Catalan scientists find explanation for unexpected cure of some cancer patients

BarcelonaEveryone has heard of cases of patients with advanced cancer who were given a short time to live by doctors but instead exceeded all expectations and are still alive after years. Although it may seem like it, they are no rarity. It is estimated that about 10% of advanced cancer patients who statistically have little time left, respond to chemotherapy unexpectedly well and, in some cases, they are cured. They are the great responders or also Lazarus patients. Now we are only beginning to know the reason for their extraordinary response to conventional drugs. A study led by the US National Cancer Institute (NCI) in which the José Carreras Research Institute against Leukaemia has participated has determined that the existence of lesions in tumours favours a good response to the drugs. The work has been published in the journal Cancer Cell.

We have seen this phenomenon of an exceptional response to all types of tumours", explains Manel Esteller, research professor at Catalan research body ICREA and director of the José Carreras Institute, "in glioblastoma [a very aggressive brain tumour], in advanced metastatic breast tumours and pancreatic tumours". In these and other forms of cancer, patient survival is often limited. "It often happens that from one visit to the next the disease leads to death," he says. There are cases, however, where the patient not only survives but also responds "exceptionally" to conventional chemotherapy. The response may be to go into total remission of the tumor.

What makes this so? "We have seen that there are tumors that have specific lesions that open the door to the action of the drugs," answers Esteller. The lesions are caused by genetic and epigenetic alterations that the tumor "cannot repair". Tumour cells, the researcher continues to explain, accumulate mutations and epigenetic alterations that condition their growth and aggressiveness. Under normal conditions, DNA corrects the errors derived from the mutations, but there are cases that escape this natural repair mechanism. "Some tumors cannot repair the errors, which causes them injuries at the molecular level," describes Esteller. This is exactly what happens with the exceptional responders, for whom tumors "open an entry point" to drugs. The patients, without anyone expecting it, almost "come back to life". Hence the name of Lazarus patients, in reference to the dead person whom Jesus resurrects in the New Testament.

The finding, according to Esteller, will help to better define what is the most appropriate therapy for a given patient based on a genomic analysis. "It will not provide prognostic value, because we already know that the patient is not doing well, but it will be predictive with respect to the medication to be administered," he considers. The fact that only conventional drugs have been considered and that these can explain one out of every four cases opens the door to see if the response is extensible with the new generation of chemotherapy agents. Similarly, Esteller believes that when tumors are subjected to "multiomic" techniques, i.e. from genomics to metabolomics through proteomics or other technologies, other types of lesions can be detected through which the drugs may enter. "If any of these lesions could be induced in the tumors, perhaps we could eliminate them by taking advantage of this entry route," he suggests.

Esteller's team has done the epigenomic analysis of the tumors in order to find out if there were common factors that led some genes to be activated or silenced.