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CDMRP Investigator Vignette

Modeling Human Epithelial Ovarian Cancer in Mice by Alteration of Expression of the BRCA1 and/or p53 Genes

Denise Connolly, PhD; Fox Chase Cancer Center

The OCRP has a strong focus on innovation for its research grants. And that presents a really unique opportunity for young investigators to develop an idea, write a grant for that idea, and obtain funding which can really be key in initiating a person's career.

When I was a post doc in a molecular pathology laboratory that was focused primarily on cervical cancer but I started to develop an interest in ovary cancer. From there, I left and came to Fox Chase to work with Tom Hamilton to develop mouse models of ovarian cancer. And based on the success of that project, I was branching out on my own, starting my own laboratory. And I applied to the DoD for a grant for one of my first research grants to start my own research program here at the center.

My OCRP grant was based on making a genetically engineered mouse model of ovarian cancer. Inherited ovarian cancer is strongly associated with mutations in BRCA1 and BRCA2 and our basic idea was to obtain mice that had conditional knockouts for p53 and BRCA1 and cross those mice. Conditional knockouts means that they have an alteration in their gene that doesn't affect them until you induce the condition by administration of an enzyme called Cre recombinase.

We used a recombinant virus that expresses Cre recombinase and administered that virus locally around the ovary to inactivate those two tumor suppressor genes just at the site of the ovary. We have to do that because inactivation of BRCA1 in the whole mouse is lethal so you have to localize the inactivation because it's an important gene. We targeted specifically the ovary to inactivate those tumor suppressor genes.

The tumors that formed however were not the type of tumor that we expected to see. We saw the formation of ovarian leiomyosarcomas, which is a relatively rare type of tumor. So we were a little bit surprised by this finding, but sometimes when you make genetically engineered mouse models, tumor types aren't always what you expect them to be or what you might predict them to be based on studies in humans.

And although the results from that particular genetic cross and inactivation of p53 and BRCA1 gave us somewhat surprising results it actually spurred other research in the laboratory which has continued over the years.

Our current research has been really centralized around combining imaging with mouse models of ovarian cancer. Ovary cancers occur deep in the mouse body. And in order to understand what's happening to a tumor over the course of time, you need ways to see the tumor. And we've developed imaging methods using magnetic resonance imaging, bioluminescent imaging, and fluorescent imaging to help us watch the tumors grow in the mice in real time.

And that actually enables us to conduct studies with genetically engineered mouse models of ovarian cancer or skid xenograft models of ovarian cancers and allows us to actually understand how tumors are responding to novel treatments that we expose them to.

The opportunity to use imaging allows us to do smaller mouse studies and obtain actually more statistically significant results because they can be more quantitative.

The OCRP, because of its focus on innovative technology, allows people to take these very creative ideas and move them forward.

The DoD grant that I received gave me that kick start, to start this laboratory.