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

LOXHD1 is an oncofusion-regulated antigen of ewing sarcoma DOI Creative Commons

Tatiana Blanchard,

Pouya Faridi,

Chong Xu

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 15, 2025

Ewing Sarcoma (EwS) is a rare pediatric malignancy characterized by unique t(11:22) (q24;q12) translocation resulting in the pathognomonic EWSR1::FLI1 fusion. Recent reports indicate that oncofusion drives aberrant expression of numerous transcripts, including Lipoxygenase Homology Domains 1 (LOXHD1). Given its highly restricted protein pattern and role EwS tumorigenesis metastasis, LOXHD1 may serve as novel immunotherapeutic target this malignancy. immunogenic epitopes to HLA-A*02:01 allowed for isolation high avidity αβTCR. LOXHD1-specific TCR engineered CD8+ T cells conferred cytotoxic activity against panel HLA-A*02:01+ tumor cell lines adoptive transfer led eradication mouse xenograft model EwS. This study nominates an regulated, non-mutated associated antigen (TAA) with limited inner hair cochlea, adult testis,

Language: Английский

Citations

0
Targeted Therapy for EWS-FLI1 in Ewing Sarcoma DOI Open Access

Helong Gong,

Busheng Xue, Jinlong Ru

et al.

Cancers, Journal Year: 2023, Volume and Issue: 15(16), P. 4035 - 4035

Published: Aug. 9, 2023

Ewing sarcoma (EwS) is a rare and predominantly pediatric malignancy of bone soft tissue in children adolescents. Although international collaborations have greatly improved the prognosis most EwS, occurrence macrometastases or relapse remains challenging. The prototypic oncogene EWS-FLI1 acts as an aberrant transcription factor that drives cellular transformation EwS. In addition to its involvement RNA splicing DNA damage response, this chimeric protein directly binds GGAA repeats, thereby modifying transcriptional profile Direct pharmacological targeting difficult because intrinsically disordered structure. However, complex downstream pathways provides additional therapeutic options. This review describes partners pathways, well related target therapies for treatment

Language: Английский

Citations

9
Co-targeting JAK1/STAT6/GAS6/TAM signaling improves chemotherapy efficacy in Ewing sarcoma DOI Creative Commons
Le Yu, Yu Deng, Xiaodong Wang

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 21, 2024

Abstract Ewing sarcoma is a pediatric bone and soft tissue tumor treated with chemotherapy, radiation, surgery. Despite intensive multimodality therapy, ~50% patients eventually relapse die of the disease due to chemoresistance. Here, using phospho-profiling, we find cells chemotherapeutic agents activate TAM (TYRO3, AXL, MERTK) kinases augment Akt ERK signaling facilitating Mechanistically, chemotherapy-induced JAK1-SQ phosphorylation releases JAK1 pseudokinase domain inhibition allowing for activation. This alternative activation mechanism leads STAT6 nuclear translocation triggering transcription secretion kinase ligand GAS6 autocrine/paracrine consequences. Importantly, pharmacological either by filgotinib or UNC2025 sensitizes chemotherapy in vitro vivo. Excitingly, inhibitor MRX-2843 currently human clinical trials treat AML advanced solid tumors, enhances efficacy further suppress growth Our findings reveal an chemoresistance immediate translational value.

Language: Английский

Citations

3
Bad to the Bone: Emerging Approaches to Aggressive Bone Sarcomas DOI Open Access
Georgina Wood, Laurie A. Graves,

Elyssa Rubin

et al.

American Society of Clinical Oncology Educational Book, Journal Year: 2023, Volume and Issue: 43

Published: May 1, 2023

Bone sarcomas are rare heterogeneous tumors that affect patients of all ages including children, adolescent young adults, and older adults. They include many aggressive subtypes patient groups with poor outcomes, access to clinical trials, lack defined standard therapeutic strategies. Conventional chondrosarcoma remains a surgical disease, no role for cytotoxic therapy approved targeted systemic therapies. Here, we discuss promising novel targets strategies undergoing evaluation in trials. Multiagent chemotherapy has greatly improved outcomes Ewing sarcoma (ES) osteosarcoma, but management those high-risk or recurrent disease challenging controversial. We describe the impact international collaborative such as rEECur study, aim define optimal treatment recurrent, refractory ES, evidence high-dose stem-cell support. also current emerging other small round cell sarcomas, CIC-rearranged, BCOR-rearranged tumors, therapeutics trial designs may offer new paradigm improve survival these notoriously bad (to bone) outcomes.

Language: Английский

Citations

8
The efficacy and safety of vincristine, irinotecan and anlotinib in Epithelioid Sarcoma DOI Creative Commons
Lu Xie,

Xin Sun,

Jie Xu

et al.

BMC Cancer, Journal Year: 2024, Volume and Issue: 24(1)

Published: Feb. 3, 2024

Abstract Background Epithelioid sarcoma is a rare soft tissue characterized by SMARCB1/INI1 deficiency. Much attention has been paid to the selective EZH2 inhibitor tazemetostat, where other systemic treatments are generally ignored. To explore alternative treatment options, we studied effects of irinotecan-based chemotherapy in series epithelioid patients. Methods We retrospectively reviewed data from patients with metastatic or unresectable at Peking University People’s Hospital treated irinotecan (50 mg/m 2 /d d 1-5 Q3W) combination Anlotinib (12 mg Qd, weeks on and 1 week off) July 2015 November 2021. Results A total 54 courses were administered. With median follow up 21.2 months (95% CI, 12.2, 68.1), 5-year overall survival rate was 83.3%. Five eight (62.5%) presented localized lesions, including local tumor thrombosis lymphatic metastasis. The had pulmonary metastases. Six (75%) progressed following two lines therapy. objective response reached 37.5% (three patients) while stabilized disease observed 62.5% (five eight) No patient initial evaluation. At last up, still using three ceased therapy due toxicities such as diarrhea, nausea, emesis. One changed tazemetostat for maintenance one stopped coronavirus 2019 (COVID-19). Another residual lesions radiated. Conclusions salvage regimen may be considered another effective option refractory sarcoma. Trial registration This study approved Medical Ethics Committee October 28, 2022 (No.: 2022PHD015-002). registered Clinicaltrials.gov identifier no. NCT05656222.

