One of my international readers, Roberto (Rob) from Spain, forwarded me this article about a Spanish research team’s goal of developing ways to overcome myeloma’s ability to develop resistance to chemotherapy:
A team of the Salamanca Cancer Center seeks to reverse the resistance of multiple myeloma tumor cells in disease treatments
A team of scientists from the Centro de Investigación del Cancer de Salamanca (Cancer Research Center of Salamanca) led by Enrique Ocio San Miguel, has achieved a pharmacological reversion of the resistance of tumor cells from multiple myeloma in treatments against the disease.
That is one of the first conclusions of a work that tries to find out the mechanisms that cause the acquired resistance to the disease (one of worst prognosis tumor processes at present) to new drugs.
Today, the development of resistance is one of the major problems in Oncology. Patients who do not respond to treatments or who relapse «demonstrate that the tumor cells have developed resistance to the drugs used», explains Dr. Ocio.
The laboratory where he works with his team analyzes the characteristics of these resistances. It tries find out how they are and what mechanisms cause them in the search of a common pattern of that cell behavior. To advance in the study there is the possibility of going to the patients or create in mice a model of resistance as the Ocio’s team does from two years ago. Trials with people will arrive shortly. In the rodents they generate a myeloma that is treated with immunomodulators drugs (thalidomide, lenalidomide, and pomalidomide) and proteasome inhibitors (bortezomib and carfilzomib). Today both are the essential treatments in patients. Just as it happens in humans (although in a more vertiginous way given that the aggressiveness of the disease in animals is greater than that which affects humans) at the beginning they respond, the tumor does not grow and even disappears. However, if you continue dealing with the same medication, the tumor reappears or cells grow and therefore the disease progresses. Scientists try to establish the differences between the initial cells and those that reappear.
Resistance is manifested in two ways. In the first case the patient does not respond to drug therapy. In the second case (this fits the model in which they are working in the CIC) the patients respond at the beginning but then the disease progresses. «Although patients get to be in complete remission and the disease is not detected, it is known that, nowadays, in most cases Myeloma is incurable even if you have a very good response,» warns Dr. Ocio, who is also part of the team of Hematology led by the prestigious Dr. Jesús San Miguel.
After two years of research, experts have focused on compare immunomodulators to see that when the cells become resistant to lenalidomide they respond to pomalidomide; they don’t have cross-resistance. «Despite being drugs of the same family, they have different mechanisms of action, » explains Ocio who is now seeing if one can override the other.
If it could be proved that to alternate treatment from one to another drug serves to fight the disease in a continuously way, it would be a decisive step towards the ‘chronicity’ of myeloma, the real goal of Ocio and his team in the search for a treatment that will cure or at least prolongs the effectiveness of the current way to deal with the disease.
Research has also enabled to determine that, when the disease becomes resistant in mice, after some time without receiving treatment again it becomes sensitive. Though in humans the disease reappears with greater virulence and the response to the treatment lasts less and less. The clinical implications of this finding are that Ocio assesses the implementation of a test «to see if it is convenient to re-treat patients with the same drug once the sensitivity comes back ».
Learn about genetics
The Enrique Ocio’s team already knows that when the tumor is treated in the initial moment, in which the cell is sensitive, many genes change and the vast majority of them will return to the initial situation when the cell becomes resistant. It’s a way of finding, explains Ocio, «that the drug is not really acting and is not able to change those genes». So, it is a priority to understand the mechanisms that they make resistant to the cells knowing the genetic imbalances that change when the cells become resistant. If one could find out if there is some gene that varies specifically the resistances ‘it would be the key to everything’ because the scientists could ‘attack’ a concrete place and come to prevent and even reverse the resistance.
In this regard, is known that one of the pathways that are activated when the cells become resistant is known as MEK-ERK. Treating the mice with pomalidomide – latest immunomodulator in use – and an ERK inhibitor is how experts have succeeded in making the diseased cell again be sensitive and therefore reverse the pharmacologically resistance. It is, says Ocio, «an interesting way for locating specific genes». He prefers to be cautious because there are still many steps for giving.
When the analysis of the effect of immunomodulating drugs is completed, in the first quarter of 2013, it will be the time to be able to move to patients the advances obtained by the clinical trial. In the coming weeks, the Ocios’s team will begin the process again but this time focusing on inhibitors of the proteasome. The steps will be repeated «to see if similar conclusions are reached and it’s found that the mechanisms are different or common to immunomodulators». It would be very interesting, recognizes Ocio, “to see that there exists a mechanism of common resistance in myeloma for any medicament”. That would suppose that there exists an alarm on which to act.
Exaggerating the optimistic tone, if the mechanism of resistance was the same for all types of tumors, it would result in the major medical revolution of contemporary history.
The experience of Ocio, however, makes him to be realistic because he recognizes the problem of that the tumor cell “learns” to escape “and if you block a mechanism is normal that appear others”. He has seen it too many times to think that one could find a definitive cure. He is resigned to make myeloma a curable disease or, at least, a chronic disease. For that it is necessary that treatments last «more and more», a goal only reachable if you are able to wipe out resistance. Today all tumors, until those of better prognosis, develop those strengths.
Enrique Ocio also has in mind going a step further. In the future he wants to test the effect of alternation of treatments (where are mixed immunomodulatory drugs and proteasome inhibitors) through a clinical trial. Now he does something similar in myelomas that affects older patients. They are divided in two groups. The half is given nine cycles of inhibitors followed by other nine of immunomodulators. The other half receives alternating cycles. They try to see if administering them in this way provoke that cell does not ‘learn’. Each cycle lasts one month. Still it is necessary to wait to know what happens. The alternation between drugs of the same family will be tested in future trials. It is matter of trying to come to the situation that more approaches to the final aim.
Though at present the investigation of resistances is fashionable, the model of the CIC team of Salamanca is unique by the meticulous way of studying their reactions. In myeloma, Ocio says, also they are studying a protein of immunomodulators called Cereblon which could be one of the mechanisms of action and of resistance to immunomodulators. It will be a question of continuing to work.
Rob took the time to translate the article into English for us. Thanks, Rob! Unfortunately, multiple myeloma is a universal language. Here’s hoping Dr. Ocio’s team is successful!
Feel good and keep smiling! Pat