Sunitinib malate

Sunitinib malate, also called sunitinib, is a novel, oral, multi-targeted , small molecule oxindole tyrosine kinase inhibitor which inhibits multiple receptor tyrosine kinases including platelet-derived growth factor receptor ( and (, vascular endothelial growth factor receptor 1, 2 and 3, c-KIT, FLT3 kinase, colony-stimulating factor 1 receptor and RET kinase [2][3] [4]. The IC50 of sunitinib is approximately 10-20 ng/ml to NB cell lines, which is within the clinically relevant human trough serum concentration (50-100 ng/ml) [1].

Receptor tyrosine kinases activated a number of different intracellular signaling pathways [5].

In neuroblastoma (NB) cell lines, SKN-BE (2), NUB-7, SH-SY5Y and LAN-5, sunitinib significantly inhibited cell proliferation after a treatment for 48 hours, in a concentration-dependent manner [1].

Treatment with 20, 30 or 40 mg/kg of sunitinib made NOD/SCID mice inoculated with xenograft tumor cells show significant reduction (P <0.05) in primary tumor growth (%T/C: 49% for SK-N-BE (2) and 55% for NB12 tumor, T/C: average treated tumor mass/average control tumor mass). Treatment with different doses of sunitinib (20, 30 or 40 mg/kg) for 14 days resulted in a dramatic decrease in the numbers and size of metastatic sites and a significant difference in liver weight in mice injected intravaneously with 106 SK-N-BE(2) cells for 7 days compared with the control group [1].

References:
[1].  Libo Zhang, Kristen M. Smith, Amy Lee Chong, et al. In Vivo Antitumor and Antimetastatic Activity of Sunitinib in Preclinical Neuroblastoma Mouse Model. Neoplasia, 2009, 11: 426-435.
[2].  Hassane Izzedine, Irina Buhaescu, Olivier Rixe, et al. Sunitinib malate. Cancer Chemother Pharmacol, 2007, 60: 357-364.
[3].  M. L. Telli, R. M. Witteles, G. A. Fisher, et al. Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate. Annals of Oncology, 2008, 19: 1613–1618.
[4].  Edwin P. Rock, Vicki Goodman, Janet X. Jiang, et al. Food and Drug Administration Drug Approval Summary: Sunitinib Malate for the Treatment of Gastrointestinal Stromal Tumor and Advanced Renal Cell Carcinoma. The Oncologist, 2007, 12: 107-113.
[5].  C. J. Marshall. Specificity of Receptor Tyrosine Kinase Signaling: Transient versus Sustained Extracellular Signal-Regulated Kinase Activation. Cel, 1995, 80: 179-185.

Combination of SL327 and Sunitinib Malate leads to an additive anti-cancer effect in doxorubicin resistant thyroid carcinoma cells.[Pubmed:28178630]

Biomed Pharmacother. 2017 Apr;88:985-990.

BACKGROUND: Receptor tyrosine kinases (RTKs) play crucial roles in numerous cancer cell processes including cell survival, proliferation, and migration. MEK1/2 MAPK kinases are very important for cancer survival and development. Anaplastic thyroid carcinoma (ATC) is a deadly type of thyroid cancer and there are no very effective systemic treatment strategies for ATC so far. Also, ATC can easily become resistant to therapy of traditional therapeutic drugs for ATC, such as doxorubicin. Drug combination treatment could be a promising therapeutic strategy for ATC, especially for drug resistant ATC. METHODS: We explored the combination effect between a MEK1/2 inhibitor SL327 and a multi-targeted RTK inhibitor Sunitinib malate in doxorubicin resistant ATC cells using cell viability assay, cell migration assay, nuclei morphology and caspase-3 activity analysis, as well as in vivo tumor growth assay. RESULTS: There is a significant additive effect between SL327 and Sunitinib malate in reducing viability, increasing apoptosis, and suppressing migration of doxorubicin-resistant ATC cells. Importantly, combination of SL327 and Sunitinib malate induced significant additive suppression of in vivo doxorubicin-resistant ATC tumor growth. CONCLUSIONS: Our results suggest that the combination of MEK1/2 inhibitor and RTK inhibitor is promising for treatment of ATC especially doxorubicin-resistant ATC. The combination might not only enhance the anti-cancer efficacy, but also reduce the side effects and overcome drug resistance developed in ATC treatment. All these might provide useful information for clinical therapeutics of ATC.

