Multi-omics investigation reveals functional specialization of transcriptional cyclin dependent kinases in cancer biology DOI Creative Commons
Micah G. Donovan, Matthew D. Galbraith, Joaquı́n M. Espinosa

et al.

Scientific Reports, Journal Year: 2022, Volume and Issue: 12(1)

Published: Dec. 28, 2022

Transcriptional addiction is recognized as a valid therapeutic target in cancer, whereby the dependency of cancer cells on oncogenic transcriptional regulators may be pharmacologically exploited. However, comprehensive understanding key factors within machinery that might afford useful window remains elusive. Herein, we present cross-omics investigation into functional specialization cyclin dependent kinases (tCDKs) through analysis high-content genetic dependency, gene expression, patient survival, and drug response datasets. This revealed among tCDKs terms contributions to cell fitness, clinical prognosis, interaction with signaling pathways. CDK7 CDK9 stand out most relevant targets, albeit distinct mechanisms oncogenicity context-dependent survival sensitivity. Genetic ablation CDK9, but not CDK7, mimics effect viability loss components machinery. Pathway co-dependency sensitivity data show have relationships major signatures, including MYC E2F oxidative phosphorylation, unfolded protein response. Altogether, these results inform improved design strategies targeting cancer.

Language: Английский

Emerging therapies in Ewing sarcoma DOI Creative Commons
Sandra J. Strauss, Pablo Berlanga, Martin G. McCabe

et al.

Current Opinion in Oncology, Journal Year: 2024, Volume and Issue: 36(4), P. 297 - 304

Published: May 22, 2024

Purpose of review There is an unmet need to improve outcomes for patients Ewing sarcoma, a rare, aggressive sarcoma with peak incidence in adolescents and young adults (AYA). Current therapy at diagnosis involves multiagent chemotherapy local therapy, but despite intensification treatment, those metastases recurrent disease have poor outcomes. Recent findings Improved understanding biology has identified novel targets promising activity patients, including tyrosine kinase inhibitors that are now undergoing evaluation as combination maintenance therapy. Other emerging therapies include target the EWSR1::FLI1 fusion oncoprotein, act on DNA damage, cell cycle apoptotic pathways. Immunotherapeutic approaches, particularly CAR-T-cell directed GD2, also hold promise. collaborative clinical trials defined international standard care newly diagnosed platform studies adaptive designs offer unique opportunities investigate these inclusive all ages. Summary Close collaboration between clinicians biologists will allow us prioritize develop biomarkers facilitate their incorporation into more rapidly translate benefit patients.

Language: Английский

Citations

11
Open-Label, Multicenter, Phase I/II, First-in-Human Trial of TK216: A First-Generation EWS::FLI1 Fusion Protein Antagonist in Ewing Sarcoma DOI
Paul A. Meyers, Noah Federman, Najat C. Daw

et al.

Journal of Clinical Oncology, Journal Year: 2024, Volume and Issue: 42(31), P. 3725 - 3734

Published: July 2, 2024

PURPOSE Ewing Sarcoma (ES), a rare cancer with pathognomonic translocation resulting in the sarcoma gene (EWS)::FLI1 oncoprotein, has poor prognosis relapsed/refractory (R/R) setting. Tokalas (TK)216 was designed to bind EWS::FLI1 proteins directly, disrupt protein-protein interactions, and inhibit transcription factor function. TK216 plus vincristine showed synergistic activity preclinical tumor models. To our knowledge, we report results of first-in-class, first-in-human phase I/II trial R/R ES. PATIENTS AND METHODS administered intravenously as continuous infusion patients ES 11 cohorts. The dosing duration 7 days later extended 10, 14, 28 days. Vincristine could be added on day 1 after cycle 2, per investigators’ choice. used 3 + design an expansion cohort at recommended II dose (RP2D). RESULTS A total 85 median age 27 years (range, 11-77) were enrolled. maximum tolerated for 14-day TK216, 200 mg/m 2 once daily, determined 9 selected RP2D. previous number systemic therapies regimens three 1-10). most frequent-related adverse events treated RP2D included neutropenia (44.7%), anemia (29.4%), leukopenia febrile (15.3%), thrombocytopenia (11.8%), infections (17.6%). In cohorts two had complete response, one partial 14 stable disease; 6-month progression-free survival 11.9%. There no responses among eight 11. CONCLUSION or without well limited

Language: Английский

Citations

7
Regulation of EWSR1-FLI1 Function by Post-Transcriptional and Post-Translational Modifications DOI Open Access
Le Yu, Ian J. Davis, Pengda Liu

et al.

