The Multiple myeloma escapes the immune system thanks to the loss of the Gabarap gene, a ‘trick’ that allows diseased cells to hide, to become invisible to the body’s natural defenses. To discover the secret of the second most frequent blood cancer in Italy, opening up new therapeutic mixes that could fight it more effectively by overcoming the neoplasm’s resistance to pharmacological treatments, is one study by researchers from the Irccs of Candiolo (Turin), published in ‘Blood’.
Multiple myeloma, caused by excessive reproduction of plasma cells in the bone marrow, every year in our country it affects around 2,700 women and 3 thousand men. After the first treatment, most patients develop a recurrence. And as the disease progresses, with relapses and therapeutic attempts, myeloma becomes increasingly difficult to treat. “The current therapeutic paradigm for multiple myeloma – explains Annamaria Gullà, head of the Laboratory of Translational Hematology and Immunology of the Irccs Candiolo – includes a combination therapy that may include immunomodulatory agents, proteasome inhibitors, corticosteroids and anti-Cd38 monoclonal antibodies However, many patients relapse and/or become refractory to these therapeutic classes. This is why our efforts are focused on finding new, more effective weapons to prolong the long-term response and improve patients’ quality of life.”
The Piedmontese team started by analyzing the mechanism of action of the drug bortezomib. It is a “proteasome inhibitor”, a set of “cellular organelles capable of removing damaged cells”, explains Gullà. Bortezomib “contrasts multiple myeloma both directly, by affecting tumor cells, and indirectly, by activating the immune system and causing so-called immunogenic cell death”. However, the drug shows a “long-term loss of efficacy”, which “may result from the onset of new forms of resistance to therapy, in which bortezomib is no longer able to stimulate the immune system to recognize the tumor”. Through “a series of analyzes in preclinical models – describes the expert – we have demonstrated that dying tumor cells, directly affected by this first-line drug, express on their surface a protein known as calreticulin, which makes the tumor visible to the immune system which can thus attack it. But the loss of the Gabarap gene compromises the exposure of calreticulin, thus reducing the action of the immune system against cancer.”
“It is no coincidence that a low level of Gabarap expression was independently associated with shorter patient survival with multiple myeloma and a reduced immune infiltration of the tumor”, underline the researchers from Candiolo. The scientists of the oncology Irccs of Piedmont have also demonstrated that “rapamycin, a drug initially used in organ transplants, can restore the immunogenic effect of bortezomib”.
“We believe – continues Gullà – that the combined use of bortezomib and rapamycin could improve patient outcomes with multiple myeloma, in case of loss of Gabarap. We have therefore identified a possible candidate, a drug already used in clinic, rapamycin, which could be added to the current treatments in use in patients with low levels of this gene. Gabarap is located on chromosome 17p, the deletion of which defines high-risk myeloma patients. This mechanism could therefore be added to those already known that contribute to the negative prognosis of these patients.”
“The results of this work – comments Salvatore Nieddu, general director of the Irccs of Candiolo – are a further demonstration of our continuous commitment aimed at researching new approaches for the therapy of tumors, even those most difficult to cure, such as multiple myeloma. This specific blood tumor appears to be able to defend itself from the drugs currently in use through various resistance mechanisms. It is therefore necessary to develop an increasingly rich armamentarium of drugs which, combined together, can reduce or prevent the tumor from developing the ability to resist treatments”.
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