13th Award: Effect of Multikinase Inhibitors on Caspase-Independent Cell Death and DNA Damage in HER2-Overexpressing Breast Cancer Cells

A combination of two drugs, trastuzumab and dasatinib, improve the treatment response by 30% in breast cancers, those in which tumour cells show an overexposure to the HER2 protein. This is the discovery of four scientists from Cancer Research Centre (CIC-IBMCC), part of the University of Salamanca and CSIC, who were awarded the 13th Esteve Foundation Research Award by an international jury. The jury found that this article was the most impactful in pharmacology written by a Spanish researcher between 2010 and 2011.

The paper, written by Samuel Seoane, Juan Carlos Montero and Alberto Ocaña, under the coordination of Athanasius Pandiella, and published in The Journal of the National Cancer Institute, demonstrates that the combination of these two drugs prevents tumour growth in animal studies. Thus far, the monoclonal antibody trastuzumab has been used with great success in the treatment of HER2 +, and its combination with dasatinib (an inhibitor of tyrosine kinase hitherto used in chronic myeloid leukaemia) increases efficacy without causing resistance.

After satisfactory findings in animals, the research has already moved onto clinical trials, being carried out by the Spanish Group for Breast Cancer Research (GEICAM). While conventional treatment with trastuzumab has an efficiency of 65%, its combination with dasatinib has obtained 100% positive responses among the ten patients in the first phase of the study. If the positive results are confirmed, more than 600,000 patients could benefit from these findings in Spain.

On July 5th, 2013, the Research Award ceremony was held at the Centre for Cancer Research of Salamanca in the presence of the Vice Rector of Research at the University of Salamanca, M ª Ángeles Serrano; the director of the CIC, Eugenio Santos; the director of the Esteve Foundation, Felix Bosch; and the first author and the coordinator of the winning article, Samuel Seoane and Athanasius Samuel Pandiella. We spoke to them before the ceremony.

What improvements can this combination of two drugs have in treating this type of breast cancer?

Atanasio Pandiella: The idea behind these studies is to improve the efficacy of treatments against a protein that occurs in a subset of breast tumours. From the genetic point of view, right now there are more than ten different types, but clinically, in breast cancer there are three subgroups: those tumours have hormone receptors, which are the most frequent and best treated; the HER2 positive and another subgroup that does not have HER2 or hormone receptors and is therefore called triple negative. The latter two are now the most aggressive and in HER2-positive tumours are a group of patients who respond well to therapies directed against this protein but there is another group that does not. The idea behind this work is to understand why these patients do not respond to this therapy and search for ways to increase the effectiveness of treatments against such tumours. Hence comes the idea of ​​combining therapies that do not work or work very inefficiently with a number of other drugs. We combined one of these drugs, trastuzumab , with other drugs. And we found that a combination of trastuzumab with another drug called dasatinib was very effective. What we aim for is that targeted therapies against HER2 are effective in all patients. So we are studying those who are stronger, trying to devise strategies to increase the efficacy of anti-HER2 therapies.

You studied more than a dozen drugs. Was it a long process?

Samuel Seoane: The truth is that we were quite lucky in that respect. When we did preliminary tests with several drugs we quickly realized that one was very good, therefore we did not lose much time in this first phase of work. The second phase was to check what was the mechanism by which the combination of trastuzumab and dasatinib worked. The whole process took nearly two years, a process that is not too long. The laboratory results were quite strong and that makes things much easier. Progress is much slower when the results are more equivocal, then one has to repeat procedures, analyse statistics and so on.

Dasatinib was the only drug that worked. What happened to the rest?

AP: Now the number of drugs that we have combined has increased. Any new drug that reaches the laboratory is always used in combination with trastuzumab. We have an important line of research in haematology in the laboratory and that keeps us up to date on the drugs in haematology but are sometimes are slow to be incorporated into other types of tumours, but as we are involved in this field, when a drug appears we think may be of interest for breast cancer we quickly try it.

It has been three years since the publication of this winning article and now the research is in clinical trials. What response are you getting?

AP: The trial is in Phase 1b, in which we mainly seek the best combination of the classic drug dose, which is trastuzumab, and that which we are combining it with, which is the dasatinib used in hematologic therapies but not in breast cancer. In this first phase we have recruited a very high number of patients because the aim is to find the perfect dose. But at the same time, it has enabled us to see promising efficacy and safety data, because the 10 patients that have been treated with this new combination have had some clinical response. This does not mean a cure, rather that by the clinical evaluation criteria used by oncologists there has been an improvement, either in terms of tumour size or condition. The data, therefore, have been promising in the first group and now what we hope is for it to be passed onto a second phase with a larger number of patients.

How long do you think it will take for this treatment to be applied?

AP: Speaking of time is very risky because there are many regulations, in Spain unfortunately even more. In this Phase 1b clinical trial there are hospitals in Barcelona, Madrid, Valencia, Galicia and Andalusia participating. And in a country with 17 autonomies, we have to ask permission from each of the ministries. I have confidence that if the data are positive, we can launch in 2014, though that will depend on the authorities.

A year ago Samuel undertook another line of research at Santiago de Compostela. Are you still working in the same line of research?

AP: We continue to work together. The fact that researchers are clearly in different centres makes the relationship not as close, but both professionally and personally we continue to maintain a very good relationship. We are working on joint projects that began here and in the future we hope to continue doing so.

Has this time of cutbacks in research that we are experiencing affected your work in some way?

SS: No doubt about it. State and regional cuts in grants and research projects have been noticeable, eg in delaying projects to save on scholarships. It has been very noticeable.

AP: We are at a dangerous time for science in Spain. Dangerous because if there is not minimal funding of researchers they are going to leave the country, as is happening already, and all the money and all the effort that has been used in the past 35 years will be lost, along with what all that entails. Science to me is synonymous with progress. If the country does not do research, it will be more expensive for us in the future. It is often said that there is a lot of investment in science and not much return. I believe that science in Spain should be compared with science in the United States, England and Germany. These countries invest in science to apply it and often as a social commitment to advancing knowledge. If Spain wants to be one of those countries at the top we must invest in science even thought the return in not always immediately visible. As a strong country we have the same commitment to increasing knowledge beyond applicability.

Finally, how does the research group feel about the Esteve Foundation Research Award?

AP: With great joy and great satisfaction, especially since it is a great reward for us that this combined treatment is being evaluated clinically, without detracting of course from the Esteve Foundation. From the laboratory we are pleased to be getting results that we believe are useful to society.

The tribunal, composed of Sergio Erill (Barcelona), Rachel Tyndale (Toronto) and John Wood (London), also wanted to highlight with an honourable mention the article Integrative Genomic and Proteomic Analyses Identify Targets for Lkb1-Deficient Metastatic Lung Tumors, written by Julián Carreteroin the journal Cancer Cell (2010; 17:547-59).