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PARP Inhibitors Could Repair DNA in Ovarian Carcinoma Cancer Cells

August 16, 2019

Dr. Connolly’s lab  indicated in this study that disruption of HSP90 function can lead to death of ovarian cancer cell lines without known defects in DNA repair mechanisms, such as BRCA1/2 mutations, when used in combination with a PARP inhibitor. Targeting of HSP90 results in destabilization of several proteins involved in DNA repair, resulting in the inability of the ovarian cancer cells to repair DNA damage.Dr. Connolly’s lab indicated in this study that disruption of HSP90 function can lead to death of ovarian cancer cell lines without known defects in DNA repair mechanisms, such as BRCA1/2 mutations, when used in combination with a PARP inhibitor. Targeting of HSP90 results in destabilization of several proteins involved in DNA repair, resulting in the inability of the ovarian cancer cells to repair DNA damage.

PHILADELPHIA (August 16, 2019) – Recently, Fox Chase Cancer Center researchers found a potential way to sensitize a new subset of patients with high-grade serous ovarian carcinoma to PARP inhibitors, a promising drug used in some cases of this disease. Ovarian carcinoma is the most lethal cancer of the female reproductive tract.

Treatments, especially for recurrent ovarian cancer patients, remain to be discovered. Many chemotherapies function by causing damage to DNA in cancer cells, but resistance to these drugs can occur by increasing proteins, such as PARP, that play a crucial role in DNA repair.

PARP inhibitors have been found to be effective in ovarian cancer patients, especially in those patients with mutations in factors that repair DNA, like the BRCA1/2 genes. However, treatment with these drugs has not been as effective in treating patients with normal BRCA1/2.

Due to the success of these PARP inhibitors in patients with DNA repair deficiencies, ways to utilize this promising drug in those individuals that can repair DNA effectively are currently under investigation.

Denise Connolly, PhD, associate professor in the Molecular Therapeutics Program at Fox Chase, and colleagues recently published a study in Cancer Biology & Therapy that examines whether a drug targeting heat shock protein 90 (HSP90), which is required for the stabilization of factors needed in DNA repair, could provide a potential way to sensitize tumor cells to  PARP inhibitors.

Connolly’s lab focuses on determining targeted therapeutics for ovarian cancer. Her group indicated in this study that disruption of HSP90 function can lead to death of ovarian cancer cell lines without known defects in DNA repair mechanisms, such as BRCA1/2 mutations, when used in combination with a PARP inhibitor. Targeting of HSP90 results in destabilization of several proteins involved in DNA repair, resulting in the inability of the ovarian cancer cells to repair DNA damage.

These studies were performed both in widely available ovarian cancer cell lines as well as in novel cell lines derived from patient tumor tissue that were generated by her laboratory.

The work was supported by a Pilot Study Award from the Rivkin Center for Ovarian Cancer, FCCC Core Grant NCI P30 CA006927, the Pennsylvania Department of Health, the Dubrow Fund, Bucks County Board of Associates, and the Mainline Board of Associates.

      

The Hospital of Fox Chase Cancer Center and its affiliates (collectively “Fox Chase Cancer Center”), a member of the Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.
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