Moffitt Researchers Help Demonstrate New Strategy to Overcome Treatment Resistance in Prostate Cancer

TAMPA, Fla. — Researchers at Moffitt Cancer Center, working with collaborators at Trinity College Dublin, have demonstrated a landmark strategy to overcome treatment resistance in prostate cancer by exploiting the way cancer cells evolve under therapy. The approach, known as an “evolutionary double-bind,” turns cancer cells’ adaptive survival mechanisms into a critical vulnerability. Results of their study were published in the International Journal of Radiation Oncology, Biology, Physics.  

Many patients with metastatic cancers receive therapies that are initially highly effective and can lead to complete remission. Over time, however, cancer cells can evolve resistance to treatment. These resistant cells then proliferate, causing tumors to recur, leading to treatment failure andpoor clinical outcomes. Increasingly, the driving force behind these adverse outcomes is the evolutionary ability for cancer cells to adapt and overcome even highly effective therapies. 

The new study shows that when prostate cancer cells evolve resistance to DNA-damaging treatments such as radiation, they expose a weakness that makes them highly vulnerable to immunotherapy. This creates an “evolutionary double-bind,” in which adaptation to one therapy makes cancer cells more susceptible to a second therapy, and vice versa. 

“The strategy is analogous to methods that might be used to control a rodent population in an agricultural field,” said Robert Gatenby, M.D., one of the senior authors of the study and co-director of the Center of Excellence for Evolutionary Therapy at Moffitt. “You might start by introducing owls, but the rodents can adapt by hiding under bushes. Here, the addition of snakes represents an evolution double bind – rodents trying to escape the owls are vulnerable to the snake and, if they avoid the snakes by staying away from bushes, they are easy prey to the owls.” 

While the concept of exploiting cancer evolution has been widely discussed in oncology, this study is the first to directly quantify and validate an evolutionary double-bind strategy using both laboratory experiments and detailed mathematical modeling. 

Researchers focused on how cancer cells become resistant to radiation therapy. For decades, scientists have known that cancer cells can survive radiation and certain chemotherapies by increasing the activity of DNA repair pathways. This allows the cells to withstand DNA damage and continue to grow. 

The new work revealed that these radiation-resistant cells also undergo predictable molecular changes that increase their expression of specific cell-surface proteins known as ligands. These ligands are recognized by natural killer cells, a key part of the immune system responsible for attacking cancer cells. 

As a result, the very adaptations that help cancer cells survive radiation also make them more sensitive to  natural killer cell–mediated killing, creating the evolutionary double-bind. 

In laboratory experiments using multiple human prostate cancer cell lines, radiation-resistant cells were up to twice as sensitive to  natural killer cell killing compared with radiation-sensitive cells. When radiation therapy was followed by  natural killer cell–based immunotherapy, the combined approach outperformed either treatment alone, suppressing both radiation-sensitive and radiation-resistant cancer cell populations. 

The researchers also found that the double-bind strategy was effective in other cancer cell types, suggesting the approach may represent a broad new treatment strategy. The findings provide a blueprint for turning cancer cell resistance into an exploitable vulnerability. 

“Importantly, this work challenges a long-held assumption in cancer biology that resistance must come at a fitness cost,” said Professor Cliona O’Farrelly, professor of Comparative Immunology at Trinity College Dublin, and one of the senior authors. “Our work shows that even when resistant cells grow faster than sensitive ones, a double-bind strategy can still be effective if the second therapy preferentially targets the resistance itself.” 

“This is very exciting as it also provides a blueprint for how we can intentionally steer tumor evolution, rather than simply trying to react to resistance after it emerges. It moves evolutionary therapy from a conceptual idea to a testable, quantitative treatment design strategy,” O’Farrelly said. 

A framework for smarter combination therapies 

In addition to its biological insights, the study introduces a new mathematical framework that rigorously defines and quantifies evolutionary double-binds. By integrating experimental data with evolution-based competition models, the researchers were able to predict optimal treatment sequencing and then validate those predictions experimentally. 

Although this study focused on prostate cancer, the researchers emphasize that the approach could be broadly applicable. 

“Any treatment that induces predictable adaptive changes in cancer cells, particularly those affecting immune recognition, could potentially be paired with a second therapy to create a double-bind,” said Kimberly Luddy, Ph.D., a research scientist at Moffitt who completed much of the work while undertaking her Ph.D. at Trinity. “This lays the groundwork for the development of evolution-informed, personalized treatment options that could anticipate how tumors will adapt over time and then time interventions to best exploit those adaptations therapeutically.” 

While emerging data, including work with radiopharmaceuticals and  natural killer cell–based approaches, continues to show promise, the researchers caution that these therapies are still under investigation and are not yet available to patients. The team is working to advance the research toward clinical translation as studies progress. 

The work was supported by funding from the National Cancer Institute through the Cancer Systems Biology Consortium and the Physical Sciences Oncology Network, as well as the Moffitt Center of Excellence for Evolutionary Therapy, the Health Research Board of Ireland, Research Ireland, and a Trinity St. James’s Cancer Institute–Cancer Immunology Stimulus Award. 

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Moffitt is dedicated to one lifesaving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 58 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt’s scientific excellence, multidisciplinary research, and robust training and education. Moffitt’s expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest distinction. For more information, call 1-888-MOFFITT (1-855-625-8815), visit MOFFITT.org, and follow the momentum on Facebook, X, Instagram and YouTube. 

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