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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The ability of dasatinib to effectively inhibit the proliferation of cells expressing nearly all imatinib-resistant mutants known at the time suggested that this compound had significant therapeutic potential for the treatment of imatinib-resistant CML. This led to a Phase I dose-escalation study in which dasatinib showed promising activity in both imatinib-resistant and imatinib-intolerant patients within all phases of CML and Philadelphia chromosome–positive ALL. Complete hematological responses were obtained in 37 out of 40 patients with chronic-phase CML, and major hematologic responses were seen in 31 out of 44 patients with accelerated-phase CML, CML in blast crisis or Philadelphia chromosome–positive ALL. Following these results, four Phase II trials (the “START” trials) showed that responses were maintained in 95% of patients with chronic-phase CML. In patients with accelerated-phase CML, 82% remained in remission, while nearly all patients with CML in blast crisis or Philadelphia chromosome–positive ALL relapsed within six months. Overall, responses were seen in patients with all Bcr-Abl genotypes with the exception of those with the T315I mutation which is known to confer resistance to dasatinib, nilotinib, and imatinib in vitro.
Targeting BCR-ABL in Chronic Myelogenous Leukemia
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Dasatinib is an orally active dual BCR-ABL/Src kinase inhibitor [45]. In vitro, it is 325 times as potent as imatinib [46, 25]. It is structurally different to imatinib and has the ability to bind both the inactive and active forms of BCR-ABL. The ability to bind both conformations of BCR-ABL may explain its potent activity against 18 out of the 19 known imatinib-resistant kinase domain mutations except T315I [47, 48].
Chronic Myeloid Leukaemia
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Dasatinib was tested at a dose of 100 mg/day in the DASISION study (Dasatinib versus Imatinib Study in Treatment-Naïve CML Patients), Nilotinib at two dosages, either 300 mg/day or 400 mg/day, in the ENESTnd study (Evaluating Nilotinib Efficacy and Safety in Newly Diagnosed Patients) and bosutinib at 500 mg/day in the BELA study (Bosutinib Efficacy and Safety in CML). Dasatinib and nilotinib, but not bosutinib, were licensed following the initial 12-month results in 2010. Table 6.4 depicts the latest results of the DASISION and ENESTnd studies, following 5 years of follow-up for both trials. The 12-month results from the BELA study showed a similar CCyR for bosutinib and imatinib (70% versus 68%); the 24-month follow-up, however, suggested an improved molecular response and protection from progression compared to imatinib, and the drug was licensed for second-line use in 2014, and may be a candidate for first-line use in the future. Indeed, the June 2017 results of the open-label, randomized, phase III trial (BFORE), in which bosutinib at a reduced dose of 400 mg/day was compared to imatinib 400 mg/day in newly diagnosed 533 patients, supports the drug’s credentials for first-line use; the reduction of the dose of bosutinib also led to improved safety. He use of dasatinib as an effective treatment, with a safety profile similar to that seen in adults, has also been confirmed in children with CML. Interestingly, no examples of pleural or pericardial effusions or pulmonary arterial hypertension were noted in children.
Managing women of childbearing age with chronic myeloid leukemia: safety and treatment considerations
Published in Expert Review of Hematology, 2023
HF Robertson, MJ Buckton, JF Apperley
Current evidence suggests that dasatinib should not be used at any point during pregnancy. Cortes et al. provided the largest series to date of female patients who conceived whilst taking dasatinib [10]. Pregnancy outcome data were available for 59% (46/78) of women. Only 20/46 (43%) pregnancies resulted in a live birth. Of the 20 live births, a quarter of patients had an abnormal pregnancy (2 intra-uterine growth restriction, 1 placental abruption, 1 premature, 1 hydrops fetalis, and 1 renal tract abnormality). One of these cases included a patient who was started on dasatinib during the second trimester. At 28 weeks, an emergency Cesarean section was performed due to the detection of hydrops fetalis, and whilst the infant was alive at birth, it died within 24 h. Furthermore, 26/46 (57%) of pregnancies were terminated: 8 spontaneously and 18 electively. Three elective terminations were undertaken due to detection of fetal abnormalities (one encephalocele, one hydrops fetalis, one unspecified). Importantly, even in the 32 women who stopped dasatinib immediately upon determination of pregnancy, there were still five pregnancy-related issues (three maternal and two fetal abnormalities).
Rationale for combining tyrosine kinase inhibitors and T cell redirecting antibodies to mitigate cytokine release syndrome (CRS)
Published in Expert Opinion on Biological Therapy, 2023
Gabrielle Leclercq-cohen, Marina Bacac, Christian Klein
Among the Bcr-Abl/Src inhibitors, we found that pharmacologically active doses of dasatinib most efficiently and reversibly switched-off cytotoxicity and cytokine release from PBMCs that were pre-stimulated with WT1-TCB (HLA-A2 TCR-like TCB) or CEA-TCB by inhibition of Src and Lck kinases, in line with findings from Leonard et al. [7,8]. In vivo, dasatinib was able to prevent CD19-TCB-mediated B cell depletion and cytokine release for up to 48 h in humanized NSG mice. Based on these findings, dasatinib was developed into a potential safety switch e.g. to be applied if there is a risk for on-target off-tumor activity, or in rare cases of life-threatening CRS. In this case, transient administration of dasatinib should start as early as possible after the first signs of CRS or on-target off-tumor activity to rapidly resolve symptoms. Besides, short administration of dasatinib around the first infusion with T cell engager therapies could also prevent the cytokine peaks and reduce the risk of CRS, while only transiently blocking activity.
Dasatinib ameliorates thioacetamide-induced liver fibrosis: modulation of miR-378 and miR-17 and their linked Wnt/β-catenin and TGF-β/smads pathways
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Mai A. Zaafan, Amr M. Abdelhamid
Dasatinib is a second-generation oral multitarget inhibitor of many tyrosine kinases10,20. Dasatinib was designed to treat some types of cancers including chronic myeloid leukaemia (CML)21. Dasatinib has recently been studied for its anti-fibrotic effects in a variety of fibrous diseases, including systemic sclerosis, lung fibrosis, and chronic pancreatitis. Through the TKs/GSK3/β-catenin pathway, dasatinib inhibits the proliferation and activation of pancreatic stellate cells (PSCs)21,22. The current study aims to investigate the potential efficacy and the molecular mechanisms of dasatinib in the treatment of thioacetamide-induced liver fibrosis by modulating miR-378 and miR-17 via the Wnt/β catenin and TGF-/smad pathways.