14th International Medical Education Workshop on Molecular Targeted Therapy of Cancer (MTTC)

Neo-angiogenesis and pathological angiogenesis in targeted molecules

Dr Wolfgang Wick - University of Heidelberg, Germany

We’re interested in the neo-angiogenesis, the pathological angiogenesis, which is one of the hallmarks of malignant glioma actually. So malignant glioma is actually, amongst all the cancers, the one that depends probably most on pathological angiogenesis so it was very early thought that this type of tumour would be a very, very rational target for all sorts of anti-angiogenic approaches. The major first finding is probably that it is not only about anti-angiogenesis but it’s about normalisation of angiogenesis because we have that pathological angiogenesis which is probably just malnutrifying the tumour but is also thereby inducing hypoxia. This hypoxia induces invasiveness, causes other problems, therefore just reducing angiogenesis is probably not the best thing for brain tumours. So what is about to be done at the moment is using drugs mainly against VEGF, VEGF receptor integrands, but also downstream targets, protein kinase C, mTOR, to normalise the vasculature and with this normalisation you will have a better access for chemotherapeutic drugs, you will have a better oxygenation and therefore a better efficacy of radiotherapy and hopefully also some direct effects on the vasculature which helps to starve the tumour tissue.

Are there any alternatives to anti-angiogenic drugs?

Perfectly true. So from all the alternatives I just mentioned, so we have the integrands not really successful so far although their preclinical rationale is really great. We have the VEGF receptor 2 inhibitors, small molecules, TKIs, which haven’t proven to be effective in brain tumours either, so the trials, the controlled trials, have been negative. We have the downstream targets, mTOR, protein kinase C, these trials have been negative so far, and the only trial that is at least showing some promise for progression free survival, we don’t have the overall survival data yet, is the anti-VEGF, so vascular endothelial growth factor trial. So this may show some promise. We have that drug, the bevacizumab, the antibody against VEGF, registered for the use in recurrent glioblastoma, not in Europe but in the US and in many other countries in the world. Not in Europe so far because there has not been a controlled trial so it’s a very tricky situation. The need in brain tumours is really high for new, effective drugs, but of course the threshold to prove should still be a controlled and reasonably well conducted trial.

Should there be trials looking at drug combinations?

So if the current concepts for the newly diagnosed glioblastoma are holding the promise then we would have radiotherapy and chemotherapy with temozolomide. This is the standard of care as of now and if bevacizumab is really showing that it is improving that combination it will be radiotherapy, alkylating chemotherapy, temozolomide and the anti-VEGF approach. So, yes, we would have a combination. For the recurrent setting we may have at some point also a combination between alkylating chemotherapy, it would be Lomustine in that time, and bevacizumab. So we are trying that combination now versus Lomustine alone. The problem that we are having so far is that, regardless of whether we’re doing radiotherapy, chemotherapy, all anti-angiogenic approaches, the tumour will pretty fast come back. We have some 10-15% of longer surviving patients, we are about to identify those subgroups so the research in brain tumours is comparably really well. So we have a lot of insights also from recent genetic analysis into the biology of the brain tumours and I think we now just have to do more trials. Compared to breast or lung or whatever we are really short on trials, I think we have done a tenth or so of trials as compared to the other major disciplines in oncology and we need to do more of those trials.

Are there any potential biomarkers?

There are a few, so there are a few. For the elderly patients we have the MGMT, it’s a resistance protein against alkylating chemotherapy which pretty nicely defines patients that benefit or do not benefit from alkylating chemotherapy, so we have that. We have for the lower grade tumours, so grade 3, just one grade below the glioblastoma, we have IDH which defines isocitrate dehydrogenase, the mutation defines a totally different subgroup of tumours. We have the 1p/19q co-deletion so chromosomal operations in the tumour tissue which is also defining a pretty much better prognosis group of tumours. And we have also MGMT in that, in that setting. There will be more and there are at the moment more molecules to come. We have ATRX, we have … so there are more molecules that are really helping to subgroup these tumours. I think this is the way to go because then we will have the ability to really focus in trials on specific subgroups which is reasonable.

Are there cases of glioblastoma that are easier to treat?

It would be the unmethylated, MGMT unmethylated, so with a hypomethylation phenotype in a more old patient. So we are pretty certain now that this methylation goes down in the tumour with age and since methylation would have been something nice for the patient to have in the tumour these tumours in older patients are really prognostically worse as compared to younger patients. So it’s not the age per se which is bad but it’s the tumour composition, the biology of the tumour, that changes with age.