Adaptive PARP Inhibitor Therapy Transforms Ovarian Cancer Treatment

A groundbreaking study presents an adaptive therapy approach that could enhance PARP inhibitor maintenance therapy, providing a more tailored and potentially less harmful treatment for patients. Ovarian cancer, which is often diagnosed at an advanced stage, poses serious treatment challenges due to the rapid development of resistance to conventional therapies. Even with aggressive treatment, recurrence rates remain high, necessitating innovative treatment strategies. Poly-adenosine ribose polymerase (PARP) inhibitors have become a treatment option by targeting specific DNA repair mechanisms in cancer cells. However, their use is frequently limited by toxicity and emerging drug resistance.

Researchers at Moffitt Cancer Center have devised an adaptive therapy approach to optimize PARP inhibitor maintenance therapy. This approach is detailed in the cover article of the June 19 issue of Cell Systems. PARP inhibitors are a targeted therapy that obstructs a protein responsible for repairing damaged DNA. By doing so, these inhibitors prevent cancer cells from repairing themselves after being damaged by chemotherapy, leading to cancer cell death. Although effective, traditional dosing methods that employ the maximum tolerated dose often cause severe side effects and necessitate dose reductions, which compromise treatment efficacy.

The Moffitt researchers employed mathematical modeling and in vitro experiments to compare adaptive dosing strategies. They developed a model to test various adaptive schedules and discovered that dose modulation based on tumor response was superior to skipping doses. Alexander Anderson, Ph.D., study author and chair of the Integrated Mathematical Oncology Department at Moffitt, explained, "Adaptive therapy tailors treatment to the tumor's dynamics, allowing us to adjust drug levels to match a patient's specific disease characteristics. Our findings suggest that modulation, rather than skipping doses, can halve the amount of drug used while maintaining its effectiveness. This approach reduces toxicity and can potentially delay the development of resistance."

The team used time-lapse microscopy to monitor ovarian cancer cell populations under different treatment schedules. The model indicated that continuous dose modulation effectively managed the tumor using significantly less medication than traditional methods. In vivo experiments validated these results, demonstrating the practical viability of the adaptive approach. However, the research is ongoing to validate and refine adaptive therapy strategies.

Maximilian Strobl, Ph.D., the lead author who conducted this work while pursuing a doctorate and postdoc at Moffitt, highlighted the significance of combining theoretical and experimental approaches. "A mathematical modeler by training, this project gave me the unique opportunity to conduct my own in vitro experiments to calibrate and test my models. Not only was this a fun and rewarding experience, but it demonstrated to me the power of closely integrating theory and experiments. I believe such an iterative and interdisciplinary approach will be crucial in developing more effective ways to schedule cancer treatment."

The study received support from the National Cancer Institute (U01CA23282, U01CA261841, R01CA249016, R01CA272601) and the Moffitt Center of Excellence for Evolutionary Therapy. The team's findings offer hope for more effective and personalized treatment options, promising a new horizon in the battle against ovarian cancer.