Translation of Pro-Angiogenic and Anti-Angiogenic Therapies into Clinical Use - Mechanical and Chemical Signaling in Angiogenesis - page 266

Fig. 4 Chemical structures
of receptor tyrosine kinase
inhibitors. a Sunitinib.
b Sorafenib
cannot provide lasting clinical responses. In fact, anti-angiogenic therapy can lead
to heightened invasiveness and increased metastasis of tumors [ 72 ]. Indeed, a
subset of glioblastoma patients experienced recurrence with more infiltrative
tumors following treatment with bevacizumab [ 73 ].
4.4 Next-Generation Anti-Angiogenic Agents
A second-generation of anti-angiogenic therapies, the receptor tyrosine kinase
inhibitor class, is currently under development (Fig. 4 ). Unlike bevacizumab, these
drugs are small molecules that inhibit multiple targets; the newer agents can thus
be used as monotherapy for cancer. For example, sunitinib is a receptor tyrosine
kinase inhibitor that blocks signaling through VEGF receptors and PDGF
receptors; sunitib also targets other tyrosine kinases including, KIT, FLT3, colony-
stimulating factor 1 (CSF-1), and RET, which are involved in several different
malignancies [ 74 ]. Sunitinib has been shown to prolong progression-free survival
for renal cell cancer. A multi-center randomized phase III clinical trial was
conducted in 750 patients with previously untreated metastatic renal cell carci-
noma; patients were randomized to receive either sunitinib or interferon alfa [ 75 ].
Sunitinib increased progression-free survival by a median time of 6 months as
compared to interferon alfa. Sunitinib also demonstrates efficacy for gastrointes-
tinal stromal tumors. A clinical trial was performed in 312 patients with
unresectable gastrointestinal stromal tumors after failure of imatinib therapy;
patients were randomized to receive either sunitinib or placebo [ 76 ]. Sunitinib
significantly increased the time to tumor progression by more than 20 weeks. The
first drug to simultaneously receive FDA approval for two different cancers,
sunitinib is now FDA-approved for metastatic renal cell carcinoma and imatinib-
resistant gastrointestinal stromal tumor [ 77 ].
Sorafenib is another second-generation anti-angiogenic agent; this receptor
tyrosine kinase inhibitor blocks signaling through VEGF receptors, PDGF receptors,