Linda R Duska1,2, Gina R Petroni3,4, Heather Lothamer5,4, William Faust6, Jan H Beumer7,8,9, Susan M Christner7, Anne M Mills10, Paula M Fracasso11,4, Sarah J Parsons6,4. 1. Department of Obstetrics and Gynecology, Division of Gynecology Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA. lduska@virginia.edu. 2. University of Virginia Cancer Center, Charlottesville, VA, USA. lduska@virginia.edu. 3. Department of Public Health Services, University of Virginia School of Medicine, Charlottesville, VA, USA. 4. University of Virginia Cancer Center, Charlottesville, VA, USA. 5. Department of Obstetrics and Gynecology, Division of Gynecology Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA. 6. Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA. 7. Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. 8. Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. 9. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA. 10. Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA, USA. 11. Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA.
Abstract
OBJECTIVE: To determine the extent of dasatinib uptake and effect on Src kinase activity in tumor, normal adjacent tissue, and blood in newly diagnosed endometrial cancer patients. METHODS: Dasatinib was dosed at 100 or 200 mg PO BID at 32 and 8 h preoperatively. Blood and tissue were collected pre-treatment and at surgery to assess active (pY419) and total Src protein (pharmacodynamics [PD]) and pharmacokinetics (PK). Plasma PK and PD were also analyzed at 2, 4 and 8 h following the second dose. RESULTS: Ten patients completed the study, 5 at each dose level (DL). Average (median, standard deviation, range) 2 h plasma concentration of drug was 119 (121, 80, 226) and 236 (162, 248, 633) ng/mL, for the 100 and 200 mg DL, respectively. Average ratio of 8 h normal and tumor tissue to plasma concentration overall was 3.6 (2.3, 3.4, 9.6) and 8.3 (3.2, 11.9, 38.7), respectively. Dasatinib concentration in tumor was higher than in plasma for both DL. Four patients displayed significant reductions in pTyr419Src at ≥ 1 time points in blood, and four patients satisfied the PD activity criteria in tissue, with reductions in pTyr419Src of ≥ 60%. CONCLUSIONS: This is the first study to show PK and PD effects of dasatinib in tumor tissue, allowing evaluation of tissue PD markers as a function of tumor dasatinib concentration. Dasatinib tissue concentrations at 8 h after dosing were associated with modulation of pTyr419Src, total Src protein, and pTyr419Src/Src ratio. All patients had reduction in at least one Src parameter in either tissue or blood.
OBJECTIVE: To determine the extent of dasatinib uptake and effect on Src kinase activity in tumor, normal adjacent tissue, and blood in newly diagnosed endometrial cancerpatients. METHODS:Dasatinib was dosed at 100 or 200 mg PO BID at 32 and 8 h preoperatively. Blood and tissue were collected pre-treatment and at surgery to assess active (pY419) and total Src protein (pharmacodynamics [PD]) and pharmacokinetics (PK). Plasma PK and PD were also analyzed at 2, 4 and 8 h following the second dose. RESULTS: Ten patients completed the study, 5 at each dose level (DL). Average (median, standard deviation, range) 2 h plasma concentration of drug was 119 (121, 80, 226) and 236 (162, 248, 633) ng/mL, for the 100 and 200 mg DL, respectively. Average ratio of 8 h normal and tumor tissue to plasma concentration overall was 3.6 (2.3, 3.4, 9.6) and 8.3 (3.2, 11.9, 38.7), respectively. Dasatinib concentration in tumor was higher than in plasma for both DL. Four patients displayed significant reductions in pTyr419Src at ≥ 1 time points in blood, and four patients satisfied the PD activity criteria in tissue, with reductions in pTyr419Src of ≥ 60%. CONCLUSIONS: This is the first study to show PK and PD effects of dasatinib in tumor tissue, allowing evaluation of tissue PD markers as a function of tumordasatinib concentration. Dasatinib tissue concentrations at 8 h after dosing were associated with modulation of pTyr419Src, total Src protein, and pTyr419Src/Src ratio. All patients had reduction in at least one Src parameter in either tissue or blood.
Authors: Przemyslaw W Twardowski; Jan H Beumer; C S Chen; Andrew S Kraft; Gurkamal S Chatta; Masato Mitsuhashi; Wei Ye; Susan M Christner; Michael B Lilly Journal: Anticancer Drugs Date: 2013-08 Impact factor: 2.248
Authors: Kan He; Michael W Lago; Ramaswamy A Iyer; Wen-Chyi Shyu; William G Humphreys; Lisa J Christopher Journal: Drug Metab Dispos Date: 2008-09-11 Impact factor: 3.922
Authors: Maria Laura Tognoli; Nikola Vlahov; Sander Steenbeek; Anna M Grawenda; Michael Eyres; David Cano-Rodriguez; Simon Scrace; Christiana Kartsonaki; Alex von Kriegsheim; Eduard Willms; Matthew J Wood; Marianne G Rots; Jacco van Rheenen; Eric O'Neill; Daniela Pankova Journal: EMBO J Date: 2021-09-17 Impact factor: 11.598