**12. Conclusion**

Tumour vascularisation is modulated by the complex interplay of several endogenous factors and processes that can be up-regulated or downregulated, depending on the tumour microenvironment and the treatment pressures that are imposed on it. A multitude of studies have shown that the majority of solid tumours exhibit an overexpression of VEGF, one of the key drivers of sprouting angiogenesis. As a result, various anti-angiogenic therapies targeting VEGF or VEGFR have now been developed and are used conventionally in the clinic. Compellingly, recent pre-clinical and clinical studies using anti-angiogenic agents in combination with immunotherapies (e.g. ICI's), have demonstrated a synergistic effect in reducing tumour growth. This highlights that there is promise, not only in incorporating anti-angiogenic therapy in the management of most cancers, but also in combining such agents with immunomodulatory agents.

However, as is the case with many cancer treatments, drug resistance can limit the efficacy of these agents. Trials of VEGF-targeted therapies in advanced malignancies have not consistently demonstrated beneficial outcomes in terms of tumour response and survival. Importantly, only a proportion of patients benefit from anti-angiogenic therapy, control of tumour growth is generally transient, there remains significant risk for therapeutic toxicity and we are still challenged by the burden of health costs.

Limited clinical outcomes with anti-angiogenic therapies are felt to be driven by either intrinsic or acquired resistance mechanisms, and several of these have now been proposed. In this chapter, we have reviewed the most commonly used antiangiogenic agents in the clinic and have highlighted the spectrum of mechanisms

**61**

**Author details**

Victoria, Australia

Sophia Frentzas1,2\*, Caroline Lum1

provided the original work is properly cited.

peutic resistance over time.

and Ting-Yu Chen3

1 Department of Medical Oncology, Monash Health, Clayton, Victoria, Australia

3 Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Department of Oncology, Monash University, Clayton, Victoria, Australia

\*Address all correspondence to: sophia.frentzas@monash.edu

*Angiogenesis and Its Role in the Tumour Microenvironment: A Target for Cancer Therapy*

that may be involved in therapeutic resistance. However, despite the plethora of pre-clinical and clinical studies that have been undertaken, these mechanisms are yet to be entirely elucidated. Importantly, the clinically relevant mechanisms that mediate such resistance to anti-angiogenic therapy are poorly understood and we still do not have means to select patients who will benefit from these agents. Furthermore, there has been a rapid expansion in the development of multiple next generation anti-vascular agents, but there is still little clarity regarding important

The data supporting the role of candidate biomarkers for response and resistance to anti-angiogenic therapies thus far have been generated from basic research, retrospective studies and limited prospective correlative studies. As such there remains a crucial need for substantial research of clinically relevant predictive biomarkers with the use of large, prospective randomised trials. This could also provide a platform for longitudinal and frequent biospecimen collection in order to further interrogate the mechanisms involved in tumour vascularisation and thera-

*DOI: http://dx.doi.org/10.5772/intechopen.89667*

biological pathways that may affect their efficacy.

#### *Angiogenesis and Its Role in the Tumour Microenvironment: A Target for Cancer Therapy DOI: http://dx.doi.org/10.5772/intechopen.89667*

that may be involved in therapeutic resistance. However, despite the plethora of pre-clinical and clinical studies that have been undertaken, these mechanisms are yet to be entirely elucidated. Importantly, the clinically relevant mechanisms that mediate such resistance to anti-angiogenic therapy are poorly understood and we still do not have means to select patients who will benefit from these agents. Furthermore, there has been a rapid expansion in the development of multiple next generation anti-vascular agents, but there is still little clarity regarding important biological pathways that may affect their efficacy.

The data supporting the role of candidate biomarkers for response and resistance to anti-angiogenic therapies thus far have been generated from basic research, retrospective studies and limited prospective correlative studies. As such there remains a crucial need for substantial research of clinically relevant predictive biomarkers with the use of large, prospective randomised trials. This could also provide a platform for longitudinal and frequent biospecimen collection in order to further interrogate the mechanisms involved in tumour vascularisation and therapeutic resistance over time.
