Disease relevance of Sutent

• In summary, monotherapy with SU11248 induced partial remissions of short duration in acute myeloid leukemia (AML) patients [1].
• Efficacy of the kinase inhibitor SU11248 against gastrointestinal stromal tumor mutants refractory to imatinib mesylate [2].
• The results suggest that edotecarin may serve as effective chemotherapy of colon cancer when used as a single agent, in combination with standard regimens and other topoisomerase inhibitors or with novel agents, such as the multitargeted tyrosine kinase inhibitor SU11248 [3].
• This method has been used to assess the therapeutic efficacy of SU11248, a multi-targeted inhibitor with demonstrated anti-tumor activity and reduction of bone loss, in a murine model of metastasized breast tumor cells [4].
• Patients on sunitinib should be strictly monitored for the appearance of hypothyroidism and promptly treated [5].
• She was offered two cycles of sunitinib maleate (Sutent) induction therapy to down-stage the thrombus and to reduce the extent of the surgery [6].
• There was one dose-limiting toxicity (grade 4 hypertension) at 37.5 mg sunitinib and 5 mg/kg bevacizumab [7].
• The effect of sunitinib on the brain tumor distribution of TMZ was dose dependent and indicated that optimal tumor exposure was achieved at a lower dose and was associated with the VNI [8].
• DCE-US is a useful tool for predicting the early efficacy of sunitinib in metastatic renal cell carcinoma patients [9].
• The increase of cellular proliferation during sunitinib withdrawal in patients with renal cell carcinoma and other solid malignancies is consistent with a VEGF receptor (VEGFR) tyrosine kinase inhibitor (TKI) withdrawal flare [10].
• Our results reveal that endothelial ATX acts through LPA signaling to promote renal tumorigenesis and is functionally involved in the acquired resistance of RCC to sunitinib [11].

High impact information on Sutent

• These data suggest that the addition of potent FLT3 inhibitors such as SU11248 to AML chemotherapy regimens could result in improved treatment results [12].
• The synergistic interaction of SU11248 and the traditional antileukemic agents was more pronounced for induction of apoptosis [12].
• SU11248 inhibited the proliferation of primary AML myeloblasts expressing mutant FLT3 ITD but not WT FLT3 protein [12].
• SU11248 is a recently described selective inhibitor with selectivity for split kinase domain RTKs, including platelet-derived growth factor receptors, vascular endothelial growth factor receptors, and KIT [13].
• We show that SU11248 also has potent activity against wild-type FLT3 (FLT3-WT), FLT3-ITD, and FLT3 activation loop (FLT3-Asp835) mutants in phosphorylation assays [13].

Chemical compound and disease context of Sutent

• CONCLUSIONS: These studies suggest that SU11248 may be a useful therapeutic agent to treat gastrointestinal stromal tumors harboring the imatinib-resistant KIT-V654A or KIT-T670I mutations, but it has no effect on the activity of the PDGFRA-D842V mutant [2].
• More importantly, tumor growth inhibition induced by sunitinib was also observed in the induced CDDP-resistant choriocarcinoma model [14].

Biological context of Sutent

• Gene expression profiling of human colon xenograft tumors following treatment with SU11248, a multitargeted tyrosine kinase inhibitor [15].
• RESULTS: The early antiangiogenic effect of SU11248 was detected by DCE-MRI with macromolecular contrast agent as a 42% decrease in vascular permeability measured in the tumor rim [16].
• FLT3 phosphorylation and plasma pharmacokinetics were evaluated at seven time points over 48 h after SU11248 administration, and FLT3 genotype was determined [17].
• 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (12b or SU11248) has been found to show the best overall profile in terms of potency for the VEGF-R2 and PDGF-Rbeta tyrosine kinase at biochemical and cellular levels, solubility, protein binding, and bioavailability [18].
• Phosphorylation of the receptor for M-CSF (CSF-1R) expressed by NIH3T3 cells was inhibited by SU11248 with an IC50 of 50-100 nM, consistent with CSF-1R belonging to the class III split kinase domain RTK family [19].