Cancers, Journal Year: 2023, Volume and Issue: 15(2), P. 382 - 382

Published: Jan. 6, 2023

Ewing sarcoma is the second most common bone tumor in childhood and adolescence. Currently, first-line therapy includes multidrug chemotherapy with surgery and/or radiation. Although patients initially respond to chemotherapy, recurrent tumors become treatment refractory. Pathologically, consists of small round basophilic cells prominent nuclei marked by expression surface protein CD99. Genetically, driven a fusion oncoprotein that results from one number chromosomal translocations composed FET gene encoding an ETS family transcription factor, ~85% expressing EWSR1::FLI1 fusion. regulates transcription, splicing, genome instability other cellular functions. tumor-specific target, EWSR1::FLI1-targeted has yet be developed, largely due insufficient understanding upstream downstream signaling, challenges targeting factors molecules. In this review, we summarize contemporary molecular sarcoma, post-transcriptional post-translational regulatory mechanisms control function.

Language: Английский

Citations

14
Inhibition of a lower potency target drives the anticancer activity of a clinical p38 inhibitor DOI Creative Commons
Debanjan Bhattacharjee,

Jaweria Bakar,

Surbhi P. Chitnis

et al.

Cell chemical biology, Journal Year: 2023, Volume and Issue: 30(10), P. 1211 - 1222.e5

Published: Oct. 1, 2023

Language: Английский

Citations

12
Mechanoresponsive ETS1 causes endothelial dysfunction and arterialization in varicose veins via NOTCH4/DLL4 signaling DOI Creative Commons

B. J. Sreelakshmi,

C. L. Karthika,

S. Ahalya

et al.

European Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 103(2), P. 151420 - 151420

Published: May 11, 2024

Varicose veins are the most common venous disorder in humans and characterized by hemodynamic instability due to valvular insufficiency orthostatic lifestyle factors. It is unclear how changes biomechanical signals cause aberrant remodeling of vein wall. Our previous studies suggest that Notch signaling implicated varicose arterialization. In arterial system, mechanoresponsive ETS1 a transcriptional activator endothelial Notch, but its involvement sensing disrupted flow formation has not been investigated. Here, we use human cultured cells show disturbed shear stress activates ETS1-NOTCH4/DLL4 signaling. components were highly expressed neointima, whereas was upregulated all histological layers veins. vitro microfluidic flow-based demonstrate even minute patterns enhance Uniform stress, albeit an inherently low-flow does induce proteins. activation under altered mediated primarily MEK1/2 and, lesser extent, MEK5 independent p38MAP kinase. Endothelial cell-specific knockdown prevented flow-induced NOTCH4/DLL4 expression. TK216, inhibitor ETS-family, inhibited acquisition molecular identity loss integrity exposed ensuing stress. We conclude senses blood disturbances may promote inducing dysfunction. Targeting rather than downstream proteins could be effective safe strategy develop therapies.

Language: Английский

Citations

4
Ewing sarcoma from molecular biology to the clinic DOI Creative Commons

Maryne Dupuy,

François Lamoureux,

Mathilde Mullard

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: Sept. 11, 2023

In Europe, with an incidence of 7.5 cases per million, Ewing sarcoma (ES) is the second most common primary malignant bone tumor in children, adolescents and young adults, after osteosarcoma. Since 1980s, conventional treatment has been based on use neoadjuvant adjuvant chemotherapeutic agents combined surgical resection when possible. These treatments have increased patient survival rate to 70% for localized forms, which drops drastically less than 30% patients are resistant chemotherapy or pulmonary metastases present at diagnosis. However, lack improvement these rates over last decades points urgent need new therapies. Genetically, ES characterized by a chromosomal translocation between member FET family ETS family. 85% cases, found (11; 22) (q24; q12), EWS RNA-binding protein FLI1 transcription factor, leading EWS-FLI1 fusion protein. This chimeric acts as oncogenic factor playing crucial role development ES. review provides non-exhaustive overview from clinical biological point view, describing its main clinical, cellular molecular aspects.

