Intermittent dosing with the immunosuppressant rapamycin can break an inflammatory loop that fuels cancer relapse, according to researchers.
The team found that rapamycin selectively breaks the cascade of inflammatory events that follow cellular senescence.
Once disrupted, it takes time for the inflammatory loop to re-establish itself. This suggests intermittent dosing could provide a way to reap the benefits of rapamycin while reducing side effects.
The researchers described these findings in Nature Cell Biology.
“We think this could provide a paradigm shift in the treatment of age-related disease, including cancer,” said study author Judith Campisi, PhD, of the Buck Institute for Research on Aging in Novato, California.
“Imagine the possibility of taking a pill for a few days or weeks every few years, as opposed to taking something with side effects every day for the rest of your life. It’s a new way of looking at how we could deal with age-related maladies.”
For this study, Dr Campisi and her colleagues administered rapamycin to mice with prostate cancer after they had received treatment with DNA-damaging chemotherapy.
The rapamycin reduced the secretion of inflammatory cytokines from senescent cells by suppressing the mTOR pathway. This suppressed the cells’ ability to stimulate tumor growth.
“DNA-damaging chemotherapy causes senescence, both to the tumor and its microenvironment,” Dr Campisi explained. “The tumor shrinks, but the immediate tissue environment is inflamed. We think signals from those inflamed cells trigger residual cancer cells to grow again. In the mice, rapamycin suppressed the ability of the tumor cells to relapse.”
The researchers said the paradigm-shifting potential of intermittent rapamycin dosing is based on the fact that it takes time for the inflammatory loop—fueled by the senescence-associated secretory phenotype (SASP)—to form and time for it to re-establish itself after a brief treatment period with rapamycin.
“Rapamycin blocks the production of a protein called IL-1α,” explained study author Remi-Martin Laberge, PhD, also of the Buck Institute.
“This in turn, suppresses IL6, a well-known inflammatory cytokine, at the level of transcription, which prevents the production of the IL6 protein. Because it acts at a deeper level within the cellular process, it takes longer for it to get started again.”
Dr Laberge also pointed out that treatment with rapamycin selectivity impacts the SASP, preserving the function of factors essential for wound healing.
“It’s an elegant solution,” Dr Laberge said. “Imagine using a small hammer to delicately knock out one thing that is causing problems. We knocked it out, and it stayed out long enough to benefit the health of the animal.”
“We have yet to fully understand why suppressing the mTOR pathway via rapamycin increases lifespan and health span in mice,” Dr Campisi added. “This work helps illuminate the puzzle. Perhaps the mice are living longer because they have less overall inflammation, and maybe intermittent dosing will make it possible for us to use [rapamycin] more widely in humans.”