Language: Английский

Citations

2
High-content drug screening in zebrafish xenografts reveals high efficacy of dual MCL-1/BCL-XL inhibition against Ewing sarcoma DOI Creative Commons
Sarah Grissenberger, Caterina Sturtzel, Andrea Wenninger-Weinzierl

et al.

Cancer Letters, Journal Year: 2022, Volume and Issue: 554, P. 216028 - 216028

Published: Dec. 1, 2022

Ewing sarcoma is a pediatric bone and soft tissue cancer with an urgent need for new therapies to improve disease outcome.To identify effective drugs, phenotypic drug screening has proven be powerful method, but achievable throughput in mouse xenografts, the preclinical standard model, limited.Here, we explored use of xenografts zebrafish high-throughput discover combination sarcoma.We subjected larvae high-content imaging subsequent automated tumor size analysis screen single agents compound combinations.We identified three combinations against cells: Irinotecan combined either MCL-1 or BCL-XL inhibitor particular dual inhibition anti-apoptotic proteins BCL-XL, which efficiently eradicated cells xenografts.We confirmed enhanced efficacy MCL-1/BCL-XL compared PDX model.In conclusion, small compounds on targeting as specific vulnerability promising therapeutic strategy sarcoma, warrants further investigation towards clinical application.

Language: Английский

Citations

11
Novel GSH-responsive prodrugs derived from indole-chalcone and camptothecin trigger apoptosis and autophagy in colon cancer DOI
Hui Wang,

Caiyun Nie,

Miao Liang Luo

et al.

Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 143, P. 107056 - 107056

Published: Dec. 26, 2023

Language: Английский

Citations

6
EWS-FLI1 and Activator Protein-1 (AP-1) Reciprocally Regulate Extracellular-Matrix Proteins in Ewing sarcoma Cells DOI Open Access
Emma E. Croushore, Christopher S. Stipp, David J. Gordon

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 8595 - 8595

Published: Aug. 6, 2024

Ribonucleotide reductase (RNR) is the rate-limiting enzyme in synthesis of deoxyribonucleotides and target multiple chemotherapy drugs, including gemcitabine. We previously identified that inhibition RNR Ewing sarcoma tumors upregulates expression levels members activator protein-1 (AP-1) transcription factor family, c-Jun c-Fos, downregulates c-Myc. However, broader functions downstream targets AP-1, which are highly context- cell-dependent, unknown tumors. Consequently, this work, we used genetically defined models, transcriptome profiling, gene-set -enrichment analysis to identify AP-1 EWS-FLI1, driver oncogene most tumors, reciprocally regulate extracellular-matrix proteins, fibronectins, integrins, collagens. cells also drives, concurrent with these perturbations gene protein expression, changes cell morphology phenotype. EWS-FLI1 dysregulates aligning previous reports demonstrating genetic physical interactions between AP-1. Overall, results provide novel insights into distinct, EWS-FLI1-dependent features a novel, reciprocal regulation components by

Language: Английский

Citations

2
Signaling pathways and targeted therapies in Ewing sarcoma DOI Creative Commons
Jia Ke, Li Cao, Yihan Yu

et al.

Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: 266, P. 108765 - 108765

Published: Nov. 30, 2024

Language: Английский

Citations

2
Activator Protein-1 (AP-1) Signaling Inhibits the Growth of Ewing Sarcoma Cells in Response to DNA Replication Stress DOI Creative Commons
Emma E. Croushore, Stacia L. Koppenhafer, Kelli L. Goss

et al.

Cancer Research Communications, Journal Year: 2023, Volume and Issue: 3(8), P. 1580 - 1593

Published: July 19, 2023

Ribonucleotide reductase (RNR) catalyzes the rate-limiting step in synthesis of deoxyribonucleosides and is required for DNA replication. Multiple types cancer, including Ewing sarcoma tumors, are sensitive to RNR inhibitors or a reduction levels either RRM1 RRM2 subunits RNR. However, polypharmacology off-target effects have complicated identification mechanisms that regulate sensitivity resistance this class drugs. Consequently, we used conditional knockout (CRISPR/Cas9) rescue approach target cells identified loss protein results upregulation expression multiple members activator protein-1 (AP-1) transcription factor complex, c-Jun c-Fos, downregulation c-Myc. Notably, overexpression c-Fos sufficient inhibit cell growth downregulate c-Myc oncogene. We also AP-1 mediated, part, by SLFN11, which replication stress response expressed at high sarcoma. In addition, small-molecule RNR, gemcitabine, histone deacetylase inhibitors, reduce level protein, activate signaling Overall, these provide novel insight into critical pathways activated activity action RNR.RNR enzyme deoxyribonucleotides. Although chemotherapy drugs, precise mechanism work, using knockout-rescue approach, inhibition upregulates downregulates tumors.

Language: Английский

Citations

5