Phase Ib pharmacodynamic study of the MNK inhibitor Tomivosertib (eFT508) combined with paclitaxel in patients with refractory metastatic breast cancer.

Autor:	Ferrario C; Lady Davis Insitute and Jewish General Hospital, Montreal, Quebec, Canada., Mackey J; University of Alberta, Edmonton, Alberta, Canada., Gelmon KA; BC Cancer Agency, Vancouver, BC, Canada., Levasseur N; BC Cancer Agency, Vancouver, BC, Canada., Sorensen PH; British Columbia Cancer Research Centre, Vancouver, BC, Canada., Oo HZ; University of British Columbia, Vancouver, British Columbia, Canada., Negri GL; Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada., Tse VWL; Canada's Michael Smith Genome Sciences Centre, Vancouver, Canada., Spencer SE; Canada's Michael Smith Genome Sciences Centre, Canada., Cheng G; BC Cancer Agency, Vancouver, BC, Canada., Morin GB; BC Cancer, Vancouver, BC, Canada., Del Rincon S; Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada., Cotechini T; Queen's University, Kingston, Ontario, Canada., Gonçalves C; Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Canada., Hindmarch CCT; Queen's University, Kingston, Ontario, Canada., Miller WH; Jewish General Hospital, McGill University, Montreal, Quebec, Canada., Amiri M; McGill University, Canada., Basiri T; McGill University, Canada., Villareal-Corpuz V; Jewish General Hospital, Canada., Sperry S; eFFECTOR Therapeutics, San Diego, CA, United States., Gregorczyk K; eFFECTOR Therapeutics, Inc., United States., Spera G; TRIO - Translational Research in Oncology, Uruguay., Sonenberg N; McGill University, Montreal, Quebec, Canada., Pollak M; McGill University, Montreal, Quebec, Canada.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Nov 22. Date of Electronic Publication: 2024 Nov 22.
DOI:	10.1158/1078-0432.CCR-24-0841
Abstrakt:	Purpose: Preclinical data motivate clinical evaluation of inhibitors of mitogen-activated protein kinase-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. 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 addition of paclitaxel until disease progression or toxicity. Serum drug levels were measured, and pharmacodynamic endpoints included immunohistochemistry, 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. Conclusion: 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.
Databáze:	MEDLINE
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