Translation of Pro-Angiogenic and Anti-Angiogenic Therapies into Clinical Use - Mechanical and Chemical Signaling in Angiogenesis - page 267

and Raf [ 78 ]. Sorafenib has been shown to increase progression-free survival in renal
cancer. A randomized, double-blind, placebo-controlled phase III clinical trial was
conducted in 903 patients with advanced renal cell carcinoma that was resistant to
standard therapy; patients were randomly assigned to receive either sorafenib or
placebo [ 79 ]. Sorafenib was associated with an increase of 2.7 months in progres-
sion-free survival; however, sorafenib therapy was also associated with increased
toxic effects, including hypertension and cardiac ischemia. Sorafenib has demon-
strated definite efficacy for hepatocellular carcinoma, prolonging overall survival.
A multi-center randomized, double-blind, placebo-controlled phase III clinical trial
was conducted in 602 patients with advanced hepatocellular carcinoma who had not
received previous systemic treatment; patients were randomized to receive either
sorafenib or placebo [ 80 ]. Sorafenib therapy increased overall survival by a median
time of nearly 3 months. Sorafenib is now FDA-approved for treatment of advanced
renal cell carcinoma and advanced hepatocellular carcinoma.
Next-generation anti-angiogenic agents such as sunitinib and sorafenib do exhibit
better efficacy than bevacizumab against certain forms of cancer, and these newer
agents do target multiple angiogenic pathways. Yet, the newer drugs still have serious
limitations; the receptor tyrosine kinase inhibitors have not proven to reduce tumor size
or lengthen overall survival time in many types of cancer [ 81 ]. As with bevacizumab
therapy, treatment with receptor tyrosine kinase inhibitors is characterized by an initial
increase in progression-free survival, but there are few significant advantages for
overall survival rate compared to patients not receiving the drug [ 82 ]. Indeed, the
receptor tyrosine kinase inhibitor sunitinib has been shown to accelerate metastatic
tumor growth and decrease overall survival in experimental metastasis models [ 83 ], as
tumor cells metastasize to distant sites in search of oxygen and nutrients [ 84 ].
The tumor microenvironment, as well as the heterogeneity of endothelial cells and
tumor cells, may contribute to tumor resistance to anti-angiogenic drugs [ 85 ]. Increased
molecular and cellular characterization of tumor pathology may enable more effica-
cious anti-angiogenic therapies. In addition, feedback pathways and compensatory
pathways influence tumor responses to therapy. The metabolic and signaling pathways
that regulate tumor growth must therefore be elucidated. Finally, the pharmacokinetics
of anti-angiogenic agents must be optimized. Maximal anti-angiogenic therapy requires
prolonged exposures of tumor cells to anti-angiogenic drugs; it is more important to
achieve a sustained optimal biological dose, rather than a maximal tolerated dose [ 86 ].
Novel drug delivery systems, which allow controlled release of anti-angiogenic
therapeutics over extended time periods, could potentially boost clinical responses.
5 Conclusion and Future Research Directions
Because all living structures require an adequate oxygen supply to maintain
viability, angiogenesis is a central process that determines the survival of cells,
tissues, organs, and ultimately human beings. The modulation of angiogenesis is
an emerging approach for attacking myriad chronic diseases. Pro-angiogenic