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The View of the Pharmacologist: What is Tumor Control?

G. Milano (France)

SlotAE-3 Milano, G.

The view of the pharmacologist Dr. Gérard Milano on Tumour Control and on the mechanism of action of Metronomic Chemotherapy

Transcription

Thank you very much, Mary, thank you for coming, good evening everybody.  Thank you to Pierre Fabre Oncology for organising this meeting tonight. 

How to achieve tumour control?

I would like to start with are some definitions, with the pharmacological background to these definitions.

Full transcription

Full transcription

 

Thank you very much, Mary, thank you for coming, good evening everybody.  Thank you to Pierre Fabre Oncology for organising this meeting tonight. 

How to achieve tumour control?

I would like to start with are some definitions, with the pharmacological background to these definitions.

You have a clinical view about tumour control; you can also have a pharmacological view, in terms of resistance, for instance, and how to achieve tumour control, and resistance is at the centre of the question, you can prevent the emergence of resistance or you can try to circumvent this resistance.

To prolong therapeutic activity

Maintenance continuation is a way to perform maintenance treatment by starting the active drug and maintaining the pressure on the tumour and avoiding unanticipated side effects. 

To prevent the emergence of resistance

The other way to perform maintenance is to shift, to shift as this is a way to prevent the resistance, to shift with another active drug and you have different ways to anticipate, to prevent resistance.  You also have the pharmacokinetic approach, for instance for TKi it is recommended to take into account some variability in terms of pharmacokinetics and to try to adapt dosage to these characteristics. 

Circumvent the resistance

The way to circumvent resistance, so you have to know the source of resistance, you have very nice examples in lung cancer.  For instance, with the mutation in position 790, so this mutation is leading to resistance to conventional TKi, but this is also the source of phenol reactive treatment and active treatments, so this is a way to circumvent resistance when you know the source of resistance and, unfortunately, there is a burning failure in this story, it is mdr-1.  Michael Gottesman years ago published interesting data and a lot of people were engaging in the research and drug companies were trying to develop inhibitors of mdr-1 and you know very well it was a fail. 

Metronomic chemotherapy – a reality

Let me give you some pharmacological considerations about metronomic chemotherapy, you heard about it, you are going to hear more in the next talks. 

The low therapeutic index of chemotherapy has led to a search for optimal therapeutic schedules:

This is another way to try to optimise chemotherapy, in terms of changing the mode of administration, you know very well about continuous administration, oral administration, weekly administration, chronomodulated administration, also, obviously, it is a way to optimise the way to deliver the drug, in terms of the optimised therapeutic index, and metronomic. 

Every-3-week vs weekly vs metronomic chemotherapy schedules

What is metronomic?  This term was coined by Kerbel two decades ago and this is a way of delivering a constant exposure to chemotherapy by reducing the dose and to maintain at the time the same pace. 

What is the optimal pace, is it weekly, is it daily?  Generally it is considered to be daily, but it is not a strict rule, the rule depends on the mechanism of action of the drug, obviously, and also depends upon the half-life of the drug. 

Metronomic chemotherapy: what’s behind?

What is behind this? 

Different impacts of metronomic chemotherapy

Surprisingly enough the cytotoxic effect of the drug given in the metronomic way is not a cytotoxic effect, the impact is more on angiogenesis, like anti-angiogenic approach and also you see an activation of immunity. 

Impact of metronomic schedules on endothelial cells

We have a lot of arguments based on the pre-clinical data, using endothelial cells in culture, showing that when giving repeated administration of small concentration of drugs, you can achieve an effect on endothelial cells and in the same experiment you have no effect at all with this concentration against tumoral cells, so there is a direct impact on endothelial cells.  

What is the common denominator of all these drugs we have here, the balance here, this is an example, they are all drugs that are acting on tubulin. 

Microtubules have a central role in the dynamics of endothelial cells

We see here why endothelial cells and tubulin.  Tubulin is playing twice on endothelial cells, it is playing at the renewal, at the level of the nucleus, the obvious role of microtubules for cell divisions, but tubulin is also acting in microtubules which are responsible for the attachment between endothelial cells, between themselves.  This is not a simple button, the attachment of cells onto cells), there is also repercussion, biochemichal repercussion sites on the endothelial cells played by microtubules.  When you target tubulin in endothelial cells you have a double action.

TSP-1 and metronomic chemotherapeutic treatments

Some illustration about the impact of angiogenesis, perhaps you do not know this protein, thrombospondin 1; thrombospondin 1 is a negative factor for angiogenesis, a factor which is produced by the stroma of tumours and which is acting against angiogenesis.  Here you have a nice demonstration that some metronomic protocols using cyclophosphamide, you have the demonstration that the more active protocol is linked with the greater release of thrombospondin 1 in the tumour stroma. 

Human Biology and metronomic treatment

The views of this parameter is taken into account in this trial by our Greek colleagues, testing metronomic chemotherapy with some translational study, with biological markers, so this is absolutely needed in order to understand and to illustrate the activity of this chemotherapeutic protocol, to associate biological translational studies, in terms, for instance, of the proof of angiogenics, the impact on angiogenesis. 

Metronomic cyclophosphamide and immunity

Another interesting aspect is the impact on immunity.  We have some pre-clinical and clinical arguments showing that metronomic chemotherapy, especially with cyclophosphamide, is restoring immunity.  For instance, here you have, again in a pre-clinical study on animals with a grafted tumour, in animals and testing different schedules, the schedule which was more active was the schedule which allowed more incorporation of cells responsible for immune response, that is the right part of the screen. 

Treg and metronomic chemotherapy

Here, in a clinical setting, you know the role of Treg, the negative role of Treg, you heard about for the immune response.  Here, this is a demonstration that metronomic cyclophosphamide is able to down-regulate significantly the level of Treg; this is very interesting.  The mechanism of action we do not know really, but it is an interesting observation. 

Ideal candidate for metronomic chemotherapy

The ideal candidate for metronomic chemotherapy, we have to target endothelial cells and also if you can have an oral schedule for this type of drug. 

Metronomic chemotherapy in a glance – A credible option for tumour control

A nice way for achieving this proposal is oral vinorelbine, because vinorelbine is a drug acting on the microtubules, this is clear, this is well known, this is well demonstrated, it is also available for oral administration. 

Here you have recapitulation of all the characteristics of metronomic chemotherapy, so in terms of minimizing side effects, this is the first objective, and also you have some original mechanism of action, in terms of impact on angiogenesis, and also impact for restoring immunity in patients.

Thank you very much for your attention.