An exceptional discovery made by a group of researchers from the European Institute of Oncology (IEO) , in collaboration with researchers from the IRCCS Foundation for the Relief of the Suffering of San Giovanni Rotondo, has identified a succession of molecular mutations that appear to cause the progression of ovarian cancer more widespread and more aggressive . The biological data obtained, with a strong therapeutic potential, were recently published in the International Journal of Cancer. The study supported by the AIRC Foundation was coordinated by Ugo Cavallaro, Director of the Research Unit in Oncological Gynecology of the IEO. A difficult tumor to cure
Ovarian cancer is still difficult to cureand high grade serous ovarian cancer is the most widespread (70% of cases) and most aggressive form. Unfortunately, the currently available therapies have limited efficacy for a clinical and a biological reason: in about 80% of cases the tumor is diagnosed at an advanced stage, being completely asymptomatic at onset , and the high level of cellular heterogeneity has so far made difficult to characterize the molecular changes that promote their progression. International research efforts have so far focused on genome sequencing of both primary cancer and metastases, to compare them and identify molecular alterationswhich determine the spread of the disease, causing its lethality. The results were only partial. An innovative approach
“To identify the” trajectory “of ovarian cancer we have thought of an innovative approach – explains Cavallaro – From the ovarian tumor of a single patient we have generated a series of experimental tumor models that each recapitulate a different passage in the progression of the disease . We thus obtained the genomic (DNA) and transcriptomic (RNA) profile of the various models, in order to obtain molecular “signatures”, that is, sets of mutations or genes specifically associated with the different models. Using this key, we then queried the worldwide databases that contain the genetic data of numerous cohorts of ovarian cancer patients. By comparing our models with the data contained in these databases, we discovered that the molecular signatures identified have prognostic power, i.e. they give indications on the biological process of evolution of the disease.. Not only that, but they also seem to have predictive capacity, that is, they can give indications on the effectiveness of treatments. In other words, the molecular signatures obtained through different experimental models but deriving from a single tumor (and therefore a single patient) have provided clinical information that can also be extended to other patients, which includes prognosis and prediction of the response to chemotherapy. We have also obtained very interesting data , at least potentially, from a therapeutic point of view, discovering a vulnerable point of ovarian cancer ». The essential role of a protein
“We have shown – continues Fabrizio Bianchi of the IRCCS Casa Sollievo della Soflievo Foundation – that the PI3K protein plays an essential rolein keeping alive the cancer stem cells of ovarian cancer, the cells from which the tumor arises and regenerates itself. PI3K could therefore be a new possible therapeutic target for the elimination of this subgroup of cells so important in the relapse and chemoresistance of the disease.
The role of PI3K as an ovarian cancer promoter has long been known and its possible inactivation has been widely explored as a therapeutic strategy. Our study extended previous observations on the link between PI3K and ovarian neoplasia by unveiling the role of a recently discovered mutation in the PIK3R1 gene, which we know is the PI3K regulator. The mutation in this genecauses an abnormal activation of PI3K, which shields the cancer stem cells, rendering them immortal. It is therefore possible to imagine – underlines Bianchi – that PI3K inhibition can overcome chemoresistance, a hypothesis that deserves further investigation due to its potential implications for the clinical management of patients with ovarian cancer “.
‘In summary, we outlined a workflow that, through DNA and RNA analysis, obtained models of molecular alterations important for the treatment of ovarian cancer, as exemplified by the PIK3R1 mutation and the consequent modified PI3K regulation. The alterations thus identified with our approach could become targets of targeted drugs, to offer new therapeutic options also for this fearful and insidious female tumor », concludes Cavallaro.
The study, which saw the collaboration of other IEO researchers led by Giuseppe Testa and the Mario Negri Institute led by Raffaella Giavazzi, was conducted with the support, as well as the AIRC Foundation, of the Ministry of Health and the IEO Foundation. Monzino.

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