In vitro cytotoxic effect of tyrosine kinase inhibitor sunitinib malate alone and in combination with hyperthermia on breast adenocarcinoma MCF-7 cells.[Pubmed:27569072]

J BUON. 2016 May-Jun;21(3):556-63.

PURPOSE: In this study, the in vitro cytotoxic effect of Sunitinib malate alone and combination with hyperthermia was evaluated on MCF-7 cells (human breast adenocarcinoma cell line). METHODS: For this purpose cell proliferation assay, mitotic index and labelling index analysis among cell kinetic parameters were assessed. Sunitinib malate doses of 1, 5 and 10 muM were applied alone and in combination with hyperthermia to cells for 24-72 hrs. RESULTS: A significant decrease (p<0.05) was noticed in cell proliferation, mitotic index and labelling index for all experimental groups and for all applications. CONCLUSION: Labeling index and mitotic index values show that Sunitinib malate combined with hyperthermia was significantly more effective in MCF-7 cells than when given alone. This combination acts through synergistic and additive effects.

A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate.[Pubmed:28129334]

PLoS One. 2017 Jan 27;12(1):e0169964.

Sunitinib is a tyrosine kinase inhibitor approved for the treatment of multiple solid tumors. However, cardiotoxicity is of increasing concern, with a need to develop rational mechanism driven approaches for the early detection of cardiac dysfunction. We sought to interrogate changes in cardiac energy substrate usage during sunitinib treatment, hypothesising that these changes could represent a strategy for the early detection of cardiotoxicity. Balb/CJ mice or Sprague-Dawley rats were treated orally for 4 weeks with 40 or 20 mg/kg/day sunitinib. Cardiac positron emission tomography (PET) was implemented to investigate alterations in myocardial glucose and oxidative metabolism. Following treatment, blood pressure increased, and left ventricular ejection fraction decreased. Cardiac [18F]-fluorodeoxyglucose (FDG)-PET revealed increased glucose uptake after 48 hours. [11C]Acetate-PET showed decreased myocardial perfusion following treatment. Electron microscopy revealed significant lipid accumulation in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid beta-oxidation and mitochondrial dysfunction were among the top myocardial signalling pathways perturbed. Sunitinib treatment results in an increased reliance on glycolysis, increased myocardial lipid deposition and perturbed mitochondrial function, indicative of a fundamental energy crisis resulting in compromised myocardial energy metabolism and function. Our findings suggest that a cardiac PET strategy may represent a rational approach to non-invasively monitor metabolic pathway remodeling following sunitinib treatment.

Targeted drug delivery of Sunitinib Malate to tumor blood vessels by cRGD-chiotosan-gold nanoparticles.[Pubmed:27956189]

Int J Pharm. 2017 Jan 30;517(1-2):269-278.

The unique characteristics of tumor vasculature represent an attractive strategy for targeted delivery of antitumor and antiangiogenic agents to the tumor. The purpose of this study was to prepare c(RGDfK) labeled chitosan capped gold nanoparticles [cRGD(CS-Au) NPs] as a carrier for selective intracellular delivery of Sunitinib malate (STB) to the tumor vasculature. cRGD(CS-Au) NPs was formed by electrostatic interaction between cationic CS and anionic AuNPs. cRGD modified CS-Au NPs had a spherical shape with a narrow size distribution. The entrapment efficiency of sunitinib molecule was found to be 45.2%+/-2.05. Confocal microscopy showed enhanced and selective uptake of cRGD(CS-Au) NPs into MCF-7 and HUVEC cells compared with non-targeted CS-Au NPs. Our results suggest that it may be possible to use cRGD(CS-Au) NPs as a carrier for delivery of anticancer drugs, genes and biomolecules for inhibiting tumor vasculature.

Molecular basis for sunitinib efficacy and future clinical development.[Pubmed:17690708]

Nat Rev Drug Discov. 2007 Sep;6(9):734-45.

