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Dose-Finding Quantitative 18F-FDG PET Imaging Study with the Oral Pan-AKT Inhibitor GSK2141795 in Patients with
Hatice Gungor1, Azeem Saleem2, Syed Babar3
1Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, United Kingdom h.gungor@imperial.ac.uk.
Unlabelled:
AKT (a serine/threonine-specific protein kinase) regulates many cellular processes contributing to cytotoxic drug resistance. This study's primary objective examined the relationship between GSK2141795, an oral, pan-AKT inhibitor, and (18)F-FDG PET markers of glucose metabolism in tumor tissue to determine whether (18)F-FDG PET could be used to guide personalized dosing of GSK2141795. Biomarker analysis of biopsies was also undertaken.
Methods:
Twelve patients were enrolled in 3 cohorts; all underwent dynamic (18)F-FDG PET scans and serial pharmacokinetic sampling at baseline, week 2, and week 4 with tumor biopsies before treatment and at week 4. Response was evaluated by RECIST v1.1 and Gynecologic Cancer Intergroup criteria. Biopsy samples were analyzed for mutations and protein expression.
Results:
GSK2141795 did not significantly influence blood glucose levels. No dose-response relationship was observed between GSK2141795 pharmacokinetics and (18)F-FDG PET pharmacodynamic measures; however, an exposure-response relationship was seen between maximum drug concentrations and maximal decrease in (18)F-FDG uptake in the best-responding tumor. This relationship also held for pharmacokinetic parameters of exposure and 1,5-anhydroglucitol (a systemic measure of glucose metabolism). Phospho-AKT upregulation at week 4 in biopsies confirmed AKT inhibition by GSK2141795. Single-agent activity was observed with a clinical benefit rate of 27% (3/11) and 30% (3/10) CA125 response in the study's platinum-resistant ovarian patients. AKT pathway activation by PIK3CA/PIK3R1 mutation did not correlate with clinical activity, whereas RAS/RAF pathway mutations did segregate with resistance to AKT inhibition.
Conclusion:
GSK2141795 demonstrated an exposure-response relationship with decreased (18)F-FDG uptake and is active and tolerable. This study's design integrating (18)F-FDG PET, pharmacokinetics, and biomarker analyses demonstrates the potential for clinical development for personalized treatment.
Insights
This study shows that the AKT inhibitor GSK2141795 has an exposure-response relationship with decreased tumor glucose metabolism, as measured by 18F-FDG PET scans. This suggests potential for personalized dosing strategies in cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- AKT signaling pathway is crucial in cellular processes and drug resistance.
- Targeting AKT with inhibitors like GSK2141795 is a strategy for cancer therapy.
- 18F-FDG PET measures tumor glucose metabolism, a potential pharmacodynamic biomarker.
Purpose of the Study:
- To investigate the relationship between GSK2141795 exposure and 18F-FDG PET markers of glucose metabolism.
- To determine if 18F-FDG PET can guide personalized dosing of GSK2141795.
- To analyze tumor biomarkers and assess clinical activity of GSK2141795.
Main Methods:
- Twelve patients with platinum-resistant ovarian cancer were enrolled in three cohorts.
- Dynamic 18F-FDG PET scans and pharmacokinetic sampling were performed.
- Tumor biopsies were collected for mutation and protein expression analysis before and after treatment.
Main Results:
- An exposure-response relationship was observed between GSK2141795 concentration and decreased 18F-FDG uptake.
- GSK2141795 demonstrated single-agent activity with a clinical benefit rate of 27% in platinum-resistant ovarian cancer patients.
- RAS/RAF pathway mutations correlated with resistance to AKT inhibition, while PIK3CA/PIK3R1 mutations did not.
Conclusions:
- GSK2141795 shows an exposure-response relationship with reduced tumor 18F-FDG uptake and is active and tolerable.
- The integrated approach using 18F-FDG PET, pharmacokinetics, and biomarker analysis shows promise for personalized cancer treatment development.
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