Intermittent SASP Disruption as Cancer Adjuvant Treatment

Researchers here demonstrate the merits of intermittently disrupting the senescence-associated secretory phenotype (SASP) in conjunction with standard cancer treatments. SASP is the name given to the tendency of senescent cells to release various signals and active molecules that change nearby cell behavior, promote inflammation, and harm the structure of tissue. Senescent cells accumulate with age, and although initially helpful in suppressing cancer risk by removing the most cancer-prone cells from the picture, eventually there are enough senescent cells for SASP to become very damaging and tip the balance back towards cancer promotion.

The researchers here are using rapamycin as a SASP-disrupting agent, but there are no doubt better methods awaiting discovery, designed drugs with fewer side-effects than those accompanying the use of this one. Rapamycin is known to extend life in mice, and there has been some debate over whether it does so by slowing aging or merely because it is good at reducing cancer incidence in that species.

While scientists have demonstrated benefits in this research, the better path forward is probably outright removal of senescent cells: don't try to engage in the long and expensive process of tinkering with cell behavior, just take the targeted cell-killing technologies under development in the cancer research community and turn them against cellular senescence. Senescent cells have a range of distinct chemical signatures, so this is a very plausible plan for near future development.

Intermittent dosing with rapamycin selectively breaks the cascade of inflammatory events that follow cellular senescence, a phenomena in which cells cease to divide in response to DNA damaging agents, including many chemotherapies. Researchers showed that rapamycin reduced the secretion of inflammatory cytokines from senescent cells in culture and in mice by suppressing the mTOR pathway, which promotes growth. The team gave rapamycin to mice with prostate cancer - after they had been treated with DNA-damaging chemotherapy that causes senescence, both to the tumor and its microenvironment. 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." Most importantly, the results may help explain why rapamycin has had mixed results as a treatment for cancer. "It's being given to patients as a way of stopping the growth of tumors. But we think that rapamycin may also be beneficial for those tumors that are driven by inflammation. It needs to be tested in a population most likely to benefit."

"Senescence-activated inflammation could be driving the increased incidence of cancer that we see with aging. While this study took place in mice, the work sets the scene to do early clinical trials in humans. Inflammation has a role in almost all tumor development and some cancers are more inflammatory than others. It would be interesting to see the effect that rapamycin has on those tumors and the surrounding tissue." The potential of intermittent dosing is based on the fact that it takes time for the inflammatory loop (fueled by the senescence-associated secretory phenotype or SASP) to form and time for it to re-establish itself after a brief treatment of rapamycin. Rapamycin blocks the production of a protein called IL-1alpha. 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. Treatment with rapamycin selectivity impacts the SASP, preserving the function of factors essential for wound healing. "It's an elegant solution - 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."



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