Language: Английский

Citations

10
DHX9 helicase impacts on splicing decisions by modulating U2 snRNP recruitment in Ewing sarcoma cells DOI Creative Commons
Valentina Frezza, Lidia Chellini, Veronica Riccioni

et al.

Nucleic Acids Research, Journal Year: 2025, Volume and Issue: 53(4)

Published: Jan. 30, 2025

Ewing sarcomas (ESs) are biologically aggressive tumours of bone and soft tissues caused by chromosomal translocations yielding in-frame fusion proteins driving the neoplastic transformation. The DNA/RNA helicase DHX9 is an important regulator cellular processes often deregulated in cancer. Using transcriptome profiling, our study reveals cancer-relevant genes whose splicing modulated DHX9. Immunodepletion experiments demonstrate that impacts on recruitment U2 small nuclear RNP (snRNP) onto pre-mRNA. Analysis structure sequence features target exons reveal DHX9-sensitive display shorter flanking introns contain HNRNPC TIA1 consensus motifs. A prominent exon 11 Cortactin (CTTN) gene, which alternatively spliced to generate isoforms with different activities cell migration tumour invasion. Alternative inclusion CTTN gene one most recurrent isoform switches multiple cancer types, thus highlighting pivotal role defining phenotype. Biochemical analyses binding promotes U2snRNP, SF3B1, SF3A2 splice sites 11. These findings uncover a new control co-transcriptional ES, may represent druggable counteract ES malignancy.

Language: Английский

Citations

0
(GGAA)3-Based TF-PROTACs Enable Targeted Degradation of ETV6 to Inhibit Ewing Sarcoma Growth DOI
Zhichuan Zhu, He Chen, Xing Qiu

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: April 11, 2025

Ewing sarcoma is a rare pediatric cancer primarily driven by the EWS::FLI1 oncofusion transcription factor. Despite being an ideal drug target, has proven challenging to inhibit with conventional approaches. Recent studies identified ETV6 as vulnerability in sarcoma, where it competes at short GGAA repeats restrain function. However, no therapies targeting have been developed. In this study, we report discovery of unique (GGAA)3 DNA oligonucleotide that specifically binds but not EWS::FLI1. We developed (GGAA)3-based TF-PROTACs, termed d(GGAA)3s, coupling VHL ligands. d(GGAA)3s effectively degraded endogenous proteins cells, thus suppressing growth. Mechanistically, enhanced oncogenic transcriptional activity, inducing cellular stress and cell death. Additionally, sensitized cells standard chemotherapy, suggesting their potential use combination therapies. Beyond also targeted ETV6-fusion found breast cancer, broadening clinical applications. summary, represent nucleotide-based approach for degrading ETV6, inhibiting growth ETV6-dependent cancers. This strategy offers promising therapeutic avenue other malignancies involving fusions.

Language: Английский

Citations

0
Identification of novel small molecule inhibitors of ETS transcription factors DOI Creative Commons

Saad Abdalla,

Zary Forghany,

Jin Ma

et al.

FEBS Letters, Journal Year: 2025, Volume and Issue: unknown

Published: April 11, 2025

The evolutionarily conserved E‐Twenty‐Six (ETS) family of transcription factors acts downstream major signal transduction pathways and plays a pivotal role in tissue development maintenance. Importantly, their function is frequently corrupted substantial proportion tumour types, they are also indispensable for angiogenic sprouting, hallmark cancer, which essential fuelling enlargement dissemination. Consequently, targeting aberrant ETS activity could potentially represent precise effective means by to block growth. Here, we present proof‐of‐principle high‐throughput screens an initial characterization candidate hits, as methodological conceptual framework the identification novel factor inhibitors, may ultimately lead new therapeutic avenues treating cancer.

Language: Английский

Citations

0
Targeting friend leukemia integration 1: A promising approach for prevention and treatment of solid tumors DOI
Moumita Kundu, Ankita Dey, Pradipta Maji

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 309, P. 143080 - 143080

Published: April 12, 2025

Language: Английский

Citations

0