Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 May 17:4:16.
doi: 10.1038/s41392-019-0049-6. eCollection 2019.

Pazopanib in advanced soft tissue sarcomas

Alex T J Lee  1   2 , Robin L Jones #  2   3 , Paul H Huang #  1
Affiliations
Review

Pazopanib in advanced soft tissue sarcomas

Alex T J Lee et al. Signal Transduct Target Ther. .

Abstract

Pazopanib is the first and only tyrosine kinase inhibitor currently approved for the treatment of multiple histological subtypes of soft tissue sarcoma (STS). Initially developed as a small molecule inhibitor of vascular endothelial growth factor receptors, preclinical work indicates that pazopanib exerts an anticancer effect through the inhibition of both angiogenic and oncogenic signaling pathways. Following the establishment of optimal dosing and safety profiles in early phase studies and approval for the treatment of advanced renal cell carcinoma, pazopanib was investigated in STS. A landmark phase III randomized study demonstrated improved progression-free survival with pazopanib compared to that with placebo in pretreated patients with STS of various subtypes. The efficacy of pazopanib in specific STS subtypes has been further described in real-world-based case series in both mixed and subtype-specific STS cohorts. At present, there are no clinically validated predictive biomarkers for use in selecting patients with advanced STS for pazopanib therapy, limiting the clinical effectiveness and cost-effectiveness of the drug. In this review, we summarize the preclinical and clinical data for pazopanib, outline the evidence base for its effect in STS and explore reported studies that have investigated putative biomarkers.

Keywords: Cancer therapy; Sarcoma.

PubMed Disclaimer

Conflict of interest statement

Competing interestsA.T.J.L., P.H.H., and R.L.J. are coinventors on a patent application regarding materials and methods for stratifying and treating cancers. R.L.J. has received compensation from Eisai, PharmaMar, Merck, ZIOPHARM and Morphotek for service as a consultant.

Figures

Fig. 1
Fig. 1
Kinase inhibitory profile of pazopanib. The bar graph indicates the kinase inhibitory concentration (IC50—drug concentration at which 50% of the target enzymatic activity is inhibited in a cell-free kinase assay) of pazopanib, as reported by Kumar et al. Involvement of kinases in canonical oncogenic processes/pathways is indicated in the table on the left (GO.0001525—angiogenesis; GO.0043410—positive regulation of MAPK cascade; GO.0014068—positive regulation of phosphatidylinositol 3-kinase signaling; GO:0046427—positive regulation of the JAK-STAT cascade; GO.0045740—positive regulation of DNA replication)
See this image and copyright information in PMC

References

    1. Kitagawa D, et al. Activity-based kinase profiling of approved tyrosine kinase inhibitors. Genes Cells. 2013;18:110–122. doi: 10.1111/gtc.12022. - DOI - PubMed
    1. Ku X, Heinzlmeir S, Helm D, Médard G, Kuster B. New affinity probe targeting VEGF receptors for kinase inhibitor selectivity profiling by chemical proteomics. J. Proteome Res. 2014;13:2445–2452. doi: 10.1021/pr401247t. - DOI - PubMed
    1. Kumar R, et al. Pharmacokinetic–pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol. Cancer Ther. 2007;6:2012–2021. doi: 10.1158/1535-7163.MCT-07-0193. - DOI - PubMed
    1. Noujaim J, Payne LS, Judson I, Jones RL, Huang PH. Phosphoproteomics in translational research: a sarcoma perspective. Ann. Oncol. 2016;27:787–794. doi: 10.1093/annonc/mdw030. - DOI - PubMed
    1. Podar K, et al. The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma. Proc. Natl Acad. Sci. USA. 2006;103:19478–19483. doi: 10.1073/pnas.0609329103. - DOI - PMC - PubMed

Publication types