as glycolysis, Warburg effect, mitochondrial function, oxidative phosphorylation, adaptability Additionally, this article examines regulator SWI/SNF complex specifically its interactions with glucose, lipids, amino acids. Summarizing aimed at pathways, including inhibitors mitochondrial-targeted drugs, exploitation vulnerabilities, recent developments related complexes potential targets. clinical significance, challenges, future directions research are discussed, overcome resistance, combination therapy, application new technologies.

Language: Английский

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Can we develop effective direct or indirect inhibitors of transcription factors? On the clinical evolution of protein degraders for multiple myeloma therapy

Expert Opinion on Therapeutic Targets, Journal Year: 2025, Volume and Issue: unknown

Published: March 23, 2025

Introduction Transcription factors (TFs) are master regulators of cellular function and orchestrate diverse signaling pathways processes. Acting as convergence points pathways, they integrate extracellular stimuli with intracellular responses to regulate cell functions. Dysregulation TFs drives tumorigenesis including proliferation, drug resistance, immune evasion multiple myeloma (MM), the second most-common hematologic malignancy.

Language: Английский

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Challenges of small cell lung cancer heterogeneity and phenotypic plasticity

Nature reviews. Cancer, Journal Year: 2025, Volume and Issue: unknown

Published: April 10, 2025

Language: Английский

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Molecular Subtypes and Targeted Therapeutic Strategies in Small Cell Lung Cancer: Advances, Challenges, and Future Perspectives

Molecules, Journal Year: 2025, Volume and Issue: 30(8), P. 1731 - 1731

Published: April 12, 2025

Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by rapid progression, early metastasis, and high recurrence rates. Historically considered homogeneous disease, recent multi-omic studies have revealed distinct molecular subtypes driven lineage-defining transcription factors, including ASCL1, NEUROD1, POU2F3, YAP1, as well an inflamed subtype (SCLC-I). These exhibit unique therapeutic vulnerabilities, thereby paving the way for precision medicine targeted therapies. Despite advances in classification, tumor heterogeneity, plasticity, therapy resistance continue to hinder clinical success treating SCLC patients. To this end, novel strategies are being explored, BCL2 inhibitors, DLL3-targeting agents, Aurora kinase PARP epigenetic modulators. Additionally, immune checkpoint inhibitors (ICIs) show promise, particularly immune-enriched of Hence, deeper understanding characteristics, evolution, regulatory mechanisms subtype-specific factors crucial rationally optimizing therapy. This knowledge not only facilitates identification targets, but also provides foundation overcoming developing personalized combination treatment strategies. In future, integration data, dynamic monitoring, approaches expected further advance translation therapies, ultimately improving patient survival outcomes.

Language: Английский

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Exploring the clinical trials, regulatory insights, and challenges of PROTACs in oncology

Seminars in Oncology, Journal Year: 2025, Volume and Issue: 52(2), P. 152339 - 152339

Published: April 1, 2025

Language: Английский

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Targeting PIKfyve-driven lipid metabolism in pancreatic cancer

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: April 23, 2025

Language: Английский

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Transcriptional co-regulator OCA-B/Pou2af1 restricts Th2 differentiation

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 29, 2025

Background Type 2 immunity is initiated through a synergistic response between innate and adaptive immune cells to facilitate host-pathogen defense wound repair, yet aberrant responses can contribute chronic inflammation allergic disease. CD4 + type helper T (Th2) the secretion of cytokines such as IL-4, IL-5, IL-13. While Th2 program governed by transcription factor GATA3, less known about regulators that fine-tune cytokine response. Method We used proximity labeling system map proteins associated with transcriptional co-regulator OCA-B, encoded Pou2af1 , in cells. series genomic, biochemical immunological assays probe interaction one particular hit from screen. Results find OCA-B indirectly associates GATA3. ChIP-seq analysis reveals coenrichment Gata3 Oct1, partner protein at genomic locations responsible for including Il4, Il13, Il5, Irf4 . DNA binding data using recombinant reporter cell lines are consistent model which restricts locus control region subsequent IL-4 IL-13 secretion. Finally, an vivo papain allergy we show expression limits frequency within lung. Conclusion These findings shown helps restrict function least part communication

Language: Английский

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Small cell lung cancer: emerging subtypes, signaling pathways, and therapeutic vulnerabilities

Experimental Hematology and Oncology, Journal Year: 2024, Volume and Issue: 13(1)

Published: Aug. 5, 2024

Abstract Small cell lung cancer (SCLC) is a recalcitrant characterized by early metastasis, rapid tumor growth and poor prognosis. In recent decades, the epidemiology, initiation mutation characteristics of SCLC, as well abnormal signaling pathways contributing to its progression, have been widely studied. Despite extensive investigation, fewer drugs approved for SCLC. Recent advancements in multi-omics studies revealed diverse classifications SCLC that are featured distinct therapeutic vulnerabilities. With accumulation samples, different subtypes specific treatments these were further explored. The identification molecular has opened up novel avenues treatment SCLC; however, inconsistent uncertain classification hindered translation from basic research clinical applications. Therefore, comprehensives review essential conclude emerging related targeting vulnerabilities within pathways. this current review, we summarized risk factors, classification, We hope will facilitate subtyping theory application.

Language: Английский

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