Novel strategy could help overcome resistance to radiotherapy in metastatic melanoma

Dr Marie Dutreix – Institut Curie, Orsay, France

What is DT01 and what is the rationale for using it in combination with radiotherapy?

DNA repair is one very important mechanism for cancer cells to survive when they are in an aggressive environment like metastatic cancer cells. In addition, it’s also a mechanism to resist treatment so if we are able to disable this activity in the tumour cells we’ll be able to restore sensitivity to the treatment and to have more efficient treatments. So this is why we have developed inhibitors and we had to develop very original inhibitors because the DNA repair is an essential mechanism for living species; it’s very robust, very dominant and very hard to disable in cells. So we developed an original method that inhibits the activity by using a lure, so it’s a small molecule that just blinds the cells and prevents the cell to recognise that they are damaged in the cells. Thereby they don’t repair this damage, they keep dividing and they die of losing their genetic content.

How specific is DT01 for cancer cells over normal tissue?

This was a big issue and in fact the molecules are the specific targeting to tumour cells because they behave as nanoparticles that are used for imagery of the tumours. So they go specifically out of the vessel, blood vessels, in tumours. In addition they lay on the modification that occurs in tumour cells during proliferation so they have a very specific effect and we didn’t observe any toxicity in normal tissue, we have no toxic dose. It doesn’t sensitise to chemotherapy or radiotherapy healthy tissue so it’s very safe, so far. According to the research we have in the first trial and in animal studies it’s very well tolerated and very safe.

What were the characteristics of the patients studied?

We chose patients that had developed local metastases of melanoma. These patients have received surgery several times but they have recurred at the same location and the disease is spreading in the area in the skin. At that level it’s very hard to treat because chemotherapy is not effective and we use radiotherapy but radiotherapy is not very effective and also the effect doesn’t last very long. So we were looking for a treatment that would be more efficient and will have a long-standing effect. This is why we associate our molecule with radiotherapy and that way we actually demonstrated that we increased the efficacy from 9% with radiotherapy alone, same protocol, to 30% of cured, a complete response in patients. The response is still standing so it’s a very stable response and we have no recurrence of most of the patients.

How were patients actually treated?

The patients received two weeks of radiotherapy every day, every open day, so ten sessions of 3Gy. Every two days, Monday, Wednesday and Friday, we inject the molecules. So we used a local injection for this demonstration to demonstrate that this is safe and well tolerated. So the skin was irradiated and received the drugs and we didn’t observe any enhancement of the radiosensitivity of healthy skin but we observed the regression and disappearance of the tumours.

What were the main results?

This was a phase I so the first endpoint was to demonstrate the tolerance of the treatment. The main result was the very good tolerance and the demonstration that we don’t sensitise healthy tissue. The second endpoint was the efficacy and the efficacy so we demonstrated that we had 30% of complete response and 39% of partial response. This is a good objective and in addition we did only one session, one cycle of treatment but we know that repeating the DT01 treatment after a first boost of radiotherapy is very efficient and in the next step we propose to keep treating with our molecules now that we know that they are safe.

What future studies are planned based on these phase I findings?

At the same time that we proposition for melanoma we are moving to general metastasis. So we plan to work on administering the molecule systemically by intravenous in combination with platinum salts for very advanced stage tumours that are resistant to several treatments before. So this is the next step and we hope to start within a year.

Is there potential to use earlier DT01 in earlier stage disease?

We lay on the deregulation of the tumour so I’m sure it works very well with advanced disease. For early stage disease I don’t think it will work for all the types of tumours and we will have really to work on. It’s not an easy part because most of the models we have correspond to the advanced stage and not to early stage. But obviously this is something we will do because the other objective is to reduce the doses of radiotherapy or chemotherapy with the same efficacy and that will be very interesting in the first line of treatment.

What is your final take home message from the trial?

Keep your imagination because we have designed a completely new way to inhibit the activities that are essential for tumours and this is the field where people have to work. It’s just test and try new methods. This will be only with this imagination and the combination of different treatments that we will transform the deadly cancer into chronic disease or even into something that we can cure.