7.10 Therapies: Vascular Disruption

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Therapies: Vascular Disruption

 

 Vascular Disrupting Agents (VDAs) are a novel class of anti-vascular drugs that have shown beneficial anti-tumour growth effects in preclinical trials. While previous drugs target and prevent the formation of blood vessels, VDAs target the endothelial cells of established tumour vasculature, resulting in hypoxia and tumour necrosis. They may also block blood vessels and capillary sprouts, thus preventing blood flow and inducing secondary necrosis in tumours. In theory, as tumour blood vessels’ differ substantially from normal vasculature, normal cells are left undamaged [2]. Unfortunately this is not the case currently: VDAs have not yet been approved for public usage because in clinical trials they have been shown to cause damage to normal endothelial vasculature, which results in side effects to the heart and brain. On the other hand, VDAs have been shown to act synergistically with other antitumor therapies, such as cytotoxic chemotherapy, external-beam radiotherapy, and radioimmunotherapy (3, 4, 5) and would likely complement current cancer therapies well. Researchers are hopeful that further understanding of tumour angiogenesis and further refinement of VDAs’ targeting abilities will soon lead to drug approval.  There are two types of VDAs currently in research and development: small molecule and ligand-directed VDAs. Small molecule VDAs may be further divided into two sub-groups: tubulin-binding agents and flavonoids to produce a local cytokine response (3). While ultimately both small molecule and ligand-directed VDAs have the same goal, the mechanistic aspect is varied. Small molecule VDAs interfere with cell scaffolding while 

 

The susceptibility of tumours to VDA drugs is through their physiological difference to normal regular blood vessels, in their immature nature- lacking pericytes (while this is the understood mechanism of damage, it has not been proven). There are many physiological differences that seperate regular blood vasculature from those within the tumour, in their poor development of blood vessel walls, often containing portions of discontinued endothelium (11). On top of this, there are usually poor connections between the pericytes and endothelial cells and poor investiture between the endothelium and smooth muscle lining. This causes the tumour blood vessels to have increased permeability to macromolecules, and subsequently causes higher interstitial fluid pressure (12). These differences are ideal for development of VDA drugs, allowing VDA drugs to specifically target tumour cells & angiogenesis and there are many mechanisms by which they work. There is no necesessity, to affect all the endothelial cells in a given vessel, simply damaging a part of the vessel and causing a collapse, will affect all downstream events; dereasing the oxygen supply & reducing their ability to excrete waste products and therefore tumour cells die. 

 

Tubulin-binding agents

 

  Microtubules are filamentous organelles in the cell that act as a scaffold, establishing cell shape and providing a network on which intracellular vesicles and organelles may travel (2). They are also responsible for the formation of spindle fibres, a network of fibres that form during mitosis and direct chromosomal separation (2). Tubulin-binding agents target microtubule functions by binding to tubulin, the main constituent of microtubules and causing tubulin depolymerisation and disorganization (3). Endothelial cells consequently have difficulty maintaining their shape, leading to blockage of blood vessels, and disruption of the endothelial cell layer. This further escalates as vessel permeability increases and interstitial pressures rise, ultimately leading to tumour necrosis (7).

 

  In theory, normal cells should be unaffected by tubulin-binding agents due to their more highly developed cellular cytoskeleton (3). However, clinical research has found tubulin polymerisation inhibitors have been largely unsuccessful due to the disruption of normal endothelial cells, leading to toxicity (2). It appears human endothelial cells may be more sensitive to VDAs than endothelial cells in experimental animals. Further research is necessary to develop tubulin-binding agents that target tumour endothelial cells more precisely before such a therapy becomes publicly available.

 

One example of a novel tubulin-binding VDA is plinabulin, which is a drug that selectively disrupts tumor vasculature (9). It accomplishes this by binding to the colchicine-binding site of tubulin, which inhibits polymerization of tubulin into microtubules (9). The consequences of this activity are quite drastic in immature endothelial cells. There is a loss of function in the cytoskeleton, loss of morphology, and loss of cohesion, which leads to destabilization of the endothelial structure and collapse of the tumor vasculature (9). Plinabulin is also capable of having cytotoxic effects on rapidly proliferating cells, which is a characteristic of cancer cells (9). Plinabulin is structurally unique from other VDAs, which gives it a different mechanism of action, and it is used to treat non-small cell lung cancer (9).

 

Flavonoids

 

   Flavonoids are a class of secondary plant metabolites that contain ketone groups, and are known to affect the permeability of mammalian capillaries (6). They are commonly found in citrus fruits, tea, wine, and chocolate (6). They have been found to have both direct and indirect anti-tumour mechanisms. They act upon the endothelial cells’ cytoskeleton, causing the partial disruption of the actin cytoskeleton. This results in endothelial cell apoptosis and DNA strand breakage (3). Studies have shown flavonoids may induce apoptosis in tumour vasculature as early as 30 minutes after being administrated to animals (4). They also activate the immune system, specifically platelets, neutrophils and cytokines, that can damage and kill tumour-associated endothelial cells (4, 10). ASA404, a flavonoid component, is currently in clinical development in combination with the standard of care for treatment of non-small-cell lung cancer (10). 

