Dose-finding quantitative 18F-FDG PET imaging study with the oral pan-AKT inhibitor GSK2141795 in patients with gynecological malignancies
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 FDG-PET markers of glucose metabolism in tumor tissue to determin...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
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Society of Nuclear Medicine
2015
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| _version_ | 1797099681642184704 |
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| author | Gungor, H Saleem, A Babar, S Dina, R El-Bahrawy, M Curry, E Rama, N Chen, M Pickford, E Agarwal, R Blagden, S Carme, S Salinas, C Madison, S Krachey, E Santiago-Walker, A Smith, D Morris, S Stronach, E Gabra, H |
| author_facet | Gungor, H Saleem, A Babar, S Dina, R El-Bahrawy, M Curry, E Rama, N Chen, M Pickford, E Agarwal, R Blagden, S Carme, S Salinas, C Madison, S Krachey, E Santiago-Walker, A Smith, D Morris, S Stronach, E Gabra, H |
| author_sort | Gungor, H |
| collection | OXFORD |
| description | 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 FDG-PET markers of glucose metabolism in tumor tissue to determine if FDG-PET could be used to guide personalized dosing of GSK2141795. Biomarker analysis of biopsies was also undertaken. <strong>METHODS:</strong> Twelve patients were enrolled in three cohorts; all had dynamic FDG-PET scans and serial pharmacokinetic sampling at baseline, Week 2 (W2) and Week 4 (W4) with tumor biopsies pre-treatment and at W4. Response was evaluated by RECIST v1.1 and GCIG criteria. Biopsy samples were analyzed for mutations and protein expression. <strong>RESULTS:</strong> GSK2141795 did not significantly influence blood glucose levels. No dose-response relationship was observed between GSK2141795 pharmacokinetics (PK) and FDG-PET pharmacodynamic (PD) measures; however an exposure-response-relationship was seen between maximum drug concentrations and maximal decrease in 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 up-regulation at W4 in biopsies confirmed AKT inhibition by GSK2141795. Single agent activity was observed with 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. <strong>CONCLUSION:</strong> GSK2141795 demonstrated an exposure-response relationship with decreased FDG uptake and is active and tolerable. This study’s design integrating FDG-PET, PK and biomarker analyses demonstrate the potential for clinical development for personalized treatment. |
| first_indexed | 2024-03-07T05:27:08Z |
| format | Journal article |
| id | oxford-uuid:e0f1fdc7-d991-486d-b04e-168d59b73e14 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T05:27:08Z |
| publishDate | 2015 |
| publisher | Society of Nuclear Medicine |
| record_format | dspace |
| spelling | oxford-uuid:e0f1fdc7-d991-486d-b04e-168d59b73e142022-03-27T09:51:03ZDose-finding quantitative 18F-FDG PET imaging study with the oral pan-AKT inhibitor GSK2141795 in patients with gynecological malignanciesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e0f1fdc7-d991-486d-b04e-168d59b73e14Symplectic Elements at OxfordSociety of Nuclear Medicine2015Gungor, HSaleem, ABabar, SDina, REl-Bahrawy, MCurry, ERama, NChen, MPickford, EAgarwal, RBlagden, SCarme, SSalinas, CMadison, SKrachey, ESantiago-Walker, ASmith, DMorris, SStronach, EGabra, HAKT (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 FDG-PET markers of glucose metabolism in tumor tissue to determine if FDG-PET could be used to guide personalized dosing of GSK2141795. Biomarker analysis of biopsies was also undertaken. <strong>METHODS:</strong> Twelve patients were enrolled in three cohorts; all had dynamic FDG-PET scans and serial pharmacokinetic sampling at baseline, Week 2 (W2) and Week 4 (W4) with tumor biopsies pre-treatment and at W4. Response was evaluated by RECIST v1.1 and GCIG criteria. Biopsy samples were analyzed for mutations and protein expression. <strong>RESULTS:</strong> GSK2141795 did not significantly influence blood glucose levels. No dose-response relationship was observed between GSK2141795 pharmacokinetics (PK) and FDG-PET pharmacodynamic (PD) measures; however an exposure-response-relationship was seen between maximum drug concentrations and maximal decrease in 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 up-regulation at W4 in biopsies confirmed AKT inhibition by GSK2141795. Single agent activity was observed with 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. <strong>CONCLUSION:</strong> GSK2141795 demonstrated an exposure-response relationship with decreased FDG uptake and is active and tolerable. This study’s design integrating FDG-PET, PK and biomarker analyses demonstrate the potential for clinical development for personalized treatment. |
| spellingShingle | Gungor, H Saleem, A Babar, S Dina, R El-Bahrawy, M Curry, E Rama, N Chen, M Pickford, E Agarwal, R Blagden, S Carme, S Salinas, C Madison, S Krachey, E Santiago-Walker, A Smith, D Morris, S Stronach, E Gabra, H Dose-finding quantitative 18F-FDG PET imaging study with the oral pan-AKT inhibitor GSK2141795 in patients with gynecological malignancies |
| title | Dose-finding quantitative 18F-FDG PET imaging study with the oral pan-AKT inhibitor GSK2141795 in patients with gynecological malignancies |
| title_full | Dose-finding quantitative 18F-FDG PET imaging study with the oral pan-AKT inhibitor GSK2141795 in patients with gynecological malignancies |
| title_fullStr | Dose-finding quantitative 18F-FDG PET imaging study with the oral pan-AKT inhibitor GSK2141795 in patients with gynecological malignancies |
| title_full_unstemmed | Dose-finding quantitative 18F-FDG PET imaging study with the oral pan-AKT inhibitor GSK2141795 in patients with gynecological malignancies |
| title_short | Dose-finding quantitative 18F-FDG PET imaging study with the oral pan-AKT inhibitor GSK2141795 in patients with gynecological malignancies |
| title_sort | dose finding quantitative 18f fdg pet imaging study with the oral pan akt inhibitor gsk2141795 in patients with gynecological malignancies |
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