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Impact of the expression of cell cycle biomarkers in ovarian carcinoma

Abstract

Ovarian cancer is the seventh most frequent neoplasm among women in the world and the eighth in mortality. Among ovarian tumors, high-grade serous carcinomas account for 90% of the deaths from the disease, with only 1% of the cases being restricted to the ovary at the time of diagnosis. Overall 5-year survival for patients with stage IIIC is only 25-30% and for patients with stage IV is 10-15%. Thus, finding new and more effective treatment strategies for this tumor type is extremely important. The main molecular alteration of these neoplasms is their great genetic instability, being a consequence of the presence of TP53 somatic mutations in 97% of the cases. Another gene frequently altered in ovarian carcinoma is CCNE1, a gene that encodes Cyclin E1, whose amplification has been observed in 15 to 20% of patients. Cyclin E1 overexpression can override the brakes imposed by the G1-S checkpoint of the cell cycle, leading cells to an aberrant S-phase where occurs the accumulation of genomic alterations that were not previously corrected. In tumors with G1-S checkpoint defects, the cells are very dependent on the G2-M checkpoint to prevent apoptosis by mitotic catastrophe. The tyrosine kinase Wee1 is one of the regulators of the G2-M checkpoint, acting through the phosphorylation of CDK1 and thus preventing the formation of the Cyclin B-CDK1 complex necessary for the mitosis. A Wee1 inhibitor, ADZ1775, was recently described. Based on the defects of the G1-S checkpoint that occur in TP53 deficient cells, ADZ1775 was used in phase II clinical trials for ovary cancer resistant to the first line of treatment, showing a partial response. Considering that cyclin E1 overexpression together with the absence of TP53 can contribute to evade the G1-S checkpoint, we believe that patients bearing these two alterations might become more sensitive to ADZ1775 treatment. Thus, this project aims to verify in pre-clinical trials the sensitivity of ovarian cancer cells overexpressing cyclin E1 to the treatment with AZD1775, in the presence or absence of TP53 mutations. In addition, we will evaluate the percentage of patients with ovarian cancer in the A.C.Camargo Cancer Center who present CCNE1 amplification/Cyclin E1 overexpression and mutations in TP53, constituting a subpopulation of patients that will potentially benefit the most from AZD1775 treatment. (AU)