Receptor tyrosine kinases (RTK), such as
vascular endothelial growth factor receptor (VEGFR),
platelet-derived growth factor receptor (PDGFR),
stem cell factor receptor (KIT), and
fms-like tyrosine kinase 3 (FLT3), are expressed in malignant tissues and act in concert, playing diverse and major roles in angiogenesis,
tumor growth, and
metastasis. With the exception of a few
malignancies, seemingly driven by a single genetic mutation in a signaling
protein, most
tumors are the product of multiple mutations in multiple aberrant signaling pathways. Consequently, simultaneous targeted inhibition of multiple signaling pathways could be more effective than inhibiting a single pathway in
cancer therapies. Such a multitargeted strategy has recently been validated in a number of preclinical and clinical studies using RTK inhibitors with broad target selectivity.
SU14813, a small molecule identified from the same chemical library used to isolate
sunitinib, has broad-spectrum RTK inhibitory activity through binding to and inhibition of VEGFR, PDGFR, KIT, and FLT3. In cellular assays,
SU14813 inhibited
ligand-dependent and
ligand-independent proliferation, migration, and survival of endothelial cells and/or
tumor cells expressing these targets.
SU14813 inhibited
VEGFR-2,
PDGFR-beta, and FLT3 phosphorylation in xenograft
tumors in a dose- and time-dependent fashion. The plasma concentration required for in vivo target inhibition was estimated to be 100 to 200 ng/mL. Used as monotherapy,
SU14813 exhibited broad and potent antitumor activity resulting in regression, growth arrest, or substantially reduced growth of various established xenografts derived from human or rat tumor cell lines. Treatment in combination with
docetaxel significantly enhanced both the inhibition of primary
tumor growth and the survival of the
tumor-bearing mice compared with administration of either agent alone. In summary,
SU14813 inhibited target RTK activity in vivo in association with reduction in angiogenesis, target RTK-mediated proliferation, and survival of
tumor cells, leading to broad and potent antitumor efficacy. These data support the ongoing phase I clinical evaluation of
SU14813 in advanced
malignancies.