An international team of researchers from Trinity College Dublin and the Moffitt Cancer Centre in the US has demonstrated a landmark “evolutionary double-bind” strategy to overcome treatment resistance in prostate cancer.
Many patients with metastatic cancers receive therapy that is initially highly effective, often resulting in complete remission. However, cancer cells have a remarkable capacity to evolve resistance to currently available therapies. As a re- sult, resistant cells eventually proliferate, causing the tumour to recur, leading to treatment failure and ultimately patient death.
In other words, increasingly, the prox- imate cause of death in cancer patients is evolution, which sees the cancer cells adapt and overcome even highly effective treatments.
The new work has found that when cancer cells successfully evolve resistance to DNA damaging treatments, they expose a critical weakness that makes them highly vulnerable to immunotherapy. This represents an “evolutionary double-bind” in which the cancer cell adaptation to one therapy makes them more vulnerable to another therapy, and vice-versa.
“The strategy is analogous to methods that might be used to control a rodent population in an agricultural field,” noted Robert Gatenby, one of the senior members of the research team from the Moffitt Cancer Centre.
“You might start by introducing owls,” he explained, “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 idea of exploiting the way cancers evolve has often been discussed in oncology conferences, this study is the first to directly quantify and validate such a method using both lab experiments and detailed mathematical modelling approaches.
The team began by investigating how cancer cells become resistant to radiation therapy. For decades, it has been well known that cancer cells can become resistant to radiation therapy and other DNA damage treatments such as some chemotherapies by increasing expression of DNA repair pathways that allow the cancer cells to survive and eventually proliferate.
But the new research, just published in the International Journal of Radiation Oncology, Biology, Physics, found that these radiation-resistant cells also under- go unexpected but predictable molecular changes that increase their expression of specific cellular membrane proteins called ligands that are recognised by natural killer (NK) cells — a key component of the immune system that attack cancer cells.