Anatomical context of Sutent

• The in vivo efficacy of SU11248 was investigated in 2 FLT3-ITD models: a subcutaneous tumor xenograft model and a bone marrow engraftment model [13].
• Apoptosis increased and clonogenic survival decreased when SU11248 was used in combination with radiation from 0 to 6 Gy on endothelial cells [20].
• Sensitivity of KIT-V654A and KIT-T670I mutants to SU11248 was confirmed using cell lines expressing these mutants [2].
• In mouse xenograft models, SU11248 exhibited broad and potent antitumor activity causing regression, growth arrest, or substantially reduced growth of various established xenografts derived from human or rat tumor cell lines [21].
• An Orally Administered Multitarget Tyrosine Kinase Inhibitor, SU11248, Is a Novel Potent Inhibitor of Thyroid Oncogenic RET/Papillary Thyroid Cancer Kinases [22].

Associations of Sutent with other chemical compounds

• Combining SU11248 and cytarabine synergistically inhibited the proliferation of primary AML myeloblasts expressing FLT3 ITD but not WT FLT3 protein [12].
• SU11248 is an oral, selective multitargeted tyrosine kinase inhibitor currently in Phase II oncology clinical trials [15].
• EXPERIMENTAL DESIGN: Primary imatinib-resistant tumor cells and cell lines expressing clinically identified imatinib-resistant KIT-V654A, KIT-T670I, or PDGFRA-D842V mutant isoforms were evaluated for sensitivity to SU11248 by Western immunoblotting and proliferation assays [2].
• Design: SU11248, SU5416, and SU6668 were synthesized, and their inhibitory potencies were evaluated using an in vitro RET/PTC kinase assay [22].
• To our knowledge, this is the second largest study reporting results of sequential therapy from sorafenib followed by sunitinib [23].
• Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of KIT in GIST following imatinib failure, illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy [24].
• Sunitinib resistance in GIST shares similar pathogenetic mechanisms identified in imatinib failure, with acquisition of secondary mutations in the activation domain after an extended initial response to the drug [25].

Gene context of Sutent

• In addition, SU11248 inhibits FLT3-induced VEGF production [13].
• Sunitinib (SU-11248, Sutent) inhibits at least eight receptor protein-tyrosine kinases including vascular endothelial growth factor receptors 1-3 (VEGFR1-VEGFR3), platelet-derived growth factor receptors (PDGFRalpha and PDGFRbeta), stem cell factor receptor (Kit), Flt-3, and colony-stimulating factor-1 receptor (CSF-1R) [26].
• To determine whether the vascular endothelial growth factor (VEGF) receptor is a molecular target to prevent metastatic disease, we utilized a non-specific inhibitor of the VEGF receptor, SU11248 [27].
• We tested the activity of SU11248, an orally active small-molecule tyrosine kinase inhibitor, to inhibit important imatinib-resistant KIT and PDGFRA mutants [2].
• Results: An in vitro kinase assay revealed that SU5416, SU6668, and SU11248 inhibited phosphorylation of the synthetic tyrosine kinase substrate peptide E4Y by RET/PTC3 in a dose-dependent manner with IC(50) of approximately 944 nm for SU5416, 562 nm for SU6668, and 224 nm for SU11248 [22].

Analytical, diagnostic and therapeutic context of Sutent

• SU11248 maintenance administration beyond the completion of radiotherapy results in prolongation of tumor control [20].
• Combined treatment with SU11248 and radiation significantly reduced tumor volume as compared with either treatment alone [20].
• SU11248-induced hair depigmentation was reversible with cessation of treatment [28].
• METHODS: C57B6J mice were treated with daily oral administration (40, 80, and 150 mg/kg) of SU11248 during 5 days after diode laser endophotocoagulation and subjected to angiographic examination and histological analysis [29].
• Western blot analyses found that SU11248 blocked autophosphorylation of c-KIT in association with inhibition of its downstream effectors, including Akt and extracellular signal-regulated kinase, but not signal transducers and activators of transcription [30].

References