 

   Epidemiological studies have shown that consumption of flavonoid rich foods is associated with a decrease in the incidence of many cancers (8). Flavanoids are well known anti-inflammatory molecules, and therefore have a chemopreventative effect (8). They exert their effect through several mechanisms (8). They reduce and prevent inflammation by decreasing the expression of pro-oxidant enzymes such as nitric oxide synthase (NOS) or inhibit thier action, which has been seen with cyclooxygenase (COX-2), as well as scavenge reactive oxidative species (ROS) (8). Flavonoids can also inhibit the production of pro-inflammatory cytokines such as IL-6 and TNF in various ways, such as modulating protein kinase signal transduction pathways to decrease transcription factor binding (8).

 

 

Ligand-directed VDAs

 

   Ligand-directed VDAs are composed of linked targeting and effector subunits. The targeting subunit is an antibody, peptide or growth factor selected against a marker specific to  tumor endothelial cells (5). While this marker is often present in many other tissues, it is special as it is upregulated in tumors but cannot be upregulated in normal vessels. These markers tend to be involved in angiogenesis, thrombosis, vascular remodelling and cell adhesion and are generally receptors (5). This is used to target a toxin or pro-coagulant to the tumour endothelium. The effector subunit is able to directly induce thrombosis, destroying endothelial cells, redirecting host defenses to attack tumour vessels and changing endothelial cells’ morphology to obstruct tumour vessels (5). The main challenge remains identifying receptors specific to tumour vessels and minimizing toxicity to normal vessels. When these receptors are found, drugs can target them with monoclonal antibodies, drugs or gene therapy. 

 

Combination Therapy 

 

Thus far, there have been many attempts to use VDAs in cancer treatment, and there have been some successfull cases of preclinical and early phase trials however most studies have shown that they have little effect unless used in combination. While VDAs thereotically would be able to kill cancer cells inside tumors, this leaves the external tumor cells to thrive and repopulate the tumor without fail (13). The outside tumor cells are thriving off normal blood vessels and are capable of proliferating rapidly. While this poses a problem for use of VDAs as sole drugs, it actually works well with in consert with radiation or chemotherapy. Radiation and chemotherapy are used to kill off well oxygenated, rapidly proliferating cells; precisely the ones thriving on the outside with access to normal blood vasculature (13). Therefore the combination of traditional chemotherapeutic drugs or radiation with VDAs should have a syngeristic effect on eliminating tumours. 

 

On top of combinations with radiation and chemotherapy, VDAs may also have a powerful affect in combination with antiangiogenesis drugs (13). Studies have shown that a small molecule VDA in consert with an antiangiogenesis drug, tumor growth was greatly decreased. It was shown that the effect of the two drugs combined, greatly out weighed the individual effect of both drugs used seperately (13). 

 

 

References

1. MarmeĢ, D., & Fusenig, N. E. (2008). Tumor angiogenesis basic mechanisms and cancer therapy. Berlin: Springer.

2. Mason, R. P., Zhao, D., Liu, L., Trawick, M. L., & Pinney, K. G. (2011). A perspective on vascular disrupting agents that interact with tubulin: preclinical tumor imaging and biological assessment. Integrative Biology. 3(4): 375-387.

3. Patterson, D. M., & Rustin, G. J. (2007). Vascular damaging agents. Clinical oncology (Royal College of Radiologists (Great Britain)). 19(6): 443.

4. 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.

5. Siemann, D. W., & Horsman, M. R. (2008). Small-Molecule Vascular Disrupting Agents in Cancer Therapy. Antiangiogenic Agents in Cancer Therapy. 297-310.

6. Rehman, F., & Rustin, G. (2008). ASA404: update on drug development.

7. Tripoli, E., Guardia, M. L., Giammanco, S., Majo, D. D., & Giammanco, M. (2007). Citrus flavonoids: Molecular structure, biological activity and nutritional properties: A review. Food Chemistry. 104(2): 466-479.

8. García-Lafuente, A., Guillamón, E., Villares, A., Rostagno, M. A., & Martínez, J. A. (2009). Flavonoids as anti-inflammatory agents: implications in cancer and cardiovascular disease. Inflammation Research. 58(9): 537-552.

9. Millward, M., Mainwaring, P., Mita, A., Federico, K., Lloyd, G., Reddinger, N., Nawrocki, S., Mita, M., & Spear, M. (2012) Phase 1 study of the novel vascular disrupting plinabulin (NPI-2358) and docetaxel. Invest New Drugs. 30: 1065-1073.

10. Shojaei, F. (2012). Anti-angiogenesis therapy in cancer: Current challenges and future perspectives. Cancer Letters. 320: 130-137.

11. Eberhard A, Kahlert S, Goede V et al. Heterogeneity of angiogenesis and blood vessel maturation in 

human tumors: implications for antiangiogenic tumor therapies. Cancer res. 2000; 60:1388-1393. 

12. Hashizume H, Baluk P, Morikawa S et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol. 2000; 156:1363-1380. 

13. Hanlon L, 2005. Taking Down Tumors: Vascular Disrupting Agents entering Clinical Trials. JNCI, (17) 1244-45