An important parcel must be delivered to the correct place.
It is so important that it can be a question of life or death.
However, uneven streets and missing railings risk to bring it off the road and leave it undelivered.
This is not the trailer of a drama, but what happens to anti-cancer drugs travelling towards the tumour area, but unable to reach it because of dysfunctional blood vessels.
The Center for Vascular Research, within the Institute for Basic Science (IBS) discovered that their antisepsis antibody ABTAA (Ang2-Binding and Tie2-Activating Antibody) also reduces tumour volume and improves the delivery of anti-cancer drugs.
Published in Cancer Cell, this study demonstrates that ABTAA restores the structural and functional integrity of tumour blood vessels in three different tumour models: breast, lungs and brain.
Blood vessels inside and around an established tumour can be described as a chaotic and dysfunctional labyrinth.
While the inner walls of healthy blood vessels are surrounded and supported by endothelial cells and other cells called pericytes; in the established tumour, the endothelial junctions are broken apart and pericytes are also detached.
Blood flow into and from the tumour is severely retarded and tumour vessels lacking an intact vessel wall become leaky.
This microenvironment causes limited drug delivery to the tumour and leads to inadequate oxygen supply (hypoxia) and even metastasis.
IBS scientists found that the antibody ABTAA normalises the tumour vessels and hence, change the whole tumour microenvironment.
"We call it normalisation of tumour vessels, because it resembles closely the wall architecture of healthy, normal vessels," explains PARK Jin-Sung, first author of the study. And continues: "Tumour can adapt to hypoxia and get more aggressive, so we tried to prevent this transition by normalising tumour vessels. ABTAA changes the whole tumour environment, oxygenation status and level of lactate, so that the immune cells and drugs can reach the core regions of the tumour more easily. In this way, we create a favourable ground for tumour treatment."
In an attempt to generate antibodies targeting the protein Ang2, which is specifically expressed by endothelial cells in stressful conditions like in tumour, the team unexpectedly discovered that ABTAA has a peculiar way of working and a dual function.
ABTAA indeed not only blocks Ang2, but it is also able to activate Tie2 at the same time.
Tie2 is a receptor present on the cell membrane of endothelial cells. ABTAA causes Ang2 to cluster together and to strongly activate Tie2 receptors. "If we activate Tie2, we can efficiently normalise tumour vessels, enhance drug delivery and change the whole microenvironment," explains KOH Gou Young, Director of the Center for Vascular Research.
Several pharmaceutical companies are developing Ang2-blocking antibodies to cure cancer.
However, even if these antibodies significantly inhibit tumour progression, they do not stop tumour hypoxia.
Moreover, most of the anti-cancer drugs target the tumour at its early stage, when tumours are still hard to diagnose.
ABTAA, instead, works with tumours that are already rooted: "When the tumour is established, hypoxia is the main driver of tumour progression. So, if we eliminate hypoxia, we make the tumour more mild, by reducing its progression and metastasis," comments Koh.
IBS researchers tested ABTAA in mice with three different types of tumours that show high levels of Ang2: glioma (a type a brain tumour), lung carcinoma and breast cancer.
They also compared the effect of ABTAA with ABA, another antibody that blocks Ang2 but misses the Tie2 activating properties.
In all three cases, ABTAA was superior to ABA in inducing tumour vessel normalisation, which led to a better delivery of the anti-cancer drugs into the tumour core region.
Glioma is one of the so-called intractable disease, because of its poor prognosis and treatment.
IBS scientists found that the glioma volume was reduced 39% by ABTAA and 17% by ABA. ABTAA profoundly reduced vascular leakage and edema formation in glioma through promoting vascular tightening.
Moreover, when ABTAA was administered together with the chemotherapeutic drug temozolomide (TMZ), the tumour volume reduces further (76% by ABTAA TMZ, 51% by ABA TMZ, and 36% by TMZ).
In the Lewis Lung Carcinoma (LLC) tumour model, the research team administered ABTAA together with a chemotherapeutic drug called cisplatin (Cpt) and observed a greater suppression of tumour growth (52%) compared with the controls and increased overall survival.
Moreover, ABTAA Cpt led to a marked increase in necrotic area within tumours.
Finally, in a spontaneous breast cancer model, ABTAA delayed tumour growth and enhanced the anti-tumour effect of Cpt.
In the future, the team would like to further understand the underlying relationship between faulty blood vessels and diseases.
"We would like to apply this antibody to an organ that is rich in blood vessels, that is the eye, and see if this antibody can be useful to treat eye diseases such as age-related macular degeneration and diabetic retinopathy," concludes Koh.
Source: Institute For Basic Science
(30 Mar 2017)
(30 Mar 2017)