A patient with severe kidney cancer survives in an extraordinary way and CNIO researchers discover why

Researchers from the National Cancer Research Center (CNIO) have managed to explain why a patient with metastatic kidney cancer has survived in an extraordinary way.

According to their findings, it had rare mutations that potentiated the effect of its treatment, the drug temsirolimus.. It is now known that this drug and others like it are suitable for those who have these mutations.

15 years ago, a woman in her thirties was diagnosed with metastatic kidney cancer.. The oncologist José Pablo Maroto, from the Hospital de la Santa Creu i Sant Pau in Barcelona, decided to treat her with the drug temsirolimus, which worked much better than expected.

The patient overcame cancer. Nine years later, a bone metastasis was detected, but this time, too, temsirolimus was effective.. Now, it has been discovered why temsirolimus has been so effective in this case and in that of two other patients.

This finding will make it possible to identify other patients with kidney cancer for whom temsirolimus and other drugs from the same family will most likely be the ideal treatment.. Today these drugs, inhibitors of the mTOR pathway, are used only when others fail.

“Currently, drugs from the temsirolimus family are not usually the first option in kidney cancer, but this result indicates that in some very specific patients, they should be, because they work very well. We now know how to identify these patients”, explained Cristina Rodríguez-Antona, researcher at the CNIO's Human Cancer Genetics programme.

Finding this answer has taken years. It was necessary to find more cases similar to those of the first patient. The Sant Pau team selected them and sent their samples to the CNIO, where they were analyzed in depth.

The key lies in very rare mutations in the USP9X protein, which regulates critical cellular processes for tumor growth.. Research shows that mutations knock out the function of USP9X, and when that happens the cell doesn't recycle its waste well and dies.. Temsirolimus acts on a different molecular pathway, but has a similar effect; in patients where USP9X does not work, the impact of this drug is potentiated.

“To understand the effect of mutations in USP9X, we developed cell models and did proteomic assays that indicated that tumor cells without USP9X had impaired cellular autophagy [the process by which the cell recycles its waste products]. Temsirolimus also alters autophagy, which causes a synergistic effect, making tumors respond better to this treatment,” Rodríguez-Antona detailed.

In addition to identifying other patients with USP9X mutations who might benefit from treatment with drugs from the temsirolimus family, this finding supports the development of new UPS9X inhibitor drugs as an innovative therapeutic strategy.

“A compound that cancels the function of UPS9X would have a synergistic effect with temsirolimus, increasing its anti-tumor efficacy”, Rodríguez-Antona pointed out.

RESEARCH FUNDED BY CARRERAS SOLIDARIA

The research, published in the scientific journal 'International Journal of Cancer', has been financed in part with donations obtained in charity races organized by the Club de Atletisme A 4 el KM, from Les Franqueses del Vallés (Barcelona), promoted by the patient .

“This publication is a pride. It is a collaboration between an association that organizes year after year a popular race for kidney cancer research; patients who provide samples in difficult times; and basic and clinical researchers. Everything, to answer why has this treatment worked so well? It is not the first case in which we ask ourselves this question, but it is one of the first in which we obtain a clear answer”, highlighted Maroto.

The authors of the study send one last message: “Translational studies are complex because they require close collaboration between clinicians and basic researchers.. In addition, patients play a leading role by donating their samples at a very difficult time.. This study in rare tumors has only been possible thanks to the generosity of the patients, whose samples are the basis of all subsequent molecular work and who drove the study from its inception.”