Currently, women with HER2-positive breast cancers are treated with therapies that target HER2. However, many women with this form of cancer either fail to ever respond to these targeted therapies or initially respond to them but then become resistant to their effects.
"Until now, PARP inhibitors have been shown to exhibit single agent activity only in tumors that are deficient in DNA repair, such as familial breast and ovarian cancers that are linked to BRCA mutations," said Eddy S. Yang, M.D., Ph.D., assistant professor in the department of radiation oncology at the University of Alabama-Birmingham.
According to Yang, only about 5 to 10 percent of all breast and ovarian cancers are BRCA-associated familial cancers, so researchers are currently trying to expand the patient population that might benefit from PARP inhibitors, which are generally well tolerated and have relatively few side effects.
"To do that, we were attempting to render nonfamilial cancers deficient in DNA repair," he said.
In prior studies, the Yang lab found that inhibiting the epidermal growth factor receptor (EGFR) pathway, which is commonly overactive in many tumor types, resulted in a DNA repair defect similar to that seen in familial cancers. They subsequently showed that this "forced" DNA repair defect increased tumor sensitivity to PARP inhibitors. Because HER2 and EGFR are in the same family of proteins, Yang and colleagues theorized that HER2-targeted therapies might force a similar DNA repair defect in HER2-positive tumors, increasing their sensitivity to PARP inhibitors.
They found that HER2-positive breast cancer cell lines were indeed sensitive to PARP inhibitors, both in culture and when transplanted into mice.
"However, the surprise was that these HER2-positive tumors were sensitive to PARP inhibitors alone, independent of a DNA repair defect," Yang said. "This means that there may be other mechanisms, outside of DNA repair, that dictate the sensitivity of a tumor to PARP inhibitors."
The researchers hope to further map out the reason why HER2-positive tumors are sensitive to PARP inhibitors. If better defined, the knowledge could ultimately broaden the clinical application for PARP inhibitors.
"Our research suggested that inhibition of NF-kB signaling is a possible cause of this sensitivity, but there may be other determinants as well," Yang said. "If we are able to find the determinants of sensitivity, we may be able to extrapolate our effects to other tumor types."
This research was supported by a career development award from the UAB Specialized Programs of Research Excellence (SPORE) in breast cancer (5P50CA089019-10), the Sidney Kimmel Foundation for Cancer Research Translational Scholar Award, the AACR-Genentech BioOncology Career Development Award for Cancer Research on the HER Family Pathway (Grant Number 12-20-18-YANG), the State of Alabama Investment Pool for Action (IMPACT) Award from the University of Alabama at Birmingham School of Medicine, and developmental support from the Comprehensive Cancer Center and Department of Radiation Oncology at the University of Alabama at Birmingham School of Medicine.
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Founded in 1907, the American Association for Cancer Research (AACR) is the world''s first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR''s membership includes 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 17,000 attendees. In addition, the AACR publishes seven peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of individual and team science grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer.
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