Sunitinib: From rational design to clinical efficacy

Laura QM Chow, S Gail Eckhardt

Research output: Contribution to journalReview article

662 Citations (Scopus)

Abstract

Sunitinib (SU011248) is an oral small molecular tyrosine kinase inhibitor that exhibits potent antiangiogenic and antitumor activity. Tyrosine kinase inhibitors such as SU6668 and SU5416 (semaxanib) demonstrated poor pharmacologic properties and limited efficacy; therefore, sunitinib was rationally designed and chosen for its high bioavailability and its nanomolar-range potency against the antiangiogenic receptor tyrosine kinases (RTKs) - vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). Sunitinib inhibits other tyrosine kinases including, KIT, FLT3, colony-stimulating factor 1 (CSF-1), and RET, which are involved in a number of malignancies including small-cell lung cancer, GI stromal tumors (GISTs), breast cancer, acute myelogenous leukemia, multiple endocrine neoplasia types 2A and 2B, and familial medullary thyroid carcinoma. Sunitinib demonstrated robust antitumor activity in preclinical studies resulting not only in tumor growth inhibition, but tumor regression in models of colon cancer, non-small-cell lung cancer, melanoma, renal carcinoma, and squamous cell carcinoma, which were associated with inhibition of VEGFR and PDGFR phosphorylation. Clinical activity was demonstrated in neuroendocrine, colon, and breast cancers in phase II studies, whereas definitive efficacy has been demonstrated in advanced renal cell carcinoma and in imatinib-refractory GISTs, leading to US Food and Drug Administration approval of sunitinib for treatment of these two diseases. Studies investigating sunitinib alone in various tumor types and in combination with chemotherapy are ongoing. The clinical benchmarking of this small-molecule inhibitor of members of the split-kinase domain family of RTKs will lead to additional insights regarding the biology, potential biomarkers, and clinical utility of agents that target multiple signaling pathways in tumor, stromal, and endothelial compartments.

Original languageEnglish (US)
Pages (from-to)884-896
Number of pages13
JournalJournal of Clinical Oncology
Volume25
Issue number7
DOIs
StatePublished - Mar 1 2007

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Neoplasms
Protein-Tyrosine Kinases
Platelet-Derived Growth Factor Receptors
Vascular Endothelial Growth Factor Receptor
Receptor Protein-Tyrosine Kinases
Colonic Neoplasms
Multiple Endocrine Neoplasia Type 2b
Multiple Endocrine Neoplasia Type 2a
Breast Neoplasms
Drug Approval
Benchmarking
Macrophage Colony-Stimulating Factor
Small Cell Lung Carcinoma
sunitinib
Combination Drug Therapy
Renal Cell Carcinoma
Acute Myeloid Leukemia
Non-Small Cell Lung Carcinoma
Biological Availability
Squamous Cell Carcinoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Sunitinib : From rational design to clinical efficacy. / Chow, Laura QM; Eckhardt, S Gail.

In: Journal of Clinical Oncology, Vol. 25, No. 7, 01.03.2007, p. 884-896.

Research output: Contribution to journalReview article

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