A First-in-Human Phase I Study of the ATP-Competitive AKT Inhibitor Ipatasertib Demonstrates Robust and Safe Targeting of AKT in Patients with Solid Tumors.
| Autor: | Saura C; Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain., Roda D; Hematology and Medical Oncology Department, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain., Roselló S; Hematology and Medical Oncology Department, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain., Oliveira M; Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain., Macarulla T; Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain., Pérez-Fidalgo JA; Hematology and Medical Oncology Department, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain., Morales-Barrera R; Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain., Sanchis-García JM; Radiology Department, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain., Musib L; Genentech, Inc., South San Francisco, California., Budha N; Genentech, Inc., South San Francisco, California., Zhu J; Genentech, Inc., South San Francisco, California., Nannini M; Genentech, Inc., South San Francisco, California., Chan WY; Genentech, Inc., South San Francisco, California., Sanabria Bohórquez SM; Genentech, Inc., South San Francisco, California., Meng RD; Genentech, Inc., South San Francisco, California., Lin K; Genentech, Inc., South San Francisco, California., Yan Y; Genentech, Inc., South San Francisco, California., Patel P; Genentech, Inc., South San Francisco, California., Baselga J; Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain., Tabernero J; Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain. jtabernero@vhio.net., Cervantes A; Hematology and Medical Oncology Department, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain. |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | Cancer discovery [Cancer Discov] 2017 Jan; Vol. 7 (1), pp. 102-113. Date of Electronic Publication: 2016 Nov 21. |
| DOI: | 10.1158/2159-8290.CD-16-0512 |
| Abstrakt: | Activation of AKT signaling by PTEN loss or PIK3CA mutations occurs frequently in human cancers, but targeting AKT has been difficult due to the mechanism-based toxicities of inhibitors that target the inactive conformation of AKT. Ipatasertib (GDC-0068) is a novel selective ATP-competitive small-molecule inhibitor of AKT that preferentially targets active phosphorylated AKT (pAKT) and is potent in cell lines with evidence of AKT activation. In this phase I study, ipatasertib was well tolerated; most adverse events were gastrointestinal and grade 1-2 in severity. The exposures of ipatasertib ≥200 mg daily in patients correlated with preclinical TGI Significance: Potent inhibition of AKT signaling with ipatasertib was associated with a tolerable safety profile and meaningful disease control in a subgroup of patients. Targeting pAKT with an ATP-competitive inhibitor provides a greater therapeutic window than allosteric inhibitors. Further investigation with ipatasertib is ongoing in phase II studies. Cancer Discov; 7(1); 102-13. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1. (©2016 American Association for Cancer Research.) |
| Databáze: | MEDLINE |
| Externí odkaz: |
|