Looking to the Future of PARP Inhibitors
Dr. Liu is also exploring the potential of other drugs to synergize with PARP inhibitors, including anti-angiogenic agents, like cediranib, which block the growth of blood vessels that feed tumors. Initial research conducted about a decade ago suggested
that combining cediranib with a PARP inhibitor could help sensitize tumor cells to a PARP inhibitor. Since then, Dr. Liu has been studying the drug combination in ovarian cancer patients in a phase 2 clinical trial as well as two large phase 3 trials.
Recent data suggests that combining the two drugs together does not improve survival beyond standard treatment with platinum-based chemotherapy.
Even so, Dr. Liu believes that the idea of combining anti-angiogenics and PARP inhibitors still holds promise and has been studying combinations that introduce a third drug, such as immune checkpoint inhibitors. These drugs, which were first approved
for use in melanoma, have had a remarkable impact on the treatment of certain forms of cancer. However, they have been less successful in ovarian tumors, in part because the tumors are "cold" — meaning the tumors have few, if any, signs of inflammation,
such as T cells, limiting the usefulness of checkpoint inhibitors.
Dana-Farber's Panagiotis Konstantinopoulos, MD, PhD, director of translational research in the Division of Gynecologic Oncology and co-director of the Center for BRCA and Related Genes has been probing ways to render immunotherapy drugs more effective in ovarian cancer. Early laboratory studies in mice, led by Dana-Farber researcher Jean Zhao, PhD, showed that a PARP inhibitor and an immune
checkpoint inhibitor can act synergistically through activation of the STING pathway. The researchers also revealed a biological explanation for this synergy: PARP inhibitors not only play a role in DNA repair but also help stoke the fires of the
immune system. Dr. Konstantinopoulos is currently involved in clinical trials combining checkpoint inhibitors with PARP inhibitors.
Dr. Konstantinopoulos and his colleagues, including Dr. Matulonis, have spent several years studying another therapeutic combination, a PARP inhibitor plus a PI3-kinase inhibitor. Over a decade of laboratory and clinical research at Dana-Farber and other
institutions indicates this pairing, too, could be synergistic, especially in ovarian cancer patients without BRCA mutations — a cohort that has been generally considered to be less responsive to PARP inhibitors alone. Now, Dr. Konstantinopoulos
is leading an international multi-site phase 3 trial to investigate the drug combination of olaparib, a PARP inhibitor, and alpelisib, a PI3-kinase inhibitor, in non-BRCA-mutated forms of platinum resistant ovarian cancer.
"These are really exciting therapeutic strategies," Dr. Konstantinopoulos said. "We'll have to wait and see what the different trials tell us, but it's very gratifying to see the early pre-clinical and clinical research we've done here at Dana-Farber
being carried forward to the next stage in service of our patients."
Alan D'Andrea, MD, director of Dana-Farber's Susan F. Smith Center for Women's Cancers and the Center for DNA Damage and Repair,
is also pursuing a novel PARP inhibitor combination, pairing the drug with novobiocin, an antibiotic developed in the 1950's. Novobiocin
is no longer prescribed for humans but is commonly used in animals. Dr. D'Andrea and his colleagues identified it in a screen for chemical compounds that could halt the growth of BRCA-deficient tumors while sparing healthy cells.
Now, Dana-Farber researchers are launching a clinical trial to study novobiocin in patients with BRCA-deficient cancers, including ovarian tumors, that have developed resistance to PARP inhibitors. "This strategy for overcoming PARP inhibitor
resistance is deeply rooted in our research on the BRCA pathway," said Dr. D'Andrea. "It's exciting to see this work moving forward."
Novobiocin, together with the various other PARP inhibitor drug combinations now under development, mark the beginning of a new era in ovarian cancer treatment.
"The post-PARP-inhibitor age is here," said Dr. Liu. "We're learning more every day about what makes these drugs work or not work, and there are a variety of strategies now being pursued to overcome therapeutic resistance."
Dr. Matulonis added, "It's been so gratifying to see ovarian cancer treatment undergo such a fundamental shift with progress being made. There is a palpable sense of urgency for developing new treatment strategies for patients with ovarian cancer; the
possibilities are truly endless."