Ovarian clear-cell carcinoma (OCCC) is an aggressive form of cancer. Although its incidence is not high, accounting for 5–20% of all epithelial ovarian cancers (EOCs), it has a poorer prognosis, higher recurrence and lower survival than other EOC types, particularly when diagnosed at advanced stages. A better understanding of OCCC development and progression could lead to improved treatments and outcomes for those affected, and a new tool for studying OCCC holds promise for delivering this necessary insight. Scientists at University of North Carolina (Chapel Hill) recently announced the creation of a genetically engineered mouse model of OCCC that recapitulates the disease in humans. The model could be used to test potential therapies and to identify disease markers for diagnostic screening.

The scientists, led by Terry Magnuson, looked for genes that were frequently mutated in human OCCC and found that ARID1A (a tumor suppressor gene) and PIK3CA (a proto-oncogene) were both mutated in about 33% of cases. The mutation in ARID1A resulted in loss of function, whereas the mutation in PIK3CA resulted in activation. Magnuson's team recreated each mutation in mice and found that neither mutation alone caused tumor growth, but mice carrying both mutations together rapidly developed ovarian tumors (Nat. Commun. 6, 6118; 2015). “When ARID1A is less active than normal and PIK3CA is overactive, the result is ovarian clear cell carcinoma 100 percent of the time in our model,” Magnuson said in a press release. “It's an extremely aggressive model of the disease, which is how this form of ovarian cancer presents in women,” he continued.

The team showed that the two mutations cooperated to promote tumor growth by spurring the overproduction of interleukin 6 (IL-6), an inflammatory cytokine. Treatment with an antibody against IL-6 suppressed tumor growth in mice with mutations of both ARID1A and PIK3CA. Treatment with BKM120, a drug that blocks PIK3CA, also inhibited tumor growth, prolonging the lives of these mice. BKM120 is being studied as a treatment for other cancers.

In addition to evaluating potential treatments, the mouse model could be used to develop a test to screen for OCCC. Ronald Chandler, first author on the published report, explained, “If we can find something measurable that's downstream of ARID1A...then we could use it as a biomarker of disease. We could create a way to screen women. Right now, by the time women find out they have [OCCC], it's usually too late. If we can find it earlier, we'll have much better luck successfully treating patients.”