紫杉醇
医学
乳腺癌
转移性乳腺癌
药效学
癌症
药代动力学
药理学
临床试验
耐火材料(行星科学)
肿瘤科
内科学
癌症研究
生物
天体生物学
作者
Cristiano Ferrario,John R. Mackey,Karen A. Gelmon,Nathalie LeVasseur,Poul H. Sorensen,Htoo Zarni Oo,Gian Luca Negri,Victor Tse,Sandra E. Spencer Miko,Grace Cheng,Gregg B. Morin,Sonia V. del Rincón,Tiziana Cotechini,Christophe Gonçalves,Charles C.T. Hindmarch,Wilson H. Miller,Mehdi Amiri,Tayebeh Basiri,Victor Villareal-Corpuz,Sam Sperry
标识
DOI:10.1158/1078-0432.ccr-24-0841
摘要
Abstract Purpose: Preclinical data motivate clinical evaluation of inhibitors of MAPK-interacting kinases 1 and 2 (MNK1/2). We conducted a phase 1b clinical trial to study target engagement and safety of tomivosertib, a MNK1/2 inhibitor, alone and in combination with paclitaxel. Patients and Methods: Eligible patients had metastatic breast cancer resistant to standard-of-care treatments. Biopsies were obtained at baseline and during treatment with tomivosertib, and then tomivosertib was continued with the addition of paclitaxel until disease progression or toxicity. Serum drug levels were measured, and pharmacodynamic endpoints included IHC, proteomics, translatomics, and imaging mass cytometry. Results: Tomivosertib alone and in combination with paclitaxel was well tolerated. There was no pharmacokinetic interaction between the drugs. We observed a clear reduction in phosphorylation of eIF4E at S209, a major substrate of MNK1/2, and identified tomivosertib-induced perturbations in the proteome, translatome, and cellular populations of biopsied metastatic breast cancer tissue. Conclusions: We conclude that tomivosertib effectively inhibits MNK1/2 activity in metastatic breast cancer tissue and that it can safely be combined with paclitaxel in future phase II studies. We demonstrate feasibility of using proteomic profiles, translatomic profiles, and spatial distribution of immune cell infiltrates for clinical pharmacodynamic studies.
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