| Autor: |
Qasim SL; Texas Children's Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center, Baylor College of Medicine, Houston, TX, 77030, USA., Sierra L; Texas Children's Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center, Baylor College of Medicine, Houston, TX, 77030, USA., Shuck R; Texas Children's Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center, Baylor College of Medicine, Houston, TX, 77030, USA., Kurenbekova L; Texas Children's Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center, Baylor College of Medicine, Houston, TX, 77030, USA., Patel TD; Texas Children's Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center, Baylor College of Medicine, Houston, TX, 77030, USA., Rajapakshe K; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA., Wulff J; Texas Children's Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center, Baylor College of Medicine, Houston, TX, 77030, USA., Nakahata K; Texas Children's Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center, Baylor College of Medicine, Houston, TX, 77030, USA., Kim HR; Texas Children's Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center, Baylor College of Medicine, Houston, TX, 77030, USA., Landesman Y; Karyopharm Therapeutics Inc., Newton, MA, 02459, USA., Unger TJ; Karyopharm Therapeutics Inc., Newton, MA, 02459, USA., Coarfa C; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA., Yustein JT; Texas Children's Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center, Baylor College of Medicine, Houston, TX, 77030, USA. yustein@bcm.edu.; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. yustein@bcm.edu.; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA. yustein@bcm.edu.; Cancer and Cell Biology Program, Baylor College of Medicine, Houston, TX, 77030, USA. yustein@bcm.edu. |
| Abstrakt: |
Ewing sarcoma (ES) is the second most common bone tumor in children and young adults. Unfortunately, there have been minimal recent advancements in improving patient outcomes, especially in metastatic and recurrent diseases. In this study, we investigated the biological role of p21-activated kinases (PAKs) in ES, and the ability to therapeutically target them in high-risk disease. Via informatics analysis, we established the inverse association of PAK1 and PAK4 expression with clinical stage and outcome in ES patients. Through expression knockdown and small-molecule inhibition of PAKs, utilizing FRAX-597, KPT-9274, and PF-3758309 in multiple ES cell lines and patient-derived xenograft models, we further explored the role of PAKs in ES tumor growth and metastatic capabilities. In vitro studies in several ES cell lines indicated that diminishing PAK1 and PAK4 expression reduces tumor cell viability, migratory, and invasive properties. In vivo studies using PAK4 inhibitors, KPT-9274 and PF-3758309 demonstrated significant inhibition of primary and metastatic tumor formation, while transcriptomic analysis of PAK4-inhibitor-treated tumors identified concomitant suppression of Notch, β-catenin, and hypoxia-mediated signatures. In addition, the analysis showed enrichment of anti-tumor immune regulatory mechanisms, including interferon (IFN)-ɣ and IFN-α responses. Altogether, our molecular and pre-clinical studies are the first to establish a critical role for PAKs in ES development and progression, and consequently as viable therapeutic targets for the treatment of high-risk ES in the near future. |
Full text from SpringerLink