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Emerging Class of Cancer Therapy Agents
An emerging class of anticancer drugs known as vascular – disrupting agents (VDAs) have been developed through preclinical and clinical trials that function to selectively target the formed blood vessel network on the tumour to cause tumour necrosis.
by Deborah Seah

Formation of a blood vessel network is essential for a solid tumour of approximately 1mm3 or larger for growth and survival. The vasculature will provide a transport system for tumour cells to receive oxygen and nutrients as well as removal of waste products from cell metabolism. The structural differences in tumour blood vessels compared to normal adult tissue vasculature makes it a promising target of interest for selective anticancer therapy.

In this article, it will discuss various types of VDAs and their function in anticancer therapy, and also their use in combination with other therapies. This article will also cover any toxicities and side effects discovered through current preclinical and clinical trials on VDAs.

Characteristics of tumour blood vessels that are exploitable for anticancer therapy

Blood vessel formation in tumours differ from normal adult tissue in both physical structure and functionality. Vasculature in normal adult tissue are relatively stable and have well defined structure. In contrast, tumour blood vessel network formation is unable to keep up with the rapid cell growth and metabolism of the solid tumour and thus, have an abnormal structure due to the imbalanced overexpression of growth factors by the tumour cells. Structural abnormalities of tumour blood vessel network include thin vessel walls, disorganized, and abnormal basement membrane coupled with increased permeability compared to normal adult tissue blood vessel network. These structural differences make targeting the tumour established vasculature a viable selective anticancer therapeutic target.

Currently, antiangiogenic drugs and VDAs are two ways used to target the tumour vasculature for tumour necrosis. However, antiangiogenic therapy mainly targets the process of angiogenesis and requires long term administration to the patient. Whereas for VDAs, they are required in smaller and short-term doses, and they target already established tumour blood vessels through various mechanisms of action to cause tumour ischemia and necrosis. This article will focus on VDAs, discussing their mechanism of action, combination therapies, and side effects.

Current VDAs and their mechanism of action

VDAs are divided into two main groups; biologics or ligand – directed VDAs and small – molecule VDAs. Both groups adopt different mechanism of action to disrupt the tumour vasculature.

Ligand – directed VDAs makes use of the binding of an antibody or a peptide to a target effector molecule usually found on the endothelial cells of the tumour. This binding can induce thrombosis that will result in tumour cell ischemia and necrosis as a result of blocked tumour blood vessels. At present, one such VDA is bavituximab, that specifically targets a monoclonal antibody against anti – phosphatidylserine which has a role in anticancer therapy. Bavituximab has shown encouraging results from preclinical and 14 phase I-II clinical trials.

Flavonoids cause tumour necrosis through the induced production of tumour necrosis factor – alpha (TNF – α) that will result in the activation of the cell apoptosis pathway in tumour blood vessel endothelial cells. Some flavonoids which are in their clinical trial phase for non – small cell lung cancer include DMXAA, AS1404, ASA404. They have shown to be associated with the production of cytokines and chemokines which will disrupt the cellular integrity of the tumour vascular endothelial cells, resulting in tumour cell ischemia and necrosis.

Another class of VDAs are small – molecule VDAs. This group is further divided into two more subgroups; flavonoids and tubulin – binding agents.

Another subgroup of small – molecule VDAs are tubulin – binding agents. As the name suggests they selectively target tumour vascular endothelial cell destruction through targeting the tubulin that results in depolymerization of microtubules. One of which is called disodium combretastatin A-4 3-O-phosphate (CA4P) that targets the endothelial cell cytoskeleton through microtubule depolymerization. Thus, resulting in rapid tumour blood vessel disruption and drop in tumour blood flow, leading to tumour ischemia and necrosis.

Some VDAs and their mechanism of action as well as their stage of development are shown in table 1.

Tumour resistance to VDAs

A common challenge of VDAs faced during their clinical trials is the presence of tumour resistance. This is the result of VDAs destroying the main bulk of the tumour except the outer rim. Thus, leaving a residual ring of viable tumour cells that can cause a relapse in tumour growth. A research done by Kanthou and Tozer published in 2009, on microtubule depolymerizing VDAs showed that despite the substantial tumour necrosis, the VDAs are still unable to fully prevent further tumour growth. This was attributed to the left-over outer cells of the tumour that was able to regenerate.

