Angiogenesis & Therapeutic Targets In Cancer

Angiogenesis is the development of new blood vessels from preexisting vasculature. The angiogenic process is controlled by the net balance between molecules with positive and negative regulatory activity. In the past three decades, the understanding of the fundamental role of angiogenesis in tumor growth, progression and metastasis has led to tremendous interest in research regarding its regulatory mechanisms and clinical implications in the management of cancer patients. Different antiangiogenic strategies, predominantly acting through inhibition of the vascular endothelial growth factor pathway have been evaluated for the treatment of various types of cancer. A plethora of angiogenesis inhibitors are currently subjected to clinical trials as monotherapy or in combination with conventional chemotherapy while few of them have been approved for clinical use in cancer therapy.

Angiogenesis is now a proven therapeutic cancer target. Approaches targeting the vascular endothelial growth factor and receptor (VEGF/VEGFR) axis have yielded success in gastrointestinal cancers. Bevacizumab is a humanized recombinant monoclonal antibody against VEGF and is the first antiangiogenic drug to enter clinical practice. Bevacizumab was approved for the treatment of advanced colorectal cancer by US FDA in 2004 in combination with fluorouracilbased chemotherapy. Hepatocellular carcinoma (HCC) is the next gastrointestinal cancer where angiogenesis proved to be of therapeutic importance. Sorafenib is a multi-kinase inhibitor of VEGFRs and Raf protein, and demonstrated anticancer effects in a subgroup of HCC patients. There are currently a number of antiangiogenic agents targeting the VEGF/VEGFR axis, which can be broadly categorized as monoclonal antibodies and tyrosine kinase inhibitors. These agents are being evaluated in a number of gastrointestinal cancers.

Breast cancer, a worldwide epidemic, remains the second leading cause of cancerrelated death in women in the USA. High priority should be given to research aimed at the identification and development of natural agents that prevent and control breast cancer. Angiogenesis, the formation of new capillaries from preexisting blood vessels, is a key component in breast tumor insurgence. There are multiple biochemical and molecular steps involved in breast tumor angiogenesis and each step provides a challenge and opportunity for therapeutic intervention. A wealth of evidence links dietary habits with risk and behavior of breast cancer. Several food constituents have been shown to possess potent growth inhibitory effects on breast cancer cells in vitro and preventive or suppressive action on mammary gland cancer in vivo, supporting numerous epidemiological findings. Inhibition of angiogenesis appears to be a common and novel mechanism for these food-derived agents. This chapter highlights the role of angiogenesis in breast cancer and how chemically diverse dietary agents prevent or treat breast cancer by targeting various components of angiogenesis. The benefits, challenges and future directions in the use of antiangiogenic dietary compounds in the prevention and intervention of breast cancer are also discussed.

Angiogenesis plays an essential role in tumor growth, invasion, and metastasis. Angiogenesis inhibition has been proposed as a general strategy to fight cancer. The initial pessimism about the usefulness of the antiangiogenic therapeutic approach for cancer, turned out into an increasing interest in the development of antiangiogenic compounds after the first approval of an antiangiogenic therapy in 2004. The formation of new blood vessels is a complex multi-step process, including endothelial cells activation by the angiogenic signal and their stimulation to synthesize and release degradative enzymes allowing them to migrate, proliferate and finally differentiate to give rise to capillary tubules. The discovery and pharmacological development of future generations of angiogenesis inhibitors will benefit from further advances in the understanding of the mechanisms involved in human angiogenesis. In this chapter, the different therapeutic targets for angiogenesis intervention are discussed with emphasis on the clinical developmental status of antiangiogenic drugs.

Mechanism of angiogenesis and its management in breast cancer disease has been discussed in this chapter. This review specifically describes on the targetted molecular markers for development of antiangiogenic therapy like anti VEGF therapy and suitable agents that target the receptors of VEGF like VEGFR. These are essentially tyrosine kinase inhibitors which block downstream signaling pathways instead of binding to VEGF directly. Block of VEGF production in clinical development that target the EGFR include agents like cetuximab, gefitinib and erlotinib. Other drugs which may be of interest including cyclooxygenase 2 inhibitors and MMP inhibitors find clinical application as angiogenic inhibitors. Tumor associates macrophage which acts as conductor of angiogenesis and notch signaling getting involved in cell proliferation, differentiation and apoptosis are also a target of therapy. Combination of antiangiogenic drugs with one another and with other biological agent is also being explored to improve efficacy and to overcome the drug resistance.

This review focuses on altered signaling pathways in schwannoma and identification of molecular markers. Platelet derived growth factors PDGFR and ErbB family of receptor kinase are overexpressed in the schwannoma. PDGFR-β inhibitors with a specific inhibitor AG1296 completely inhibited both basal and PDGF mediated proliferation of human scwannoma cells. Sorafenib, a PDGFR inhibitor currently applied for advanced renal cancer treatment also effectively reducing tyrosine kinase activity and decreased cell proliferation in human schwannoma cells at low concentration. This suggests that this drug could be a promising tool in the treatment of schwannoma.

