Repairing broken DNA is a crucial feature of normal cells that prevents cancerous mutations from developing. But compromised DNA repair is a common feature of most cancers, making DNA repair in cancer cells heavily reliant on one or a few repair mechanisms.

A researcher who studies the mechanisms of DNA repair in normal cells says this may be a vulnerability in cancer cells that can be exploited therapeutically. Geneticist Francesca Cole was recruited from Memorial Sloan-Kettering to the University of Texas MD Anderson Cancer Center, Science Park, with the help of a First-Time Tenure-Track Award from CPRIT in 2012.

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Repairing broken DNA is a crucial feature of normal cells that prevents cancerous mutations from developing. But compromised DNA repair is a common feature of most cancers, making DNA repair in cancer cells heavily reliant on one or a few repair mechanisms.

A researcher who studies the mechanisms of DNA repair in normal cells says this may be a vulnerability in cancer cells that can be exploited therapeutically. Geneticist Francesca Cole was recruited from Memorial Sloan-Kettering to the University of Texas MD Anderson Cancer Center, Science Park, with the help of a First-Time Tenure-Track Award from CPRIT in 2012.

Cole studies a DNA repair mechanism called homologous recombination, which uses an intact DNA template to faithfully repair a double-stranded break. Any defects in this repair mechanism can lead to cancer. Inherited defective genes like BRCA1, which are crucial for homologous recombination, can lead to a predisposition to cancer, such as breast or ovarian cancer.

“It’s important to understand homologous recombination in order to improve cancer therapies,” Cole says, “both because of its role in the etiology of cancer and in providing novel targets for therapeutics.” Most tumors, no matter how they are formed, have defects in homologous recombination, which means the cancer cells rely heavily on a fewer number of possible pathways to repair their genomes. Knowing what these pathways are, and which ones are the most vulnerable to targeting, means cancer drugs can be made more precise and effective.

Cole studies homologous recombination by looking at the ways in which sperm and eggs are formed. It’s a perfect model system for studying the mechanism of homologous recombination, because the process by which these sex cells are created makes heavy use of it. During meiosis, the parent cell divides, deliberately inducing a number of double-stranded DNA breaks. The cells then combine genetic information from each parent to create unique daughter cells, using the DNA from the opposite parent as the repair template.

“The parent chromosomes are not identical, so any differences will allow us to track the outcomes of DNA repair highly accurately,” Cole says.

By studying homologous recombination in animal models, using selective mutation of the genes involved, Cole says she can study the roles of specific proteins. She is also looking at the efficiencies and vulnerabilities of various backup pathways, with an eye toward identifying which ones might be most susceptible to an anticancer drug.

Cole has found that there are multiple redundant and independent pathways that contribute to the repair of double-stranded breaks. By interrupting the repair pathways in her model system, she is finding out which pathways compensate for each other and which ones might make the best therapeutic targets.

Because each of these pathways is multifaceted, Cole said the project is labor-intensive. “Having the CPRIT investment in my lab allowed us to have a large team of researchers that is able to look at each of those pathways individually, as well as target those pathways individually and in combination,” she says. “We needed a very large team and lots of resources to do that.”

Leveraging the CPRIT investment, Cole received a prestigious $2.4 million Director’s New Innovator Award from the National Institutes of Health in 2015.

Cole received her undergraduate training in biology at Hunter College and her Ph.D. in biomedical sciences from Mount Sinai School of Medicine of New York University. She became a postdoctoral fellow at Sloan-Kettering in 2004.

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