Sunitinib malate (SU11248/Sutent; Pfizer) is a multitargeted tyrosine kinase inhibitor that has potent anti-angiogenic and antitumour activities. Definitive efficacy has been demonstrated in advanced renal cell carcinoma and in gastrointestinal stromal tumours that are refractory or intolerant to imatinib (Gleevec; Novartis), which has provided the basis for the recent regulatory approvals for these indications. This article summarizes the discovery and development of sunitinib, and discusses key issues for the multitargeted approach in cancer treatment, such as markers of response and development of resistance, and their significance for the future development of sunitinib and other multikinase inhibitors.

In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship.[Pubmed:12538485]

Clin Cancer Res. 2003 Jan;9(1):327-37.

One challenging aspect in the clinical development of molecularly targeted therapies, which represent a new and promising approach to treating cancers, has been the identification of a biologically active dose rather than a maximum tolerated dose. The goal of the present study was to identify a pharmacokinetic/pharmacodynamic relationship in preclinical models that could be used to help guide selection of a clinical dose. SU11248, a novel small molecule receptor tyrosine kinase inhibitor with direct antitumor as well as antiangiogenic activity via targeting the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), KIT, and FLT3 receptor tyrosine kinases, was used as the pharmacological agent in these studies. 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. To predict the target SU11248 exposure required to achieve antitumor activity in mouse xenograft models, we directly measured target phosphorylation in tumor xenografts before and after SU11248 treatment and correlated this with plasma inhibitor levels. In target modulation studies in vivo, SU11248 selectively inhibited Flk-1/KDR (VEGF receptor 2) and PDGF receptor beta phosphorylation (in a time- and dose-dependent manner) when plasma concentrations of inhibitor reached or exceeded 50-100 ng/ml. Similar results were obtained in a functional assay of VEGF-induced vascular permeability in vivo. Constant inhibition of VEGFR2 and PDGF receptor beta phosphorylation was not required for efficacy; at highly efficacious doses, inhibition was sustained for 12 h of a 24-h dosing interval. The pharmacokinetic/pharmacodynamic relationship established for SU11248 in these preclinical studies has aided in the design, selection, and evaluation of dosing regimens being tested in human trials.

SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo.[Pubmed:12531805]

Blood. 2003 May 1;101(9):3597-605.

FLT3 (fms-related tyrosine kinase/Flk2/Stk-2) is a receptor tyrosine kinase (RTK) primarily expressed on hematopoietic cells. In blasts from acute myelogenous leukemia (AML) patients, 2 classes of FLT3 activating mutations have been identified: internal tandem duplication (ITD) mutations in the juxtamembrane domain (25%-30% of patients) and point mutations in the kinase domain activation loop (7%-8% of patients). FLT3-ITD mutations are the most common molecular defect identified in AML and have been shown to be an independent prognostic factor for decreased survival. FLT3-ITD is therefore an attractive molecular target for therapy. 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. 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. SU11248 inhibits FLT3-driven phosphorylation and induces apoptosis in vitro. In addition, SU11248 inhibits FLT3-induced VEGF production. The in vivo efficacy of SU11248 was investigated in 2 FLT3-ITD models: a subcutaneous tumor xenograft model and a bone marrow engraftment model. We show that SU11248 (20 mg/kg/d) dramatically regresses FLT3-ITD tumors in the subcutaneous tumor xenograft model and prolongs survival in the bone marrow engraftment model. Pharmacokinetic and pharmacodynamic analysis in subcutaneous tumors showed that a single administration of an efficacious drug dose potently inhibits FLT3-ITD phosphorylation for up to 16 hours following a single dose. These results suggest that further exploration of SU11248 activity in AML patients is warranted.

Sunitinib Malate (SU 11248 Malate) is a multi-targeted receptor tyrosine kinase inhibitor with IC50s of 80 nM and 2 nM for VEGFR2 and PDGFRβ, respectively. Sunitinib Malate, an ATP-competitive inhibitor, effectively inhibits autophosphorylation of Ire1α by inhibiting autophosphorylation and consequent RNase activation.

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