A preclinical review of sunitinib, a multitargeted receptor tyrosine kinase inhibitor with anti-angiogenic and antitumour activities

ArticleinAnnals of Oncology 18 Suppl 10(suppl 10):x3-10 · October 2007with13 Reads
DOI: 10.1093/annonc/mdm408 · Source: PubMed
Abstract
Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor that targets both angiogenic pathways (i.e., vascular endothelial growth factor receptor and platelet-derived growth factor receptor) and direct pro-oncogenic pathways (e.g., stem-cell factor receptor and FMS-like tyrosine kinase-3). Preclinical studies with this agent have indicated that it exhibits robust inhibitory activity against these targets. Clinical trial results have demonstrated the therapeutic potential of this agent and have implicated sunitinib targets in the pathophysiology of malignancies such as renal cell carcinoma and gastrointestinal stromal tumour. This paper reviews the preclinical data supporting the development of this agent and its translation from benchtop to bedside. It also highlights the importance of the multiple pathways that may be involved in cancer progression and the importance of these pathways in selected malignancies.
    • "However, the therapeutic indices of angiogenesis inhibitors are generally limited [2,678. The multi-targeted tyrosine kinase inhibitor (TKI) Sunitinib inhibits a variety of receptor tyrosine kinases (RTKs), including VEGFRs, Platelet-derived growth factor receptors (PDGFRs), c-kit and others, and exhibits potent anti-angiogenesis and anti-tumor growth activities910111213. Sunitinib has been approved by FDA in 2006 for the treatment of renal cell carcinoma (RCC) and Imatinib-resistant gastrointestinal stromal tumors (GISTs) [14,15] . "
    [Show abstract] [Hide abstract] ABSTRACT: Patients have responded well to the multi-targeted tyrosine kinase inhibitor (TKI) Sunitinib in the clinic. But the severe toxic side effects associated with Sunitinib limit its therapeutic index. To improve the therapeutic index of Sunitinib, a prodrug strategy was employed to modify Sunitinib. The inactive prodrug AST-003 can be converted to Sunitinib in vitro and in vivo. Compared with Sunitinib, AST-003 has unique biochemical, cellular and pharmacokinetic properties with improved tolerability in mice and yield higher efficacy in tumor xenograft models. This prodrug strategy may constitute a novel paradigm to improve the therapeutic index of Sunitinib and other TKI or anti-angiogenesis drugs in general.
    Full-text · Article · Oct 2015
    • "The RET tyrosine kinase becomes activated by this rearrangement, leading to constitutively activated MAPK signaling and tumorigenesis in thyroid cells [4]. Sunitinib, a multitargeted receptor tyrosine kinase inhibitor, acts as an inhibitor of RET and exhibits some efficacy in these tumor types [53]. Chromosomal rearrangements involving neurotrophic tyrosine receptor kinases (NTRKs) can also occur in thyroid carcinomas and are known as TRK rearrangements. "
    [Show abstract] [Hide abstract] ABSTRACT: Thyroid cancer is an endocrine malignancy with an incidence rate that has been increasing steadily over the past 30 years. While well-differentiated subtypes have a favorable prognosis when treated with surgical resection and radioiodine, undifferentiated subtypes, such as anaplastic thyroid cancer (ATC), are far more aggressive and have a poor prognosis. Conventional therapies (surgical resection, radiation, chemotherapy, and radioiodine) have been utilized for treatment of ATC, yet these treatments have not significantly improved the overall mortality rate. As cancer is a genetic disease, genetic alterations such as mutations, fusions, activation of oncogenes, and silencing of tumor suppressors contribute to its aggressiveness. With the use of next-generation sequencing and the Cancer Genome Atlas, mutation-directed therapy is recognized as the upcoming standard of care. In this review, we highlight the known genetic landscape of ATC and the need for a comprehensive genetic characterization of this disease in order to identify additional therapeutic targets to improve patient outcomes.
    Full-text · Article · Sep 2014
    • "Meanwhile, the indirect inhibitors of angiogenesis interfere in the pro-angiogenic communication between the tumor cells and the endothelial cells (Folkman et al., 1998). SU5416 is a tyrosine kinase lipophilic synthetic inhibitor (TKI), indirect inhibitor of angiogenesis that blocks the phosphorylation of VEGF receptor, and has potent antiangiogenic properties in preclinical studies (Fong et al., 1999; Abdollahi et al., 2003; Christensen, 2007). On the other hand, the TNP-470 direct angiogenesis inhibitor, a fumagillin analog , has a potent cytostatic action in endothelial cells and also significant antitumor properties (Masiero et al., 1997; Folkman, 2005). "
    [Show abstract] [Hide abstract] ABSTRACT: The aim of this study was to evaluate the structural and molecular effects of antiangiogenic therapies and finasteride on the ventral prostate of senile mice. 90 male FVB mice were divided into: Young (18weeks old) and Senile (52weeks old) groups; Finasteride group: Finasteride (20mg/kg); SU5416 group: SU5416 (6mg/kg); TNP-470 group: TNP-470 (15mg/kg,) and SU5416+TNP-470 group: similar to the SU5416 and TNP-470 groups. After 21days, prostate ventral lobes were collected for morphological, immunohistochemical and Western Blotting analyses. The results demonstrated atrophy, occasional proliferative lesions and inflammatory cells in the prostate during senescence, which were interrupted and/or blocked by treatment with antiangiogenic drugs and finasteride. Decreased AR and Endostatin reactivities, and an increase for ER-α, ER-β and VEGF were seen in the senile group. Decreased VEGF and ER-α reactivities and increased ER-β reactivity were verified in the finasteride, SU5416 groups and especially in SU5416+TNP-470 group. The TNP-470 group showed reduced AR and ER-β protein levels. The senescence favored the occurrence of structural and/or molecular alterations suggesting the onset of malignant lesions, due to the imbalance in the signaling between the epithelium and stroma. The SU5416+TNP-470 treatment was more effective in maintaining the structural, hormonal and angiogenic factor balance in the prostate during senescence, highlighting the signaling of antiproliferation via ER-β.
    Full-text · Article · May 2014
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