7.9 Normalization Hypothesis and Combination Therapies

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Normalization Hypothesis and Combination Therapies


  Cancer therapies are likely to be more successful if they are combinatorial- that is, if they target multiple pathways concurrently. It has been shown that anti-angiogenesis agents plus traditional chemotherapy and/or radiation either additively or synergistically exert anti-tumour effects, although it is undetermined if this effect is agent specific (1). When administered alone, anti-angiogenesis agents have modest and short-lived effects in clinical trials (2). The molecular targets of angiogensis inhibition therapies are different than those targeted in conventional chemotherapy, which typically targets rapidly proliferating tumor cells; anti-angiogenesis therapy targets the endothelial cells supporting the tumor (6). This means that the toxicities resulting from these two therapies are often non-overlapping, and consequently they have the potential to work synergistically.


  The combination approach would at first seem counter-intuitive as destroying the blood vessels leading to the tumour would prevent chemotherapeutic agents from reaching the cancer cells (2). Despite this, two effective mechanisms of using chemotherapy and anti-angiogenic therapy have been implemented. The first, and more conventional method delivers agents at the maximum tolerated dose, with breaks between cycles of treatment (1) The second prescribes low dosages, in close intervals with no prolonged breaks (1). This is called metronomic therapy. These combination of chemotherapy and anti-angiogenic factors may work though the following mechanism. Chemotherapy, when implemented at the right dose, preferentially damages endothelial cells in tumour blood vessels. In a tumour where angiogenisis is occurring, these endothelial cells would be dividing. So adding an anti-angiogenic factor such as one that targets VEGF-A results in a compound effect; the simultaneous destruction of blood vessels and the inhibition of new blood vessel formation.


  While BMCs are sensitive to both administration methods, BMC levels tend to rebound rapidly during drug free periods, which are longer and more often in conventional therapy (1). It has been suggested that anti-angiogenesis therapy should be continued during breaks in chemotherapy and/or radiation therapy, in order to prevent this rebound (1). As cancer cells are often able to adapt when only one factor is blocked, using multiple anti-angiogenic factors has a lot of potential. New targeted therapies against EGFR/Her2, PDGFR/bcr-abl inhibitors, proteasome inhibitors, and other inhibitors of angiogenesis (eg. inhibitors of integrins) could potentially be used in tandem with for synergistic effects (1). This could alleviate the need for toxic chemotherapeutic agents which have severe side effects in patients, or be used in conjunction to further lessen the chance of rebound between treatments.


  It has also been hypothesized that usage of low doses of an anti-angiogenic agent such as anti-VEGFR-2 antibodies can improve chemotherapeutic effectiveness though another mechanism. Due to the irregular nature of tumour vasculature, high interstitial pressures are can be seen within tumours (4). This makes it hard for chemotherapeutic agents to leave the vessels and actively target cancer cells. Anti-VEGFR-2 antibodies can counter this problem by normalizing the vasculature (2,3). At a submaximal dose, excess endothelial and perivascular cells can be "pruned", high interstitial pressure in tumours would decrease, and oxygenation levels would improve (3). Radiation, among other therapies, require nearby oxygen species to be effective. The compound effect of improved delivery and oxygen levels improve the effectiness of these therapies. Having increased oxygen levels in the tumour may also seem counter intuitive as it would seemingly aid in cancer progression. Despite the improved delivery of oxygen and nutrients during normalization of the vasculature, tumour growth is not accelerated (2). Under low oxygen conditions, interstitial hypertension, hypoxia, and acidosis rates could increase (2,3). These conditions cause the tumour to become more aggressive and less treatable, selecting for more malignant and metastatic cells (3).


   These mechanisms of action have been shown in several studies. A study on the effects of Avastin on rectal carcinoma found that with only one dose, excess blood vessels were removed and both the structure and function of the vasculature were normalized (3). Interstitial pressure within the carcinomas also decreased, allowing more efficient drug delivery (3). Similar results occurred in a trial of Recentin on glioblastoma patients, revealing rapid normalization and reduction of oedema, a marker for interstitial fluid pressure (3). Although promising. there is only a window of normalized vascularization before the vasculature either gets disrupted or returns to a tumour-like state (3). As both trials showed immediate normalization as soon as one treatment, anti-angiogenesis agents would be beneficially administered along with the first chemoradiotherapy treatment (3).




1. Ferrara, N. and Kerbel, R.S. (2005). Angiogenesis as a therapeutic target. Nature 438, 967-974.

2. Jain, R. K. (2005). Normalization of tumour vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58-62.

3. Jain, R. K. (2008). Opinion: Lessons from multidisciplinary translational trials on anti-angiogenic therapy of cancer. Nature Reviews Cancer 8, 309-316.

4. Tong, R. T., Boucher, Y., Kozin, S. V., Winkler, F., Hicklin, D. J., & Jain, R. K. (2004). Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer research, 64(11), 3731-3736.