Pathological angiogenesis, a hallmark of cancer, is a rational target for the treatment of lung cancer which is the most lethal cancer worldwide. In this article we reviewed angiogenesis targets that have potential applications for lung cancer treatment, including endogenous angiogenesis inhibitors and molecules in proangiogenic signaling. With an ever-growing list of angiogenesis activators and inhibitors, a better understanding of the molecular basis of angiogenesis offers various targets for antiangiogenic cancer therapy. A number of therapeutic strategies, including gene therapy approaches, have been explored in preclinical models with direct and indirect angiogenesis inhibitors. Gene therapy approaches with emphasis on viral vectors for lung cancer are discussed here. Recent advances in clinical application in lung cancer treatment with antiangiogenic therapy are also reviewed. Some small molecule inhibitors have given hope to lung cancer patients in clinical trials, these are also described. In this article, we aim to bridge the gap between basic science understanding of angiogenesis mechanisms and clinical applications of our current knowledge in lung cancer treatment.

Gastric cancer is a leading cause of cancer-related deaths worldwide. Despite recent improvements in surgical techniques, as well as in adjuvant and neoadjuvant treatment strategies, involving chemotherapy and radiotherapy, gastric cancer remains a therapeutic challenge. Due to the rapid occurrence of systemic metastasis, advanced gastric cancer is associated with a poor prognosis. However, progresses in defining molecular biology and carcinogenesis have recently led to a successful development of molecular targeting agents that substantially may improve survival and quality of life for many cancer patients. Regarding gastric cancer, various molecular pathways and signaling components have been identified that promote angiogenesis, metastasis, and cell growth, hence offering multiple targets for therapeutic intervention with new targeting agents. Such molecular targeting agents are currently being developed and clinically evaluated.

In this chapter we describe the current status of targeted therapies for treatment of gastric cancer, particularly focusing on antiangiogenic treatment strategies. Moreover, other novel agents including EGFR inhibitors, promoters of apoptosis, cell cycle inhibitors and matrix metalloproteinase inhibitors will be discussed. Encouraging results from clinical trials evaluating these compounds have provided novel opportunities in the therapy of gastric malignancies that will probably help to significantly improve the prognosis of gastric cancer patients in the near future.

Angiogenesis is one of the key rate limiting factors in tumor growth. The concept of antiangiogenic therapy was first considered over 50 years ago but the first antiangiogenic therapy for breast cancer was only given regulatory status in 2008. A large number, and diverse range, of therapeutic agents are, however, currently in development for use in breast cancer with results suggesting great promise. Some of these agents directly target molecules in the angiogenic cascade and others have secondary antiangiogenic effects as a consequence of inhibition of target molecules that are not directly involved in the angiogenic process. Here some of the agents currently under development are discussed together with other, currently hypothetical, targets.

The human bone marrow microenvironment (HBMM) plays a crucial role in the pathogenesis, growth, survival and drug resistance of multiple myeloma (MM) cells. The growing number of information about the HBMM in MM has allowed the definition of a new paradigm and the design of novel approaches against this disease, taking in account the need to target not only tumor cells but also the non-tumor compartment. Novel drugs such as thalidomide, lenalidomide or bortezomib are one example of these new strategies and have already been included in clinics. However, the lack of adequate experimental models for the study of both compartments has significantly limited the identification of new targets as well as a wide screening of several new investigational drugs. Therefore, novel preclinical models recapitulating the HBMM together with genomic studies might provide new insights into mechanisms of new drugs and their molecular targets.

Renal cell carcinoma (RCC) is diagnosed in approximately 170,000 patients worldwide annually, resulting in 82,000 deaths. The 5-year survival rate for metastatic RCC (mRCC) is < 10% and up to 30% of patients treated with radical nephrectomy are at risk of relapse. Cytokine therapy, such as interferon-a (INF-a) and interleukin-2 (IL-2), has been the standard of therapy for mRCC for many years. Recently, the better understanding of the molecular pathogenesis of RCC has led to the development of a number of new targeted drugs, particularly anti-VEGF (vascular endothelial growth factor) drugs and mammalian target of rapamycin (mTOR) inhibitors that have been approved for the treatment of advanced disease, and many other compounds are undergoing preclinical or early clinical evaluation.

However, several questions remain to be addressed, including: The identification of the optimal methodological approach in the clinical development of these new agents and of the best clinical setting to evaluate them, the identification of the optimal schedule of treatment and of surrogate predictive markers of activity that could lead to a better selection of patients, the evaluation of these agents in other histological subtypes, particularly papillary and chromophobe RCC, and finally, the management of new emerging toxicity.

The development of antiangiogenic compounds for the treatment of cancer has indicated a need for new clinical tools to evaluate their efficacy, to assess the optimal dose with minimal side-effects and to early select patients who might benefit from antiangiogenic therapies. The use of so-called surrogate biomarkers of angiogenesis and antiangiogenic drug activity in the clinic does not yet belong to the standard of care. Most research has been dedicated towards introduction and refining of imaging techniques, the detection of circulating angiogenic factors and/or related molecules, and characterization and measurement of circulating endothelial cells and early progenitor cells. This chapter will discuss the various possibilities and their limitations illustrated with clinical data on antiangiogenic therapies in cancer patients.

A number of reports implicated targeting TGF-a as a promising therapeutic target for the treatment of many types of cancer including prostate cancer. This cytokine not only have the ability to suppress cancer cell growth and proliferation during the early stage of cancer but to promote tumor progression and metastasis during the advance stage of disease. The elucidation of mechanism responsible for the TGF-a switch for a tumor suppressor to tumor promoting cytokine is critical for implementation of TGF-a as a promising therapeutic target for advanced stage of cancer towards tumor progression and metastasis.