Anticancer combination therapy with VDAs to overcome tumour resistance

Research has found a few methods to overcome tumour resistance to VDAs, making them effective anticancer therapies. Some strategies include the use of combination therapies together with VDAs. Combining other present therapies such as antiangiogenic agents, chemotherapy, radiotherapy, and radioimmunotherapy has shown to be effective in the full necrosis of solid tumours. Recent preclinical studies have also made use of other unique techniques such as using a pericyte – targeting prodrug that will selectively destroy the cytoskeleton of tumour cells in the core and the periphery of the tumour. A study conducted on xenografts showed promising results using the prodrug together with VDAs as a potential strategy to eradicate the residual viable rim of tumour cells.

VDA toxicities and common side effects

Although an attractive strategy for antitumor therapy, VDAs also shown a number of side effects and toxicities that is hindering their clinical development.

Taken as a standalone therapy, VDAs has shown to have cardiovascular and neurological toxicities. It was found by Hollebecque and colleagues in a study published in 2012 that when used in combination therapy with chemotherapy haematological toxicity also developed. Some known toxicities have been identified as shown in table 2 with reference from a review by Hasani and Leighl (2011).

Further research is still underway to focus on the dose limits of VDAs in order to obtain the best efficacy with minimal side effects and toxicities.

Conclusion

With much potential shown from preclinical and current clinical trials by VDAs and their role in tumour vasculature disruption, they have proven to be an effective emerging new class of antitumor drugs. Many VDAs are still undergoing various phases of their clinical trials and have shown promising results. Further research also has to be done on combination therapies with VDAs so as to ensure full necrosis of the solid tumour and prevention of recurrence.

References:

  1. Cesare Gridelli, et. al. (2009) Vascular Disrupting Agents: A Novel Mechanism of Action in the Battle Against Non-Small Cell Lung Cancer. The Oncologist 2009, 14: 612-620, doi:10.1634/theoncologist.2008-0287

  2. Chen, Minfeng et. al. (2017). Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents. Journal of Clinical Investigation. 127. 10.1172/JCI94258.

  3. Hasani A. & Leighl N. (2011) Classification and toxicities of vascular disrupting agents. Clinical Lung Cancer, 12(1):18 – 25. Doi: 10.3816/CLC.2011.n.002

  4. Hollebecque A., et. al. (2012) Vascular disrupting agents: a delicate balance between efficacy and side effects. Current Opinion in Oncology. 24(3): 305 – 315, doi: 10.1097/CCO.0b013c32835249de

  5. Kanthou, C., & Tozer, G. M. (2009). Microtubule depolymerizing vascular disrupting agents: novel therapeutic agents for oncology and other pathologies. International Journal of Experimental Pathology, 90(3), 284–294. http://doi.org/10.1111/j.1365-2613.2009.00651.x

  6. Liang, W., Ni, Y., & Chen, F. (2016). Tumor resistance to vascular disrupting agents: mechanisms, imaging, and solutions. Oncotarget, 7(13), 15444–15459. http://doi.org/10.18632/oncotarget.6999

  7. Nagy, J. A., et. al. (2009). Why are tumour blood vessels abnormal and why is it important to know? British Journal of Cancer, 100(6), 865–869. http://doi.org/10.1038/sj.bjc.6604929

  8. Shafaee, M.N. & Ibrahim, N.K.. (2015). BAVITUXIMAB: Phosphatidylserine-targeting MAb Ligand-directed vascular disrupting agent. Drugs of the Future. 40. 281. 10.1358/dof.2015.040.05.2303032.

  9. Siemann, D. W. (2011). The Unique Characteristics of Tumor Vasculature and Preclinical Evidence for its Selective Disruption by Tumor-Vascular Disrupting Agents. Cancer Treatment Reviews, 37(1), 63–74. http://doi.org/10.1016/j.ctrv.2010.05.001

 

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