Looking for biomarkers in metronomic chemotherapy

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Published: 10 Jul 2014
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Prof Guido Bocci - University of Pisa, Pisa, Italy

Prof Bocci talks to ecancertv at the Metronomic Chemotherapy Meeting in Milan about the benefits of metronomic treatment. He highlights the difficulties faced in trying to research such treatment in light of limited knowledge on the mechanics and biomarkers which make it work, as well as logistical difficulties, such as funding. 

I am studying a lot of metronomic chemotherapy and anti-angiogenic drugs but with the prospective of pharmacokinetic and pharmacodynamic biomarkers, including pharmacogenomic biomarkers and pharmacogenetic analysis. Biomarkers in metronomic chemotherapy are a nightmare, but I’m saying it because it’s a very difficult type of research because there are not a lot of randomised phase III clinical trials so we have to do pilot studies with a small number of patients. So the people that are looking at biomarkers in metronomic chemotherapy usually are doing hypothesis generating studies, not validating studies because it needs a randomisation and that’s the main difficulty in the field. But on the other side there is the need for biomarker research, also metronomic chemotherapy, especially what I pointed out in my presentation that we need a better knowledge of pharmacokinetic aspects of metronomic chemotherapy. Not only pharmacodynamic biomarkers like plasma BGF, bFGF or other pro-angiogenic factors but also how much concentration of a drug is present in the plasma of our patients treated with metronomic chemotherapy; how is it related with the efficacy or resistance of metronomic chemotherapy.

What does this entail?

Actually I have a pharmacological background because I’m a clinical pharmacologist so after my postdoc in Bob Kerbel’s lab I decided to focus my research on this particular aspect that I think is a kind of dark side of metronomic chemotherapy because nobody is interested in studying that. We came up with at least two interesting articles that have been recently published where we found out that the concentration of 5FU is related to the efficacy of metronomic UFT in colorectal cancer patients. So it’s a kind of predictive pharmacokinetic biomarker for this kind of therapy.

What is a pharmacogenomic biomarker?

Basically instead of using PK analysis or, for example…

PK is pharmacokinetics, yes?

Pharmacokinetic analysis or, for example, concentration levels or various factors in plasma we look at the genetic background of the patients, especially we looked at the pharmacogenetic of metronomic cyclophosphamide in prostate cancer patients and we looked at the VEGF single nucleotide polymorphisms in these patients. We found out that, based on which type of genotypes have these patients, there is a longer or a slower PFS. So basically you can stratify to the very beginning your patients that are candidates for metronomic chemotherapy based on VEGF polymorphism, at least theoretically because it’s a pilot study, it needs extra validation in a phase III randomised study. But at least there is the idea to personalise the metronomic chemotherapy at the very beginning and stratifying your patients, especially prostate cancer ones.

Why is it not called simply ‘genomic’?

This is called pharmacogenomics or pharmacogenetics because these RNA transcripts or genotypes are related to the response of a drug or the toxicity of a drug but in metronomic chemotherapy toxicities are so low that the only way to study it is as a predictive biomarker, pharmacogenomic biomarker of efficacy. So basically it’s efficacy of a therapeutic approach and you look at the RNA transcripts or EGF or single nucleotide polymorphism but also many others. As an example in tissue samples you can look at the mutations, it depends on what you are looking for. But in our mind there was the genetic background of the patients, the host, not of the mutation of the tumours that lead to a better response to metronomic chemotherapy.

Have you identified any biomarkers?

Yes. Well of course these are pilot studies, we have to remind that, so they need validation. But, for sure, what has been published also by Francesco Bertolini et al. in beautiful clinical trials and that for sure plasma VEGF, at least independently by various groups, has been found out that there is a correlation with efficacy of metronomic chemotherapy. Lower VEGF concentration, better as metronomic chemotherapy. And not only in patients are we seeing this but also, for example, in animal models like pet dogs, we have made a study on that, and we replicate what we have found in patients. So for sure the data are there. But of course there are so many mechanisms for metronomic chemotherapy so you can add tumour biomarkers or other biomarkers in the near future to enquire and to investigate also other possible mechanisms that are going on with metronomic chemotherapy. So that’s one, another is a pharmacogenetic that we have found as VEGF SNPs or especially the promoter region of VEGF. Another one we’ve found is the gene expression of v-cadherin in prostate cancer patients that actually was inspired by the work of Bertolini in 2004 and we published that in 2009.

So v-cadherin is a marker of people that will respond better?

Yes, v-cadherin basically is a marker of viable circulating endothelial cells and people that do not respond to metronomic cyclophosphamide have higher levels of transcript of  v-cadherin genes. People that instead respond, that are stable disease for example, have lower levels of RNA transcripts of a gene and maintain stable during all their time on the therapy.

So it would be better to have a biomarker pre-treatment?

Yes, it’s nice to have a pre-treatment marker like genotype or at least after a very first injection of your injection or administration of your drug like a PK biomarker, pharmacokinetic biomarker, sorry. Yes, that’s the best picture that you can have. But, of course, there could be also after two months of treatment you still have the option to change your therapeutic approach, as shown by Francesco Bertolini, or after three weeks as we presented some data that we will publish soon in prostate cancer. Of course it’s a less interesting biomarker after two months, three months, four months of therapy because you cannot really change and affect the prognosis of your patients. But everything is still on an on-going pilot study so we have to be careful with that.

People administering metronomic treatment should be measuring pharmacokinetics?

Yes.

Why is this?

Because I believe that metronomic chemotherapy is a matter not of the dose but the concentration of a steady state in patients. So you have to know the concentration of your drug in the patients to establish the activity of metronomic chemotherapy. In terms of principle you can monitor the concentration of your drugs in your patients during therapy and so you can adjust the dose based on your single patients to maintain the range of activity of metronomic chemotherapy.

What do you think the future holds for metronomics?

I’ve worked with metronomic chemotherapy for almost fifteen years and the future is not easy but with the, as also Nicolas André and Ed Pasquier have said, probably if this global initiative of metronomic chemotherapy can really change, or help to change, the perception of metronomic chemotherapy in oncologists and may help to do more research on this area. Because, honestly, research on this area is a kind of niche in the scientific community and we go further, we need a wider community to see what we have done in these years and how strong are the basis of metronomic chemotherapy built up with preclinical studies, pilot studies, now starting with phase III clinical studies. So there is a strong background should we choose to go ahead.