A new combination of drugs slowed the growth of cancer cells by an unexpected mechanism that may one day lead to improved treatment of cervical cancer, a UT Southwestern-led study published in Molecular Cancer Research suggests.
Despite advances in screening, early diagnosis, and prevention through HPV vaccination, cervical cancer remains the second-leading cause of cancer-related death in women between ages 20 and 39.
Most treatment regimens used for cervical cancer involve the platinum-based chemotherapy drug cisplatin in combination with other drugs. But tumors can become resistant to cisplatin, which has greatly hindered its use and suggests the need for alternative drug combinations that improve treatment outcomes.
PARP inhibitors (PARPi), which block the repair of DNA damage in cancer cells, were recently approved by the FDA as cancer therapeutics, particularly for gynecological cancers. UTSW researchers found that the combination of cisplatin and PARP inhibitors is more effective at restricting some cervical cancer cells' growth than either used alone.
Our work shows that when combined, platinum-based therapies and PARP inhibitors can induce new cellular pathways in cancer cells and potentially open up new therapeutic opportunities."
W. Lee Kraus, Ph.D., Study's Principal Investigator, Professor of Obstetrics and Gynecology and Pharmacology, Member of the Harold C. Simmons Comprehensive Cancer Center, and Director of the Cecil H. and Ida Green Center for Reproductive Biology Sciences
Using cell lines that represent different types of cervical cancer, including adenocarcinoma, epidermoid, and squamous, the researchers tested the cells' growth and survival in response to treatment with PARPi, cisplatin, or a combination of the two. They found that PARPi treatment alone could slow the growth of cells derived from adenocarcinoma and squamous cell carcinoma. A combination of PARPi with cisplatin, however, was more toxic to the cells than either agent alone.
The researchers also showed that the combination of PARPi and cisplatin does not kill these cells simply by blocking the repair of damaged DNA in cancer cells, the therapeutic mechanism historically associated with PARPi. They found that when used in combination with cisplatin, PARP-1 stimulated the expression of genes whose proteins inhibit the cell cycle, block the growth and division of cells, and promote apoptosis, a form of cell death. This mechanism was independent of PARPi's role in enhancing DNA damage in cancer cells.
The UTSW research team that brought together the expertise of scientists and clinicians "built on a long-standing interest in expanding the therapeutic potential of PARPi in gynecologic cancers," said Dr. Kraus.
Other UTSW researchers who contributed to this study include Rebecca Gupte, Tulip Nandu, Ken Y. Lin, and Jayanthi S. Lea.
This research was supported in part by grants from the National Institutes of Health and UTSW's Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowment.
Dr. Kraus is a founder, consultant, and member of the scientific advisory board for ARase Therapeutics Inc., and a founder and former member of the scientific advisory board for Ribon Therapeutics Inc. He also has a patent issued and licensed to EMD Millipore.
Dr. Kraus holds the Cecil H. and Ida Green Distinguished Chair in Reproductive Biology Sciences. Dr. Lea holds the Patricia Duniven Fletcher Distinguished Professorship in Gynecological Oncology.
Gupte, R., et al. (2022) Combinatorial Treatment with PARP-1 Inhibitors and Cisplatin Attenuates Cervical Cancer Growth through Fos-Driven Changes in Gene Expression. Molecular Cancer Research. doi.org/10.1158/1541-7786.MCR-22-0111.