Women have a 1 in 78 chance of being diagnosed with ovarian cancer in their lifetime. When it comes to cancer-related deaths among women, ovarian cancer ranks fifth, accounting for more deaths than any other cancer of the female reproductive system according to the American Cancer Society.
Although some progress has been made, the outlook for women diagnosed with ovarian cancer has remained little changed over the past 20 years.
A team of researchers from UConn’s School of Medicine has received a $1,875,750 grant from the National Cancer Institute to determine ways to improve the outlook of ovarian cancer patients. Investigators on the project include Drs. Frank Torti, Suzy Torti, and Molly Brewer.
Currently, the most effective and widely-used drugs for ovarian cancer – cisplatin and carboplatin – have been shown to lose their effectiveness over time due to drug resistance that develops in the patient: that is, ovarian cancers acquire the ability to repair the DNA damage caused by cisplatin and other DNA-damaging drugs.
Poly (ADP-ribose) polymerase (PARP) inhibitors are targeted therapies used to treat ovarian cancers. PARP is protein involved in DNA repair. PARP inhibitors prevent cancer cells from repairing damage to their DNA, which leads to the ultimate decline and extermination of the cancerous cells.
Specifically, inhibiting PARP plays an important role in treating cancers that have errors in their DNA repair genes including the BRCA mutations. However, although PARP inhibitors have exhibited promising results, patients with germline or acquired mutations in DNA repair genes only account for a small fraction of patients with ovarian cancer.
Recently, Dr. Torti and his team discovered a new method that may be applicable to a larger population of ovarian cancer patients. They found that reducing levels of sideroflexin 4 (SFXN4), a mitochondrial protein, can simultaneously inhibit DNA repair and increase DNA damage in ovarian cancers.
Additionally, the UConn team hypothesizes that SFXN4 inhibitors can be utilized to enhance the success of DNA-damaging drugs like cisplatin and broaden the effectiveness of PARP inhibitors in patients who do not have defects in DNA repair.
The researchers plan to explore the extent to which SFXN4 reduction increases oxidative stress and inhibits DNA repair. They will also look at how SFXN4 inhibition increases the efficacy of both PARP inhibitors and platinum-based compounds. This will help them determine the exact molecular mechanism of SFXN4 function.
The results from this research will aid in the development of innovative treatments for ovarian cancer and may ultimately help to successfully treat ovarian cancer patients and reduce related deaths.
“SFXN4 reduction as a strategy to enhance the effectiveness of DNA-damaging drugs such as cisplatin and expand the use of PARP inhibitors to patients with normal DNA-repair function is still in its early stages,” says Dr. Torti. “Because SFXN4 is a new target and SFXN4 inhibition is a new approach to the treatment of ovarian and other cancers, moving our observations from the laboratory to the clinic would, if successful, be a substantial advance – certainly one worth pursuing.”
Dr. Frank Torti received his BA and an MA from Johns Hopkins University, his MD from Harvard Medical School, and his MPH from the Harvard School of Public Health. He served as Director of the Comprehensive Cancer Center and Chair of the Department of Cancer Biology at Wake Forest School of Medicine. He came to UConn in 2012 and is currently a Board of Trustees Professor in Medicine. He held a merit award from the National Institutes of Health, and has received continuous funding from the NIH since his laboratory’s inception.
Suzy Torti attended Reed College for her BA in Biology and then Tufts University for her Ph.D. in Molecular Biology and Microbiology. Currently, she is a professor in the Department of Molecular Biology and Biophysics at the University of Connecticut. Her research interests revolve around the regulation of iron metabolism and the relationship between iron and cancer.
Dr. Molly Brewer obtained her BS and DVM at Texas A&M University, her MD from SUNY Upstate Medical School, and her MS for a Statistics and Clinical Research Design at the University of Michigan’s School of Public Health. Currently, Brewer is professor and chair in the Department of Obstetrics and Gynecology at UConn Health. In regards to her research, Brewer is interested in cancer stem cells and their role in the recurrence of ovarian cancer and chemoresistance.
Grant #1R01CA233636-01A1
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