A window-of-opportunity clinical trial of dasatinib in women with newly diagnosed endometrial cancer

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 hours 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 hours 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 8h 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.

Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies SRPK1 As Candidate Therapeutic Target

“…The pan-Tyrosine kinase (TK) inhibitor Dasatinib, represents a plausible drug therapy for EC tumors based on increased MIB-binding of Dasatinib-targets LYN, DDR1 and/or SRC. Indeed, Dasatinib is currently being evaluated in EC highlighting the utility of Q-MIBs to predict kinase drug targets(32). Elevated levels of the RTK, c-MET (MET), were also observed in EC tumors relative to NE tissues by Q-MIBs profiling, consistent with previous reports demonstrating high expression of c-MET and its ligand hepatocyte growth factor (HGF) in endometrial carcinomas(33).…”

RASSF1C oncogene elicits amoeboid invasion, cancer stemness, and extracellular vesicle release via a SRC/Rho axis

“…A similarly compelling clinical target could be the SRC kinase. Clinical trials for tyrosine kinase (including SRC) inhibitors have shown beneficial outcome for adult patients with Philadelphia chromosome‐positive chronic myeloid leukemia (CML; Cortes et al , 2018) and are being tested in combination with EGFR inhibitors for advanced pancreatic cancer (Cardin et al , 2018) or alone for the treatment of newly diagnosed endometrial cancer (Duska et al , 2019). Evidence that SRC kinase directly governs cancer EV release (Mineo et al , 2012) may reinforce the testing of SRC inhibitors in the clinic.…”

Small-Molecule Inhibitors (SMIs) as an Effective Therapeutic Strategy for Endometrial Cancer

“…They found that Dasatinib entered the solid tumour tissue and modulated Src activity. Similarly, they demonstrated that Dasatinib concentrations were higher in tumour tissue than in adjacent normal tissue, providing for the first time an insight into the biological effects and potential therapeutic efficacy of Dasatinib in EC [ 71 ]. Nowadays, there is an ongoing phase I trial (NCT01440998), which aims to evaluate Dasatinib, Paclitaxel, and Carboplatin treatment in patients with stage III-IV or recurrent EC; there is also a phase II clinical trial (NCT02059265) on patients with recurrent or persistent ovarian, fallopian tube, endometrial, and peritoneal cancers.…”