Ovarian cancer, a more aggressive molecular process of cancer development discovered at IEO. The findings were published in the International Journal of Cancer
A group of researchers fromEuropean Institute of Oncologyin collaboration with researchers of the IRCCS House for Relief of Suffering Foundation Of San Giovanni Rotondohas 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, have recently been published in the International Journal of Cancer.
The study supported by AIRC Foundation was coordinated by Ugo CavallaroDirector of the Research Unit in Oncological Gynecology of the IEO. Ovarian cancer is still difficult to treat and the high-grade serous ovarian cancer it 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 at the onset. asymptomatic, and the high level of cellular heterogeneity has so far made it difficult to characterize the molecular changes that promote their progression. The efforts of international research have so far focused on the sequencing of the genome of both the primary tumor and the metastases, to compare them and identify the molecular alterations that determine the spread of the disease, the cause of its lethality. The results were only partial.
“To identify the ‘trajectory’ of the ovarian cancer we have thought of an innovative approach – he explains Cavallaro. – From the ovarian cancer of a single patient we have generated a series of experimental tumor models that each recapitulate a different step 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 to say, 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 patients with ovarian cancer. By comparing our models with the data contained in these databases, we discovered that the molecular signatures identified have prognostic power, that is, they give indications on the biological process of evolution of the disease. Not only that, but they also seem to have predictive capabilities, 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“.
Ovarian cancer, the key role of PI3K protein
“We have demonstrated – he continues Fabrizio Bianchi from the IRCCS House for Relief of Suffering Foundation – that the PI3K protein it plays an essential role in keeping ovarian cancer stem cells alive, the cells from which cancer 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. PI3K’s role as a promoter of ovarian cancer has been known for some time 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, revealing the role of a recently discovered mutation in gene PIK3R1, which we know to be the regulator of PI3K. The mutation in this gene causes an abnormal activation of PI3K, which shields the cancer stem cells, rendering them immortal. It is therefore conceivable that PI3K inhibition could overcome chemoresistance, a hypothesis that deserves further investigation for its potential implications for the clinical management of patients with ovarian cancer. “
“In summary we have outlined a workflow that, through DNA and RNA analysis, has obtained models of molecular alterations important for the treatment of ovarian cancer, as exemplified by the PIK3R1 mutation and the consequent modified regulation of PI3K. 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 researchers from the IEO driven by Giuseppe Testa andMario Negri Institute driven by Raffaella Giavazziwas conducted with the support, as well as of AIR FoundationC, of Ministry of Health and of IEO-Monzino Foundation.