Angiogenesis Inhibitors: Current Strategies and Future Prospects

Abstract/Full free access (chapters): 

Introduction
Inhibition of Angiogenesis for Anticancer Purposes 
Process of Carcinogenesis and Subsequent Tumor Angiogenesis
Angiopoietins and TIE Receptors
Delta/Jagged-Notch Signaling
HIF
Antiangiogenesis Compounds
Inhibitors of Growth Factors, RTKs, and Signaling Pathways
Monoclonal Antibodies Directed at EGFRPI3K/AKT/mTOR Pathway Inhibitors
MAPK-Farnesyltransferase Rho and Ras InhibitorsHIF Pathways and Binding...
Known and Potential Side Effects From the Inhibition of AngiogenesisConclusions
References

Conclusions:
The complex molecular pathways that govern tumor angiogenesis are logical targets for pharmacological manipulation given the important role they play in the growth and development of cancers.
Initial trials of putative antiangiogenesis inhibitors have shown some promise in cancer, although this has not always translated to the clinic. A lack of validated biomarkers and patient screening restricts our ability to tailor specific drugs to patient cohorts, and might be viewed as one of the largest barriers to success in angiogenesis inhibition. As cancer pharmacology moves away from cytotoxic to so-called molecularly targeted drugs that are expected to have minimal side effects and toxicity, predictive biomarkers could be used to screen for patients likely to demonstrate a clinical response. Biomarkers also need to be validated for use as objective response measurements, because antiangiogenic monotherapies may only act as cytostatic agents, making objective response measurements such as tumor shrinkage less useful for determining the efficacy of a drug. The long time period required for an observable response also demonstrates the need for a rapid biomarker so that response to a treatment can be measured. Although some clinical trials have demonstrated that particular surrogate biomarkers of angiogenesis, such as circulating VEGF and microvessel density, have value as prognostic markers, more validated biomarkers need to be found so that antiangiogenic agents can be properly used and evaluated in the clinic.203,204

The end goals of antiangiogenesis inhibitors also need to be determined. It is still not understood whether angiogenesis inhibitors will eliminate or shrink tumors or simply inhibit further growth and spread. If angiogenesis inhibitors are used as cytostatic agents, then further studies are needed to examine the effect of vessel normalization, whereby the tumor vessels become more organized and blood flow is improved, and whether improved tumor delivery of chemotherapeutics could be achieved. This means more studies using combination therapies with angiogenesis inhibitors and determining whether angiogenesis inhibitors are more effective in combination with chemotherapy or as single agents. In vitro studies have found that combination with traditional chemotherapies and/or radiotherapy increases the antitumor efficacy of kinase inhibitors,149 and this appears to be true with many of the antiangiogenesis inhibitors.205 It is also believed that combination therapies could be used to provide maximum antitumor effect and minimal side effects if a lower dose of each drug were to be used. Treatments could be tailored to target the specific altered pathways in a tumor with a combination of drugs to minimize resistance and provide a more effective combined treatment. Future clinical studies may provide the information needed to find the best combination of treatments for maximum anticancer effect and minimal side effects.

The research within the past decade has led to major advances in understanding the molecular pathways involved in tumor angiogenesis. This basic research has led to the identification of new targets associated with angiogenesis, leading to the development of an extensive number of preclinical, antiangiogenesis agents. Ongoing studies of different approaches currently are evaluating some of the molecular targets and agents, with some even in clinical trials, and data regarding efficacy and safety are currently emerging.