Currently we are focussing on pharmacology of all types of novel drugs which seems to be quite essential because all the tyrosine kinase inhibitors are so much dependent on their pharmacology in order to be active. It’s a field which has been ignored in the early development of these compounds and actually quite a few of them just failed because of that.
Could you tell us about the Pharmacokinetics and Metabolism Group (PAMM) that you’re a part of?
PAMM is one of the translational research groups of EORTC; PAMM stands for Pharmacology and Molecular Mechanism group, in the past we were called Pharmacokinetics and Metabolism. So, we are focussing on how a drug is being taken up in a patient, how it’s being distributed in the patient, how it’s being metabolised in the patient, how it exerts an action. This deals with any type of anti-cancer drugs, whether it’s a classical cytotoxic DNA directed drug, if DNA is a molecular target, or whether it’s one of the tyrosine kinases or [other] kinases, that doesn’t matter for the PAMM. We are developing tools to predict whether an anti-cancer drug is effective in the patient so it would say predictive biomarker, it’s one of the major aims of the PAMM to develop.
Next to that the PAMM is very much involved in drug development. We have some working groups: the drug discovery committee, which was previously called the Screening and Pharmacology Group, and the preclinical tumour models group which also became part of the PAMM. So we have an active drug discovery meeting and you may remember that in the ‘90s we started a collaboration with the NCI in order to develop the compounds which were submitted to the NCI-60 cell line panel. Some of these drugs which subsequently came out and have been developed into clinical studies, one of the achievements, for instance, of the SPG group is the development of temozolomide by Malcolm Stevens. That was done within this group and subsequently a number of other drugs have emerged out of this screening model which went through phase I, phase II, unfortunately not yet in further stage. But that was all based on initiatives which were developed within the EORTC PAMM group. So we are a group which can help in drug development and which can help and helps a lot in how to give an anti-cancer drug in the most optimal way to patients.
What is PAMM’s strategy for testing drug metabolism in a pre-clinical setting?
When we are studying metabolism of anti-cancer drugs we first look at the structure – what type of drug is it? Is it a classical anti-metabolite? Is it a platinum analogue which needs to be metabolised? Is it a topoisomerase inhibitor? Or when we are looking at some of the tyrosine kinase inhibitors we look at the structure and see whether it might be a substrate for one of the phase I or phase II enzymes, so whether it can be hydrolysed or whether it has to be glucolysed etc. So you can predict most of these things from structural formula.
So then using the model systems you can use in vitro model systems which tell you whether it’s metabolised but, most importantly of course, you need in vivo model systems or subsequently you carefully have to analyse what’s happening in the patient. That’s often neglected; the step in the development of drugs when you have a target then the target is not sufficient. You need the drug to reach the target, if it doesn’t reach the target it’s just hopeless, it doesn’t work. It’s a lot of effort, lot of waste of money and a lot of waste of human exercise in that and resource, of course. Patients are being given drugs which are inactive. So you have to prevent this. There are a number of different model systems for that and we have the expertise within the PAMM group to do that. In this we always collaborate very closely with clinicians. We have the families composed of a mixed group of preclinical scientists, pharmacologists, medicine chemists, biologists and clinicians with different backgrounds, medical oncologists but also radiation oncologists. That interaction is really essential to get these tests being done and to be done in the right model system and looking at the right things because that’s, of course, very important.
We prefer to do this in phase I clinical studies; we have been very strong in the previous collaboration with the other clinical trial groups and I believe this is a field where the EORTC should become stronger again. The EORTC is very strong in phase II, phase III studies but we miss a number of drugs which are coming in the phase I which could be subsequently tested in the phase II. We need to have an early contact with pharmaceutical companies who are the major developers of drugs so that they know that we can do this very efficiently within the EORTC together with, for instance, CR UK or with the local groups in France, in Germany, in the Netherlands, they are becoming much more important. That’s a little bit due to the change in EU rules which make it more complicated to do a European study so that it’s sometimes more efficient to do all these studies in the separate countries which is a shame, especially when we are talking about diseases which we don’t have that many patients. We are currently having epigenetic activation of tumours; the populations in several studies are getting smaller and so you need an international collaboration because otherwise you will not be able to achieve large numbers of patients in a certain group. That’s where the EORTC is very strong so they have been able to do this and we have to put more effort in this also to change the EU rules again to make this possible which will reduce the cost of clinical studies as well because they are now excessively high. We are not able to put real new drugs into the clinic, we have too many me too drugs at this moment. So we really need new drugs with new targets and whether this is a targeted tyrosine kinase inhibitor or whether it’s molecular targets like DNA, because DNA is a molecular target as well, we cannot ignore this. I saw a couple of interesting posters here with DNA as the target and they’re really promising. We should not forget that dihydrofolate reductase is a molecule as well and very well targeted, in my mind, by methotrexate. We can cure a lot of patients. Just consider all the paediatric leukaemia which are cured by combinations, clever combinations of methotrexate, mercaptopurin [?] and so on. So we should not forget that, we should not forget this knowledge to develop new combinations and new drugs.
When is the next meeting?
The next meeting of the PAMM will be in Marseilles, it will be organised by Joseph Ciccolini and he has really done a marvellous job in putting together a programme and inviting a number of international speakers. We have a couple of speakers on pharmacogenetics like Howard McLeod; of course it’s in France so we have a number of French speakers. It will be organised with the GPCO which is the Group of Pharmacological Clinical Oncologists in France, so they have a number of speakers as well. We have a couple of speakers on drug development; we have speakers on novel combinations which Annette Larsen, our treasurer, who is going to present a study on combinations of two tyrosine kinase inhibitors which she developed in preclinical models which went through to the clinic and it showed its efficacy as well. So that’s some kinds of presentations which are going to be presented.
